presentation of herpes simplex virus type 1

Fact sheets

• Facts in pictures

Publications

• Questions and answers
• Tools and toolkits
• Endometriosis
• Excessive heat
• Mental disorders
• Polycystic ovary syndrome
• All countries
• Eastern Mediterranean
• South-East Asia
• Western Pacific
• Data by country
• Country presence 
• Country strengthening 
• Country cooperation strategies 
• News releases
• Feature stories
• Press conferences
• Commentaries
• Photo library
• Afghanistan
• Cholera 
• Coronavirus disease (COVID-19)
• Greater Horn of Africa
• Israel and occupied Palestinian territory
• Disease Outbreak News
• Situation reports
• Weekly Epidemiological Record
• Surveillance
• Health emergency appeal
• International Health Regulations
• Independent Oversight and Advisory Committee
• Classifications
• Data collections
• Global Health Observatory
• Global Health Estimates
• Mortality Database
• Sustainable Development Goals
• Health Inequality Monitor
• Global Progress
• World Health Statistics
• Partnerships
• Committees and advisory groups
• Collaborating centres
• Technical teams
• Organizational structure
• Initiatives
• General Programme of Work
• WHO Academy
• Investment in WHO
• WHO Foundation
• External audit
• Financial statements
• Internal audit and investigations 
• Programme Budget
• Results reports
• Governing bodies
• World Health Assembly
• Executive Board
• Member States Portal
• Fact sheets /

Herpes simplex virus

• An estimated 3.7 billion people under age 50 (67%) globally have herpes simplex virus type 1 (HSV-1) infection, the main cause of oral herpes.
• An estimated 491 million people aged 15–49 (13%) worldwide have herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.
• Most HSV infections are asymptomatic or unrecognized, but symptoms of herpes include painful blisters or ulcers that can recur over time.
• Infection with HSV-2 increases the risk of acquiring and transmitting HIV infection.

Herpes simplex virus (HSV), known as herpes, is a common infection that can cause painful blisters or ulcers. It primarily spreads by skin-to-skin contact. It is treatable but not curable.

There are two types of herpes simplex virus.

Type 1 (HSV-1) mostly spreads by oral contact and causes infections in or around the mouth (oral herpes or cold sores). It can also cause genital herpes. Most adults are infected with HSV-1.

Type 2 (HSV-2) spreads by sexual contact and causes genital herpes.

Most people have no symptoms or only mild symptoms. The infection can cause painful blisters or ulcers that can recur over time. Medicines can reduce symptoms but can’t cure the infection.

Recurrent symptoms of both oral and genital herpes may be distressing. Genital herpes may also be stigmatizing and have an impact on sexual relationships. However, in time, most people with either kind of herpes adjust to living with the infection.

Most people with herpes have no symptoms or only mild symptoms. Many people aren’t aware they have the infection and can pass along the virus to others without knowing.

Symptoms can include painful, recurring blisters or ulcers. New infections may cause fever, body aches and swollen lymph nodes.

Symptoms may be different during the first episode (or ‘outbreak’) of infection than during a recurrent episode. If symptoms occur, they often begin with tingling, itching or burning near where the sores will appear. 

Common oral herpes symptoms include blisters (cold sores) or open sores (ulcers) in or around the mouth or lips.

Common genital herpes symptoms include bumps, blisters, or open sores (ulcers) around the genitals or anus.

These sores and blisters are typically painful. Blisters may break open, ooze and then crust over. 

During their first infection, people may experience: 

• sore throat (oral herpes)
• swollen lymph nodes near the infection.

People can have repeated outbreaks over time (‘recurrences’). These are usually shorter and less severe than the first outbreak.

Medicines are often used to treat first or recurrent episodes of herpes. They can decrease how long symptoms last and how severe they are, but they can’t cure the infection.

Treatment for recurrent episodes is most effective when started within 48 hours of when symptoms begin. 

Antiviral medicines commonly given include acyclovir, famciclovir and valacyclovir.

Taking a lower daily dose of one of these medicines can also decrease how often symptoms occur (‘outbreaks’).

Treatment is often recommended for people who get very painful or frequent recurrent episodes or who want to lower the risk of giving herpes to someone else.

Medicines to help with pain related to sores include paracetamol (acetaminophen), naproxen or ibuprofen. Medicines that can be applied to numb the affected area include benzocaine and lidocaine. 

Herpes simplex virus lives inside of nerve cells and alternates between being inactive and active. Certain triggers can make the virus active including:

• illness or fever
• sun exposure
• menstrual period
• emotional stress

For people whose oral herpes is activated by sunlight, avoiding sun exposure and wearing sunscreen can lower the risk of recurrences. 

To decrease symptoms of oral herpes, people can: 

• drink cold drinks or suck on popsicles
• use over-the-counter pain medicines.

For genital herpes, people can:

• sit in a warm bath for 20 minutes (without soap)
• wear loose fitting clothes

There are ways to lower the risk of spreading herpes including:

• talk to your partner about having herpes
• don’t have sex if you have symptoms and always wear a condom
• don’t share items that touched saliva (oral herpes).

Talk to your healthcare provider if you are pregnant, because there is a risk of passing herpes to your baby.

Scope of the problem

In 2016 (last available estimates), 3.7 billion people under the age of 50, or 67% of the global population, had HSV-1 infection (oral or genital). Most HSV-1 infections are acquired during childhood.

Genital herpes caused by HSV-2 affects an estimated 491 million (13%) people aged 15–49 years worldwide (2016 data). HSV-2 infects women almost twice as often as men because sexual transmission is more efficient from men to women. Prevalence increases with age, though the highest number of new infections are in adolescents.

Transmission

HSV-1 is mainly transmitted via contact with the virus in sores, saliva or surfaces in or around the mouth. Less commonly, HSV-1 can be transmitted to the genital area through oral-genital contact to cause genital herpes. It can be transmitted from oral or skin surfaces that appear normal; however, the greatest risk of transmission is when there are active sores. People who already have HSV-1 are not at risk of reinfection, but they are still at risk of acquiring HSV-2.

HSV-2 is mainly transmitted during sex through contact with genital or anal surfaces, skin, sores or fluids of someone infected with the virus. HSV-2 can be transmitted even if the skin looks normal and is often transmitted in the absence of symptoms.

In rare circumstances, herpes (HSV-1 and HSV-2) can be transmitted from mother to child during delivery, causing neonatal herpes.

Possible complications

Hsv-2 and hiv infection.

HSV-2 infection increases the risk of acquiring HIV infection by approximately three-fold. Additionally, people with both HIV and HSV-2 infection are more likely to spread HIV to others. HSV-2 infection is among the most common infections in people living with HIV.

Severe disease

In immunocompromised people, including those with advanced HIV infection, herpes can have more severe symptoms and more frequent recurrences. Rare complications of HSV-2 include meningoencephalitis (brain infection) and disseminated infection. Rarely, HSV-1 infection can lead to more severe complications such as encephalitis (brain infection) or keratitis (eye infection).

Neonatal herpes

Neonatal herpes can occur when an infant is exposed to HSV during delivery. Neonatal herpes is rare, occurring in an estimated 10 out of every 100 000 births globally. However, it is a serious condition that can lead to lasting neurologic disability or death. The risk for neonatal herpes is greatest when a mother acquires HSV for the first time in late pregnancy.

People with symptoms of oral herpes should avoid oral contact with others (including oral sex) and sharing objects that touched saliva. Individuals with symptoms of genital herpes should abstain from sexual activity while experiencing symptoms. Both HSV-1 and HSV-2 are most contagious when sores are present but can also be transmitted when no symptoms are felt or visible.

For sexually active people, consistent and correct use of condoms is the best way to prevent genital herpes and other STIs. Condoms reduce the risk; however, HSV infection can still occur through contact with genital or anal areas not covered by the condom. Medical male circumcision can provide life-long partial protection against HSV-2 infection, as well as against HIV and human papillomavirus (HPV).

People with symptoms suggestive of genital herpes should be offered HIV testing.

Pregnant women with symptoms of genital herpes should inform their health care providers. Preventing acquisition of HSV-2 infection is particularly important for women in late pregnancy when the risk for neonatal herpes is greatest.

WHO response

WHO is working to increase awareness about HSV infection and its symptoms, improve access to antiviral medications, and promote HIV prevention efforts for those with genital herpes, such as pre-exposure prophylaxis (PrEP). 

WHO and partners are also supporting research to develop new strategies for prevention and control of HSV infections, such as vaccines and topical microbicides.

• Vaccine special issue on STI vaccines
• STI prevention
• Global strategy for the prevention and control of sexually transmitted infections: 2006–2015
• Global estimates of prevalent and incident Herpes Simplex Virus Type 2 infections in 2012 PLoS ONE 9(12): e114989
• More about sexually transmitted diseases

• Herpes Simplex
• Author: Folusakin O Ayoade, MD; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Herpes Simplex
• Microbiology
• Pathophysiology
• Epidemiology
• Laboratory Studies
• Imaging Studies
• Approach Considerations
• Medical Care
• Consultations
• Medication Summary
• Viral helicase-primase inhibitor
• Deterrence/Prevention
• Complications
• Patient Education
• Questions & Answers
• Media Gallery

Herpes simplex viruses are ubiquitous, host-adapted pathogens that cause a wide variety of disease states. Two types exist: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Both are closely related but differ in epidemiology. HSV-1 is traditionally associated with orofacial disease, whereas HSV-2 is traditionally associated with genital disease. Lesion location, however, is not necessarily indicative of viral type, as HSV-1 is associated with genital infections more often than HSV-2 in some unique subpopulations.

The term herpes is derived from the Greek word “to creep or crawl” and dates back to early Greek civilization, approximately 2000 years ago, in reference to the spreading nature of herpetic skin lesions.

See Herpes Simplex Viruses: Test Your Knowledge , a Critical Images slideshow, for more information on clinical, histologic, and radiographic imaging findings in HSV-1 and HSV-2.

Also, see the 20 Signs of Sexually Transmitted Infections and Clues in the Oral Cavity: Are You Missing the Diagnosis? slideshows to help make an accurate diagnosis.

Up to 80% of herpes simplex infections are asymptomatic. Symptomatic infections can be characterized by significant morbidity and recurrence. In immunocompromised hosts, infections can cause life-threatening complications.

The prevalence of HSV infection worldwide has increased over the last several decades, making it a major public health concern. Prompt recognition of herpes simplex infection and early initiation of therapy are of utmost importance in the management of the disease.

HSV belongs to the alpha herpesvirus group. It is an enveloped virus that is approximately 160 nm in diameter with a linear, double-stranded DNA genome. The overall sequence homology between HSV-1 and HSV-2 is about 50%. HSV-1 has tropism for oral epithelium, while HSV-2 has tropism for genital epithelium. HSV infection is mediated through attachment via ubiquitous receptors to cells, including sensory neurons, leading to establishment of latency. [ 1 ]

HSV-1 and HSV-2 are characterized by the following unique biological properties [ 1 ] :

• Neurovirulence (the capacity to invade and replicate in the nervous system)
• Latency (the establishment and maintenance of latent infection in nerve cell ganglia proximal to the site of infection): In orofacial HSV infections, the trigeminal ganglia are most commonly involved, while, in genital HSV infection, the sacral nerve root ganglia (S2-S5) are involved.
• Reactivation: The reactivation and replication of latent HSV, always in the area supplied by the ganglia in which latency was established, can be induced by various stimuli (eg, fever, trauma, emotional stress, sunlight, menstruation), resulting in overt or covert recurrent infection and shedding of HSV. In immunocompetent persons who are at an equal risk of acquiring HSV-1 and HSV-2 both orally and genitally, HSV-1 reactivates more frequently in the oral rather than the genital region. On the other hand, HSV-2 reactivates 8-10 times more commonly in the genital region than in the orolabial regions. Reactivation is more common and severe in immunocompromised individuals. [ 2 ]

Cellular immunity is an important defense against herpes simplex. Dissemination of herpes simplex infection can occur in people with impaired T-cell immunity, such as in organ transplant recipients and in individuals with AIDS . Herpes simplex infection can also complicate burn wounds or damaged skin such as in atopic dermatitis or other allergic dermatoses.

HSV is distributed worldwide. Humans are the only natural reservoirs, and no vectors are involved in transmission. Endemicity is easily maintained in most human communities owing to latent infection, periodic reactivation, and asymptomatic virus shedding. [ 3 ]

HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and fomitic spread are rare.

United States

HSV is the most common cause of genital ulcers in the United States. HSV-1 is usually acquired in childhood by contact with oral secretions that contain the virus. The presence of HSV-2 can be used as an indirect measure of sexual activity. Seroprevalence rates do not reflect how many of these individuals have or will have symptomatic episodes of HSV recurrence, as the presence of antibodies is poorly correlated with disease protection. Epidemiology of HSV-1 infection in the US is undergoing a remarkable and subtle transition, with less exposure in childhood and more in adulthood, and less oral acquisition but more genital acquisition. [ 4 ]  HSV-1 could be overtaking HSV-2 as the main cause of first episode of genital herpes in the United States and elsewhere. [ 5 , 6 ]  In a study of college students in the US, the percentage of genital herpes attributed to HSV-1 (as opposed to HSV-2) increased from 31% in 1993 to 78% in 2001. [ 6 ]  

Seroprevalence:

Based on the National Health and Nutrition Examination Survey (NHANES) during 2015–2016, prevalence of herpes simplex virus type 1 (HSV-1) was 47.8%, and prevalence of herpes simplex virus type 2 (HSV-2) was 11.9%. Prevalence of both HSV-1 and HSV-2 increased with age.    Antibodies to HSV-1 increase with age starting in childhood and correlate with socioeconomic status, race, and cultural group. By age 30 years, 50% of individuals in a high socioeconomic status and 80% in a lower socioeconomic status are seropositive. Antibodies to HSV-2 begin to emerge at puberty, correlating with the degree of sexual activity. More than 90% of adults have antibodies to HSV-1 by the fifth decade of life. [ 1 ] ​A slight crossover of immunity occurs between HSV-1 and HSV-2, allowing for milder subsequent infection by the partner virus type.

International

HSV is well distributed worldwide, with over 23 million new cases per year. An increase in seroprevalence of antibodies to HSV-2 has been documented throughout the world (including the United States) over the last 20 years. [ 1 ]

Mortality/Morbidity

Morbidity and mortality rates associated with HSV infections are discussed in Complications. Overall, the mortality rate associated with herpes simplex infections is related to 3 situations: perinatal infection , encephalitis , and infection in the immunocompromised host.

HSV-2 is most prevalent among non-Hispanic blacks (40.3%) compared with the members of other US racial/ethnic groups;  13.7% among non-Hispanic whites and 11.9% among Mexican Americans. [ 7 ]

Seropositivity to HSV-2 is more common in women (25%) than in men (17%). [ 8 ]

HSV-1 infections transmitted via saliva are common in children, although primary herpes gingivostomatitis can be observed at any age. HSV-2 infections are clustered perinatally (from a maternal episode at delivery) and primarily once sexual activity begins. HSV-2 genital infections in children can be an indication of sexual abuse. Increased age (after onset of sexual activity) and total number of sexual partners are independent factors associated with increased seroprevalence of HSV-2 antibodies. [ 8 ]

Schiffer J, Corey L. Herpes Simplex Virus. Mandell Gl, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases . 8th ed. Pennsylvania: Elsevier; 2015. Vol 2: 1713-30.

Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. N Engl J Med . 2004 May 6. 350(19):1970-7. [QxMD MEDLINE Link] .

Mark KE, Wald A, Magaret AS, Selke S, Olin L, Huang ML. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis . 2008 Oct 15. 198(8):1141-9. [QxMD MEDLINE Link] .

Ayoub HH, Chemaitelly H, Abu-Raddad LJ. Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: model-based predictions. BMC Med . 2019 Mar 11. 17 (1):57. [QxMD MEDLINE Link] .

Bernstein DI, Bellamy AR, Hook EW 3rd, Levin MJ, Wald A, Ewell MG, et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis . 2013 Feb. 56 (3):344-51. [QxMD MEDLINE Link] .

Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis . 2003 Oct. 30 (10):797-800. [QxMD MEDLINE Link] .

Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA . 2006 Aug 23. 296 (8):964-73. [QxMD MEDLINE Link] .

Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med . 1997 Oct 16. 337(16):1105-11. [QxMD MEDLINE Link] .

Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis . 2006 May. 12(3):254-70. [QxMD MEDLINE Link] .

Spruance SL, Overall JC Jr, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis: implications for antiviral therapy. N Engl J Med . 1977 Jul 14. 297(2):69-75. [QxMD MEDLINE Link] .

Scoular A, Gillespie G, Carman WF. Polymerase chain reaction for diagnosis of genital herpes in a genitourinary medicine clinic. Sex Transm Infect . 2002 Feb. 78 (1):21-5. [QxMD MEDLINE Link] .

Jin F, Prestage GP, Mao L, Kippax SC, Pell CM, Donovan B, et al. Transmission of herpes simplex virus types 1 and 2 in a prospective cohort of HIV-negative gay men: the health in men study. J Infect Dis . 2006 Sep 1. 194 (5):561-70. [QxMD MEDLINE Link] .

Tunbäck P, Bergström T, Andersson AS, Nordin P, Krantz I, Löwhagen GB. Prevalence of herpes simplex virus antibodies in childhood and adolescence: a cross-sectional study. Scand J Infect Dis . 2003. 35 (8):498-502. [QxMD MEDLINE Link] .

Reeves WC, Corey L, Adams HG, Vontver LA, Holmes KK. Risk of recurrence after first episodes of genital herpes. Relation to HSV type and antibody response. N Engl J Med . 1981 Aug 6. 305 (6):315-9. [QxMD MEDLINE Link] .

Vyse AJ, Gay NJ, Slomka MJ, Gopal R, Gibbs T, Morgan-Capner P, et al. The burden of infection with HSV-1 and HSV-2 in England and Wales: implications for the changing epidemiology of genital herpes. Sex Transm Infect . 2000 Jun. 76 (3):183-7. [QxMD MEDLINE Link] .

Wald A, Zeh J, Selke S, Warren T, Ryncarz AJ, Ashley R, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med . 2000 Mar 23. 342 (12):844-50. [QxMD MEDLINE Link] .

Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med . 1995 Sep 21. 333(12):770-5. [QxMD MEDLINE Link] .

Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med . 1999 Jul 6. 131(1):14-20. [QxMD MEDLINE Link] .

Sköldenberg B, Jeansson S, Wolontis S. Herpes simplex virus type 2 and acute aseptic meningitis. Clinical features of cases with isolation of herpes simplex virus from cerebrospinal fluids. Scand J Infect Dis . 1975. 7(4):227-32. [QxMD MEDLINE Link] .

Singh A, Preiksaitis J, Ferenczy A, Romanowski B. The laboratory diagnosis of herpes simplex virus infections. Can J Infect Dis Med Microbiol . 2005 Mar. 16 (2):92-8. [QxMD MEDLINE Link] .

Lafferty WE, Krofft S, Remington M, Giddings R, Winter C, Cent A, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population. J Clin Microbiol . 1987 Feb. 25 (2):323-6. [QxMD MEDLINE Link] .

Whitley RJ. Herpes simplex virus infections of the central nervous system. A review. Am J Med . 1988 Aug 29. 85(2A):61-7. [QxMD MEDLINE Link] .

Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet . 1991 Jan 26. 337(8735):189-92. [QxMD MEDLINE Link] .

Liang QN, Zhou JW, Liu TC, Lin GF, Dong ZN, Chen ZH, et al. Development of a time-resolved fluorescence immunoassay for herpes simplex virus type 1 and type 2 IgG antibodies. Luminescence . 2014 Nov 5. [QxMD MEDLINE Link] .

Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes . 2004 Jun. 11 Suppl 2:57A-64A. [QxMD MEDLINE Link] .

Álvarez DM, Castillo E, Duarte LF, Arriagada J, Corrales N, Farías MA, et al. Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection. Front Microbiol . 2020. 11:139. [QxMD MEDLINE Link] .

Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med . 2008 Jun 9. 168 (11):1137-44. [QxMD MEDLINE Link] .

Gnann JW Jr, Whitley RJ. Herpes Simplex Encephalitis: an Update. Curr Infect Dis Rep . 2017 Mar. 19 (3):13. [QxMD MEDLINE Link] .

Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev . 2003 Jan. 16 (1):114-28. [QxMD MEDLINE Link] .

Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis . 2003 Mar. 71 (3):239-42. [QxMD MEDLINE Link] .

Rooney JF, Straus SE, Mannix ML, Wohlenberg CR, Alling DW, Dumois JA, et al. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med . 1993 Feb 15. 118 (4):268-72. [QxMD MEDLINE Link] .

Farr Zuend C, Nomellini JF, Smit J, Horwitz MS. Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease. Sci Rep . 2018 Feb 12. 8 (1):2786. [QxMD MEDLINE Link] .

Johnston C, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomized, open-label, cross-over trials [published online ahead of print January 5, 2012]. Lancet. doi:10.1016/S0140-6736(11)61750-9.

Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future. F1000Res . 2018. 7: [QxMD MEDLINE Link] .

Chen YC, Sheng J, Trang P, Liu F. Potential Application of the CRISPR/Cas9 System against Herpesvirus Infections. Viruses . 2018 May 29. 10 (6): [QxMD MEDLINE Link] .

Green LK, Pavan-Langston D. Herpes simplex ocular inflammatory disease. Int Ophthalmol Clin . 2006 Spring. 46(2):27-37. [QxMD MEDLINE Link] .

Bedoui S, Greyer M. The role of dendritic cells in immunity against primary herpes simplex virus infections. Front Microbiol . 2014. 5:533. [QxMD MEDLINE Link] . [Full Text] .

Byers RJ, Hasleton PS, Quigley A, Dennett C, Klapper PE, Cleator GM, et al. Pulmonary herpes simplex in burns patients. Eur Respir J . 1996 Nov. 9 (11):2313-7. [QxMD MEDLINE Link] .

Baras L, Farber CM, Van Vooren JP, Parent D. Herpes simplex virus tracheitis in a patient with the acquired immunodeficiency syndrome. Eur Respir J . 1994 Nov. 7 (11):2091-3. [QxMD MEDLINE Link] .

Taplitz RA, Jordan MC. Pneumonia caused by herpesviruses in recipients of hematopoietic cell transplants. Semin Respir Infect . 2002 Jun. 17 (2):121-9. [QxMD MEDLINE Link] .

Bouza E, Giannella M, Torres MV, Catalán P, Sánchez-Carrillo C, Hernandez RI, et al. Herpes simplex virus: a marker of severity in bacterial ventilator-associated pneumonia. J Crit Care . 2011 Aug. 26 (4):432.e1-6. [QxMD MEDLINE Link] .

Hutto C, Arvin A, Jacobs R, Steele R, Stagno S, Lyrene R, et al. Intrauterine herpes simplex virus infections. J Pediatr . 1987 Jan. 110 (1):97-101. [QxMD MEDLINE Link] .

Ratanajamit C, Vinther Skriver M, Jepsen P, Chongsuvivatwong V, Olsen J, Sørensen HT. Adverse pregnancy outcome in women exposed to acyclovir during pregnancy: a population-based observational study. Scand J Infect Dis . 2003. 35 (4):255-9. [QxMD MEDLINE Link] .

Management of Genital Herpes in Pregnancy: ACOG Practice Bulletinacog Practice Bulletin, Number 220. Obstet Gynecol . 2020 May. 135 (5):e193-e202. [QxMD MEDLINE Link] .

Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson GL, Wendel GD Jr. Acyclovir suppression to prevent clinical recurrences at delivery after first episode genital herpes in pregnancy: an open-label trial. Infect Dis Obstet Gynecol . 2001. 9 (2):75-80. [QxMD MEDLINE Link] .

Stránská R, Schuurman R, Nienhuis E, Goedegebuure IW, Polman M, Weel JF, et al. Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol . 2005 Jan. 32 (1):7-18. [QxMD MEDLINE Link] .

Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the international acyclovir pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol . 2004 Apr. 70 (4):201-7. [QxMD MEDLINE Link] .

James SH, Kimberlin DW. Neonatal herpes simplex virus infection: epidemiology and treatment. Clin Perinatol . 2015 Mar. 42 (1):47-59, viii. [QxMD MEDLINE Link] .

Harris JB, Holmes AP. Neonatal Herpes Simplex Viral Infections and Acyclovir: An Update. J Pediatr Pharmacol Ther . 2017 Mar-Apr. 22 (2):88-93. [QxMD MEDLINE Link] .

Looker KJ, Elmes JAR, Gottlieb SL, Schiffer JT, Vickerman P, Turner KME, et al. Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis . 2017 Dec. 17 (12):1303-1316. [QxMD MEDLINE Link] .

Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS . 2006 Jan 2. 20 (1):73-83. [QxMD MEDLINE Link] .

Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr . 2004 Apr 15. 35(5):435-45. [QxMD MEDLINE Link] .

Nagot N, Ouedraogo A, Foulongne V, Konate I, Weiss HA, Vergne L. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med . 2007 Feb 22. 356(8):790-9. [QxMD MEDLINE Link] .

Baeten JM, Strick LB, Lucchetti A, Whittington WL, Sanchez J, Coombs RW, et al. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis . 2008 Dec 15. 198(12):1804-8. [QxMD MEDLINE Link] . [Full Text] .

Posavad CM, Wald A, Kuntz S, Huang ML, Selke S, Krantz E, et al. Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy. J Infect Dis . 2004 Aug 15. 190 (4):693-6. [QxMD MEDLINE Link] .

• Herpes simplex virus type 1. Primary herpes can affect the lips, and the ruptured vesicles may appear as bleeding of the lips. Courtesy of A.K. ElGeneidy, DDS.
• Herpes simplex virus type 1. Recurrent herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the lip vermilion and often on the perioral skin. Recurrences generally occur in the same area each time, although their severity may vary. Courtesy of Sara Gordon, DDS.
• This neonate displayed a maculopapular outbreak on his feet due to congenitally acquired herpes simplex virus infection. Courtesy of the CDC/Judith Faulk.
• Herpes simplex virus type 1. Recurrent herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only keratinized tissues, such as the gingiva or the hard palate. Vesicles often break quickly, so the clinician may observe small clustered ulcers. Courtesy of Sheldon Mintz, DDS.
• Herpetic whitlow in a young child who earlier had developed herpes gingivostomatitis. Courtesy of Wikimedia Commons [James Heilman, MD] (https://commons.wikimedia.org/w/index.php?search=Herpetic+whitlow+in+a+young+child&title=Special:MediaSearch&go=Go&type=image).
• Eczema herpeticum; cluster of blisters and punched out erosions of HSV in a child. Courtesy of Wikimedia Commons [Mohammad2018] (https://commons.wikimedia.org/wiki/File:Eczema_herpitcum.jpg).
• HSV encephalitis; coronal T2-weighted MRI showing increased intensity in the temporal lobes (arrow) in a 33-year-old female who presented with fever, confusion, agitation, and mutism and was diagnosed with HSV encephalitis. Courtesy of Wikimedia Commons [Dr Laughlin Dawes] (https://commons.wikimedia.org/wiki/File:Hsv_encephalitis.jpg).
• Genital herpes (female); outbreak of genital herpes affecting the vulva. Courtesy of Wikimedia Commons [SOA-AIDS Amsterdam] (https://commons.wikimedia.org/wiki/File:SOA-Herpes-genitalis-female.jpg).
• Genital herpes (male); vesicular lesions of HSV affecting the penis. Courtesy of Wikimedia Commons [SOA-AIDS Amsterdam] (https://commons.wikimedia.org/wiki/File:SOA-Herpes-genitalis-male.jpg).

Contributor Information and Disclosures

Folusakin O Ayoade, MD Assistant Professor of Clinical Medicine, Division of Infectious Diseases, Department of Medicine, University of Miami, Leonard M Miller School of Medicine; Attending Physician in Infectious Diseases, Jackson Health System; Attending Physician in Infectious Diseases, University of Miami Hospital Folusakin O Ayoade, MD is a member of the following medical societies: American College of Physicians , American Federation for Medical Research , American Medical Association , Infectious Diseases - International Research Initiative , Infectious Diseases Society of America Disclosure: Nothing to disclose.

Shuba Balan, MD, DFM Chief Fellow, Division of Infectious Diseases, Jackson Health System, University of Miami, Leonard M Miller School of Medicine Shuba Balan, MD, DFM is a member of the following medical societies: American College of Physicians , American Association of Clinical Endocrinologists , Infectious Diseases Society of America , Royal College of General Practitioners Disclosure: Nothing to disclose.

John R Todd, IV, MD Professor of Clinical Medicine, Department of Medicine, Section of Infectious Diseases, Louisiana State University School of Medicine in Shreveport John R Todd, IV, MD is a member of the following medical societies: American College of Physicians , American Federation for Medical Research , American Society for Microbiology , Infectious Diseases Society of America Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine in New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics , Alpha Omega Alpha , American Association for Physician Leadership , American Association for the Advancement of Science , American Association of University Professors , American Clinical and Climatological Association , American College of Physicians , American Federation for Medical Research , American Geriatrics Society , American Lung Association , American Medical Association , American Society for Microbiology , American Thoracic Society , American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology , Association of American Medical Colleges , Association of American Physicians , Association of Professors of Medicine , Infectious Disease Society for Obstetrics and Gynecology , Infectious Diseases Society of America , Louisiana State Medical Society , Orleans Parish Medical Society , Royal Society of Medicine , Sigma Xi, The Scientific Research Honor Society , Society of General Internal Medicine , Southeastern Clinical Club , Southern Medical Association , Southern Society for Clinical Investigation , Southwestern Association of Clinical Microbiology , The Foundation for AIDS Research Disclosure: Receives royalties from Baxter International for: Takeda-receives royalties; UpToDate-receives royalties.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Larry I Lutwick, MD, FACP Editor-in-Chief, ID Cases; Moderator, Program for Monitoring Emerging Diseases; Adjunct Professor of Medicine, State University of New York Downstate College of Medicine Larry I Lutwick, MD, FACP is a member of the following medical societies: American Association for the Advancement of Science , American Association for the Study of Liver Diseases , American College of Physicians , American Federation for Clinical Research , American Society for Microbiology , Infectious Diseases Society of America , Infectious Diseases Society of New York, International Society for Infectious Diseases , New York Academy of Sciences , Veterans Affairs Society of Practitioners in Infectious Diseases Disclosure: Nothing to disclose.

Meena Seenivasan, MD Fellow, Department of Infectious Disease, State University of New York Health Science Center at Brooklyn Disclosure: Nothing to disclose.

Thomas J Marrie, MD Dean of Faculty of Medicine, Dalhousie University Faculty of Medicine, Canada Thomas J Marrie, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Society for Microbiology , Association of Medical Microbiology and Infectious Disease Canada , Royal College of Physicians and Surgeons of Canada Disclosure: Nothing to disclose.

Swati Kumar, MD Assistant Professor of Pediatrics, Division of Infectious Diseases, Medical College of Wisconsin, Consulting Staff, Children's Specialty Group, Children's Hospital of Wisconsin Swati Kumar, MD is a member of the following medical societies: American Academy of Pediatrics , Infectious Diseases Society of America , Pediatric Infectious Diseases Society Disclosure: Nothing to disclose.

Michelle R Salvaggio, MD, FACP Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, Director, Clinical Trials Unit, Director, Ryan White Programs, Department of Medicine, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Infectious Diseases Institute, OU Medical Center Michelle R Salvaggio, MD, FACP is a member of the following medical societies: American College of Physicians , Infectious Diseases Society of America Disclosure: Received honoraria from Merck for speaking and teaching.

What would you like to print?

• Print this section
• Print the entire contents of
• Print the entire contents of article

• Pediatric Herpes Simplex Virus Infection
• Herpes Simplex Virus (HSV) Keratitis
• Herpes Simplex Virus (HSV) Empiric Therapy
• Herpes Simplex Virus (HSV) in Emergency Medicine
• Herpes Simplex Encephalitis
• Dermatologic Manifestations of Herpes Simplex
• Diabetes Raises Herpes Zoster Hospitalisation Risk
• Oral Herpes Tied to Double Dementia Risk in Older Adults
• Real-World RA Data Find JAK Inhibitor Infection Risk Is Low and No Greater Than Other DMARDs, Other Than Herpes Zoster
• Acute Liver Failure due to Herpes Simplex Viral Hepatitis Diagnosed by Skin Lesions and Blood Tests

• Drug Interaction Checker
• Pill Identifier
• Calculators

When viewing this topic in a different language, you may notice some differences in the way the content is structured, but it still reflects the latest evidence-based guidance.

Herpes simplex virus infection

• Overview  
• Theory  
• Diagnosis  
• Management  
• Follow up  
• Resources  

Herpes simplex virus infection is common and has multiple clinical manifestations.

The classic clinical presentation of vesicles progressing to painful ulcers is unusual; atypical and mild symptoms are common, and most people have unrecognised disease.

Symptoms of oral herpes (herpes labialis) include tingling and burning followed by development of vesicular then ulcerative lesions involving the oropharynx and perioral mucosa.

Symptoms of genital herpes range from asymptomatic to tingling and burning without lesions, to recurrent genital ulcerations.

Aciclovir, famciclovir, and valaciclovir are effective at shortening the duration and severity of an outbreak.

Daily suppressive therapy reduces recurrences by 80% and reduces transmission risk by approximately 50%.

Glycoprotein G-based type-specific serology testing is used to diagnose infection with or without lesions and distinguish between type 1 and 2.

The major clinical manifestations of infection with herpes simplex virus (HSV) type 1 (HSV-1) or HSV type 2 (HSV-2) are oral, genital, and ocular ulcers. Less commonly, primary or recurrent HSV infections may also present at other sites with neurological, hepatic, or respiratory complications. The primary episode occurs during initial infection with HSV, in which the host lacks an antibody response.

Herpes labialis is an infection of the mouth area and lips, most commonly with HSV-1.

Genital herpes is caused by infection with either HSV-1 or HSV-2. The first clinical episode of genital ulceration may represent either new acquisition of the virus or newly recognised disease with remote acquisition of the virus.

For both HSV-1 and HSV-2, asymptomatic shedding and transmission of the virus may occur in the absence of lesions. HSV establishes latency in neuronal ganglia and periodically reactivates. Most reactivations are asymptomatic but can result in transmission of the virus.

For details of management of ophthalmic HSV infection, please refer to the Uveitis and Keratitis topics. For details of management of suspected HSV encephalitis, please refer to the Encephalitis topic.

History and exam

Key diagnostic factors.

• presence of risk factors
• dysuria (in women)
• lymphadenopathy
• genital ulcer

Other diagnostic factors

• tingling sensation
• headache/aseptic meningitis

Risk factors

• HIV infection (risk factor for clinical disease)
• immunosuppressive medications (risk factor for clinical disease)
• female sex (risk factor for seropositivity)
• black race (risk factor for seropositivity)
• increasing age (risk factor for seropositivity)
• high-risk sexual behaviour (risk factor for seropositivity)
• lack of condom use (risk factor for seropositivity)

Diagnostic investigations

1st investigations to order.

• HSV polymerase chain reaction (PCR)
• viral culture
• Glycoprotein G-based type-specific serology (gG1 and gG2)

Treatment algorithm

Disseminated visceral involvement: pneumonitis, hepatitis, or cns involvement (meningitis or encephalitis), genital disease: first episode, immunocompetent, genital disease: first episode, immunocompromised, genital disease: recurrent episode, immunocompetent, genital disease: recurrent episode, immunocompromised, genital disease: pregnant (36 weeks of gestation), oral disease: first episode, immunocompetent, oral disease: first episode, immunocompromised, oral disease: recurrent episode, immunocompetent, oral disease: recurrent episode, immunocompromised, genital disease: sexually active or frequent severe recurrences, immunocompetent, genital disease: sexually active or frequent severe recurrences, immunocompromised, oral disease: frequent severe recurrences, immunocompetent, oral disease: frequent severe recurrences, immunocompromised, contributors, benjamin d. lorenz, md.

Assistant Professor

Division of Hospital Medicine

MedStar Georgetown University Hospital

Disclosures

BDL declares that he has no competing interests.

Acknowledgements

Dr Benjamin D. Lorenz would like to gratefully acknowledge Dr Christine Johnson and Dr Anna Wald, previous contributors to this topic.

CJ reports funding from AiCuris; grants from Agenus, Gilead, Genocea, Sanofi, and Vical to conduct clinical research studies; and royalties from Up To Date. AW reports grants from Agenus, Gilead, Genocea, Sanofi, and Vical to conduct clinical research studies. AW receives royalties from Up To Date. AW is an NIH grant recipient (NIH AI30731 and AI071113) and a consultant for Aicuris, Eisai, and Amgen.

Peer reviewers

Giuseppe pizzo, dds.

Associate Professor

Department of Surgical, Oncological and Oral Sciences

School of Dentistry

University of Palermo

GP declares that he has no competing interests.

Peter Leone, MD

Professor of Medicine

University of North Carolina at Chapel Hill

Chapel Hill

PL declares that he has no competing interests.

Differentials

• Lymphogranuloma venereum
• Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV
• Red Book 2021. Section 3: summary of infectious diseases. Herpes simplex

Patient information

Genital herpes

Use of this content is subject to our disclaimer

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of bmj best practice, help us improve bmj best practice.

Please complete all fields.

I have some feedback on:

We will respond to all feedback.

For any urgent enquiries please contact our customer services team who are ready to help with any problems.

Phone: +44 (0) 207 111 1105

Email: [email protected]

Your feedback has been submitted successfully.

• Type 2 Diabetes
• Heart Disease
• Digestive Health
• Multiple Sclerosis
• Diet & Nutrition
• Health Insurance
• Public Health
• Patient Rights
• Caregivers & Loved Ones
• End of Life Concerns
• Health News
• Thyroid Test Analyzer
• Doctor Discussion Guides
• Hemoglobin A1c Test Analyzer
• Lipid Test Analyzer
• Complete Blood Count (CBC) Analyzer
• What to Buy
• Editorial Process
• Meet Our Medical Expert Board

HSV-1 vs. HSV-2: What Are the Differences?

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two highly contagious viruses that can cause outbreaks of watery blisters on the skin and mucous membranes of the mouth, lips, nose, genitals, rectum, and eyes.

Although HSV-1 is more commonly associated with oral herpes (cold sores) and HSV-2 is more commonly linked to genital herpes , they can be passed to other parts of the body through oral sex . Because of this, it is possible for a cold sore to be caused by HSV-2 and a genital herpes outbreak to be caused by HSV-1.

Boy_Anupong / Getty Images

Today, there is an increasing crossover between the two herpes types, and only diagnostic testing can reveal which virus is causing which type of infection. Differentiating the two can be important as the treatment approach for each can differ significantly.

This article looks at the differences and similarities between HSV-1 and HSV-2, including their symptoms and causes and how each is diagnosed and treated.

The majority of HSV infections are asymptomatic (meaning with little or no symptoms) and may never cause symptoms. In people who are symptomatic (with symptoms), HSV-1 and HSV-2 mainly differ by where the episode, called outbreaks, occurs.

In most cases, HSV-1 is passed through mouth-to-mouth contact, causing oral herpes (also known as herpes labialis ), while HSV-2 is almost exclusively passed through sexual contact, causing genital herpes (or herpes genitalis ).

Beyond the location of the outbreak, the symptoms of HSV-1 and HSV-2 are largely indistinguishable.

In symptomatic people, HSV-1 and HSV-2 both develop in characteristic stages:

• Prodromal stage : This is the early stage of infection. There may be redness, swelling, and a burning or tingling sensation at the site of the impending outbreak. Headache, fatigue, weakness, swollen lymph nodes , and fever may accompany the infection.
• Blister stage : The prodromal symptoms are quickly followed by the outbreak of tiny blisters filled with clear to whitish-yellow fluid. The blisters tend to develop in clusters and can be very tender.
• Eruptive stage : This is the stage when the blisters break open and leak fluids, leaving painful open sores (ulcers) that quickly crust over.
• Healing stage : After about four to seven days, the crusted sores will start to scab and heal. The healing process can take anywhere from one to three weeks. First outbreaks tend to take longer and be more severe than subsequent outbreaks.

Is It HSV-1 or HSV-2?

While it may seem reasonable to assume that a cold sore is caused by HSV-1 and genital herpes is caused by HSV-2, a 2015 study in PLoS One suggested that more than half of all new genital herpes cases in people 14 to 49 are caused by HSV-1.

In the end, you cannot differentiate HSV-1 from HSV-2 by either the appearance or location of the outbreak. This can only be done with diagnostic testing.

One key difference between HSV-1 and HSV-2 is the risk of recurrence. All herpes viruses tend to recur (repeat) after the initial outbreak, often within the first year. But, with a genital herpes outbreak, HSV-1 is 80% less likely to recur within a year. In some cases, you would only have one outbreak with no recurrence.

In contrast, recurrence is common with HSV-2. If left untreated, some people may experience recurrent outbreaks anywhere from one to 12 times per year. Moreover, the recurrent episodes tend to be far more severe than with HSV-1 and can persist for many years.

HSV-1 and HSV-2 belong to a family of viruses called Herpesviridae, which also includes the varicella-zoster virus (VZV) cauaing chicken pox and shingles .

As with VZV, HSV-1 and HSV-2 are never cleared from the body after the infection. Instead, the viruses embed themselves in nerve cells, where the viruses remain in a latent (dormant) state. In some people, HSV-1 and HSV-2 can spontaneously reactivate and cause a new outbreak of oral or genital herpes.

During reactivation, a process known as viral shedding occurs in which the herpes virus starts to multiply and migrate to the skin at the site of the initial infection. It is then that the virus can be transmitted (passed) to others through close physical contact.

The transmission can occur both when there are visible sores and also when a person with HSV-1 or HSV-2 is asymptomatic. This is known as asymptomatic shedding.

In fact, according to the Centers for Disease Control and Prevention (CDC), the transmission of HSV-2 most often occurs when a person is asymptomatic and may not even realize they have the virus.

While the same can occur with HSV-1, a genital HSV-2 infection is substantially more severe in terms of recurrences and viral shedding. With HSV-2, high rates of shedding can occur years after the first outbreak. Shedding with HSV-1 tends to wane quickly, and it becomes less transmissible.

How Common Is HSV-1 and HSV-2?

More than half of all adults in the United States have HSV-1, while nearly 1 in 7 sexually active adults have HSV-2. The prevalence of both increases with age.

Studies suggest that around 27% of teens in the United States have HSV-1, increasing to nearly 60% by ages 40 to 49. In contrast, less than 1% of teens have HSV-2, rising to just over 21% by ages 40 to 49.

Differences Between HSV-1 and HSV-2

While the mechanisms of transmission are similar, HSV-1 and HSV-2 vary in several key ways, including:

• Latent infection : During latency, HSV-1 tends to embed itself in a cluster of nerve cells called the trigeminal ganglia situated around the head and face. HSV-2, on the other hand, tends to embed itself in the sacral ganglia of the lower trunk and limbs. This explains why HSV-1 is more likely to affect the upper body, while HSV-2 is more likely to affect the lower body.
• Route of transmission : HSV-2 is nearly twice as common in females as in males. This is likely because genital infections are more easily passed from males to females during vaginal sex. HSV-1 is only slightly more common in females than in males (50.4% vs. 45.8%), likely because the route of transmission (mouth-to-mouth) involves the same anatomy in people of all sexes.
• Declining infection rates : While rates of HSV-1 have decreased by more than 10% since the 1970s, the rate of genital HSV-1 has increased by more than 60%. Because fewer people are being exposed to HSV-1 during childhood (and therefore have no antibodies to the virus), they are more likely to experience a genital outbreak if exposed to the virus for the first time through oral sex.

Diagnosis of HSV-1 and HSV-2

HSV-1 and HSV-2 are both diagnosed in the same way and with the same tools. The tests are commonly used to:

• Determine whether sores on your mouth or genitals are caused by HSV.
• Diagnose herpes during pregnancy (to prevent transmission of the virus to the fetus).
• Find out if a newborn has herpes.

Newer herpes tests can detect herpes and differentiate between HSV-1 and HSV-2, the differentiation of which may influence the treatment plan.

Types of Tests

Herpes testing is usually done as a swab test, a blood test, or a lumbar puncture (spinal tap). The test you get will depend on the type of symptoms you have:

• Swab tests are used in symptomatic people to collect fluids and cells from a herpes sore. They can differentiate HSV-1 from HSV-2 based on their genetic material using a technology called polymerase chain reaction (PCR) . This is the gold standard for herpes testing.
• Blood tests can be used in symptomatic or asymptomatic people. These include PCR tests and antibody-based tests (which detect immune proteins produced in response to the virus rather than the virus itself). Some antibody tests can differentiate HSV-1 and HSV-2, while others cannot. Testing too early in asymptomatic people can lead to a false-negative result, which claims a person does not have the infection when they actually do.
• Lumbar puncture is used when herpes is suspected to have spread to the brain and spinal cord, causing encephalitis . This is a rare complication mostly seen in immunocompromised people, such as those with advanced HIV (human immunodeficiency virus) . The PCR test screens cerebrospinal fluid .

CDC Screening Recommendations

The CDC recommends testing for all people with genital herpes symptoms to confirm if they have herpes. The CDC does not recommend testing for those without symptoms as doing so has not been shown to alter risk behaviors or slow the spread of the virus.

HSV blood testing may be useful if:

• Your sex partner has genital herpes, and you want to know if you acquired it.
• You are pregnant, and you and your partner have had genital herpes in the past or currently have genital herpes symptoms.

HSV-1 and HSV-2 are both treated with antiviral drugs . The drugs don't "cure" herpes but rather prevent the virus from binding to and infecting healthy cells.

There are three oral antivirals approved for the treatment of HSV-1 and HSV-2:

• Zovirax (acyclovir)
• Valtrex (valacyclovir)
• Famvir (famciclovir)

While these drugs can treat both HSV-1 and HSV-2, how they are used can vary significantly based on which virus is involved and whether it is a first or subsequent outbreak.

For instance, if you have a cold sore, your healthcare provider will likely forego testing and prescribe a course of antivirals to shorten the duration and severity of the infection.

The same may not be true if you have genital herpes. While the differentiation of HSV-1 and HSV-2 won't necessarily alter the course of treatment, particularly during a first outbreak, it can when there is a recurrence.

According to the CDC, genital HSV-1 and HSV-2 should be treated in the following manner for first and recurrent episodes:

• First outbreak : Anyone with a first episode of genital herpes should receive oral antiviral therapy, irrespective of whether they have HSV-1 or HSV-2. Treatment is prescribed for seven to 10 days.
• Recurrent HSV-2 : Almost everyone with genital HSV-2 will experience recurrent outbreaks. In such cases, suppressive therapy (in the form of a daily antiviral drug) may be prescribed to lower the risk of recurrence and the odds of transmitting the virus to others. If there is an outbreak, episodic therapy can be prescribed for anywhere from one to five days to resolve the acute infection.
• Recurrent HSV-1 : Recurrences are less common after a first outbreak of genital HSV-1. Because of this, episodic therapy is more commonly prescribed during incidental outbreaks. Suppressive therapy is reserved for uncommon cases in which outbreaks are more frequent and severe.

The prevention strategies for HSV-1 and HSV-2 are largely the same but vary by the source of the transmission. As herpes is spread through direct, physical contact, the best method of prevention is to avoid physical contact with a person's herpes sores while they are having an outbreak.

With HSV-1, which is mainly spread through oral contact, this means avoiding kissing and any other contact with a cold sore.

To prevent the spread of HSV-1 to the genitals or anus, abstain from sex while you or a sex partner have visible sores or prodromal symptoms. If you have sex, you can reduce the risk of transmission by using condoms for oral-penile sex and dental dams for oral-vaginal or oral-anal sex.

As HSV-2 is almost exclusively passed through sex, the same rules regarding abstinence, condoms, and dental dams apply. If you have HSV-2 and are prone to frequent recurrence, speak with your healthcare provider about daily suppressive antiviral therapy to reduce the risk of transmission.

Condoms provide only partial protection as the virus may be shed through skin not covered by the condom.

Herpes simplex virus type 1 (HSV-1) is more commonly associated with oral herpes (cold sores), while herpes simplex virus type 2 (HSV-2) is more commonly associated with genital herpes. Even so, HSV-1 is increasingly linked to genital herpes due to oral sex.

While the symptoms of HSV-1 and HSV-2 are indistinguishable. HSV-2 is more likely to recur and cause high levels of viral shedding years after the initial infection. Moreover, with HSV-2 especially, viral shedding can occur with no symptoms, meaning that the virus can be passed without a person even realizing they have herpes.

This is why screening is recommended for all people with genital herpes symptoms. The differentiation of HSV-1 and HSV-2 can influence the treatment plan, especially when there are frequent recurrences.

Frequently Asked Questions

Yes. In fact, the CDC suggests that the majority of cases of genital herpes are transmitted by people who are asymptomatic (without symptoms). Viral shedding (the spontaneous release of infectious viruses) occurs in people who are asymptomatic on 10.2% of days, compared to 20.1% of days in those who have symptoms.

If you have herpes simplex virus type 2 (HSV-2), the type most commonly associated with genital herpes, the likelihood of recurrence is high. According to the CDC, between 70% and 80% of people with a first genital herpes outbreak will have future outbreaks.

Only partially. Because the virus can be shed through tissue not covered by a condom, it can be passed to others even with condoms. Based on current evidence, the CDC suggests that latex condoms provide "limited protection" against herpes simplex virus type 2 (HSV-2), the type commonly associated with genital herpes.

World Health Organization. Herpes simplex virus .

Ayoub HH, Chermaitelly H, Abu-Raddad LJ. Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: model-based predictions . BMC Med.  2019;17:57. doi:10.1186/s12916-019-1285-x

Centers for Disease Control and Prevention.  Sexually transmitted infections treatment guidelines, 2021: genital herpes .

National Institutes of Health. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: herpes simplex virus .

Sauerbrei A.  Herpes genitalis: diagnosis, treatment and prevention .  Geburtshilfe Frauenheilkd.  2016;76(12):1310–1307, doi:10.1055/s-0042-116494

Looker KJ, Magaret AS, May MT, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012 . PLoS One.  2015;10(10):e0140765. doi:10.1371/journal.pone.0140765

Sauerbrei A. Optimal management of genital herpes: current perspectives . Infect Drug Resist . 2016;9:129-141. doi:10.2147/IDR.S96164

Centers for Disease Control and Prevention. Genital herpes – CDC detailed fact sheet .

Whitley RJ, Hook EW. Shedding patterns of genital herpes simplex virus infections . JAMA.  2022;328(17):1710-1711. doi:10.1001/jama.2022.18930

McQuillan G, Kruszon-Moran D, Flagg EW, Paulose-Ram R. Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States . NCHS Data Brief . 2018;(304):1-8.

Nath P, Kabir A, Doust SK, Ray A. Diagnosis of herpes simplex virus: laboratory and point-of-care techniques . Infect Dis Rep.  2021;13(2):518–539. doi:10.3390/idr13020049

Galen BT. Screening cerebrospinal fluid prior to herpes simplex virus PCR testing might miss cases of herpes simplex encephalitis . J Clin Microbiol.  2017;55(10):3142–3143. doi:10.1128/JCM.01129-17

Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future . F1000Res.  2018;7:F1000 Faculty Rev-1726. doi:10.12688/f1000research.16157.1

Chi CC, Wang SH, Delamere FM, et al. Interventions for prevention of herpes simplex labialis (cold sores on the lips) . Cochrane Database Syst Rev.  2015;2015(8):CD010095. doi:10.1002/14651858.CD010095.pub2

Centers for Disease Control and Prevention. Fact sheet for public health personnel: condom effectiveness .

By James Myhre & Dennis Sifris, MD Dr. Sifris is an HIV specialist and Medical Director of LifeSense Disease Management. Myhre is a journalist and HIV educator.

RICHARD P. USATINE, MD, AND ROCHELLE TINITIGAN, MD

Am Fam Physician. 2010;82(9):1075-1082

Patient information: See related handout on cold sores , written by the authors of this article.

Author disclosure: Nothing to disclose.

Nongenital herpes simplex virus type 1 is a common infection usually transmitted during childhood via nonsexual contact. Most of these infections involve the oral mucosa or lips (herpes labialis). The diagnosis of an infection with herpes simplex virus type 1 is usually made by the appearance of the lesions (grouped vesicles or ulcers on an erythematous base) and patient history. However, if uncertain, the diagnosis of herpes labialis can be made by viral culture, polymerase chain reaction, serology, direct fluorescent antibody testing, or Tzanck test. Other nonoral herpes simplex virus type 1 infections include herpetic keratitis, herpetic whitlow, herpes gladiatorum, and herpetic sycosis of the beard area. The differential diagnosis of nongenital herpes simplex virus infection includes aphthous ulcers, acute paronychia, varicellazoster virus infection, herpangina, herpes gestationis (pemphigoid gestationis), pemphigus vulgaris, and Behçet syndrome. Oral acyclovir suspension is an effective treatment for children with primary herpetic gingivostomatitis. Oral acyclovir, valacyclovir, and famciclovir are effective in treating acute recurrence of herpes labialis (cold sores). Recurrences of herpes labialis may be diminished with daily oral acyclovir or valacyclovir. Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatment.

Nongenital herpes simplex virus type 1 (HSV-1) is a common infection that most often involves the oral mucosa or lips (herpes labialis). The primary oral infection may range from asymptomatic to very painful, leading to poor oral intake and dehydration. Recurrent infections cause cold sores that can affect appearance and quality of life. Although HSV-2 also can affect the oral mucosa, this is much less common and does not tend to become recurrent.

Epidemiology

HSV-1 is initially transmitted in childhood via nonsexual contact, but it may be acquired in young adulthood through sexual contact. In the United States, the seroprevalence of HSV-1 decreased from 62.0 percent between 1988 and 1994 to 57.7 percent between 1999 and 2004. 1 In a cross-sectional survey of U.S. college students, the prevalence of HSV-1 antibodies was 37.2 percent in freshmen and 46.1 percent in fourth-year students. 2 A history of cold sores was reported in 25.6 percent of freshmen and 28 percent of fourth-year students. Significant predictors of HSV-1 antibodies in this population were female sex, sexual intercourse before 15 years of age, greater total years of sexual activity, history of a partner with oral sores, and personal history of a non-HSV sexually transmitted disease. 2 Approximately 90 percent of recurrent HSV-1 infections cause the orofacial lesions known as herpes labialis 3 ( Figure 1 ).

Pathophysiology

HSV invades and replicates in neurons, as well as in epidermal and dermal cells. The virus travels from the skin during contact to the sensory dorsal root ganglion, where latency is established. Oral HSV-1 infections reactivate from the trigeminal sensory ganglia, affecting the facial, oral, labial, oropharyngeal, and ocular mucosa.

Primary infection appears two to 20 days after contact with an infected person. The virus can be transmitted by kissing or sharing utensils or towels. Transmission involves mucous membranes and open or abraded skin. During one study of herpes labialis, the median duration of HSV-1 shedding was 60 hours when measured by polymerase chain reaction (PCR) and 48 hours when measured by culture. 4

Peak viral DNA load occurred at 48 hours, with no virus detected beyond 96 hours of onset of symptoms. 4 Recurrent infections may be precipitated by various stimuli, such as stress, fever, sun exposure, extremes in temperature, ultraviolet radiation, immunosuppression, or trauma. The virus remains dormant for a variable amount of time. Oral HSV-1 usually recurs one to six times per year. 5 The duration of symptoms is shorter and the symptoms are less severe during a recurrence.

The likelihood of reactivation of HSV infection differs between HSV-1 and HSV-2, and between the sacral and trigeminal anatomic sites. In one study, the mean monthly frequencies of recurrence were 0.33 genital HSV-2 infections, 0.12 orolabial HSV-1 infections, 0.020 genital HSV-1 infections, and 0.001 oral HSV-2 infections. 6 This shows that recurrences are more likely when HSV-1 is oral and HSV-2 is genital.

Clinical Presentation

In primary oral HSV-1, symptoms may include a prodrome of fever, followed by mouth lesions with submandibular and cervical lymphadenopathy. The mouth lesions (herpetic gingivostomatitis) consist of painful vesicles on a red, swollen base that occur on the lips, gingiva, oral palate, or tongue. The lesions ulcerate ( Figure 2 ) and the pain can be severe. Refusal to eat or drink may be a clue to the presence of oral HSV. The lesions usually heal within 10 to 14 days. 5

In recurrent herpes labialis, symptoms of tingling, pain, paresthesias, itching, and burning precede the lesions in 60 percent of persons. 5 The lesions then appear as clusters of vesicles on the lip or vermilion border ( Figure 1 ). The vesicles may have an erythematous base. The lesions subsequently ulcerate and form a crust ( Figure 3 ). Healing begins within three to four days, and reepithelization may take seven to eight days. 5 However, many persons who are exposed to HSV-1 demonstrate asymptomatic seroconversion.

Herpetic keratitis is an HSV infection of the eye. Common symptoms are eye pain, light sensitivity, and discharge with gritty sensation in the eye. Fluorescein stain with a ultraviolet light may show a classic dendritic ulcer on the cornea ( Figure 4 7 ). Without prompt treatment, scarring of the cornea may occur ( Figure 5 ).

Herpetic whitlow is a vesicular lesion found on the hands or digits ( Figures 6 8 and 7 ). It occurs in children who suck their thumbs or medical and dental workers exposed to HSV-1 while not wearing gloves. Herpes gladiatorum is often seen in athletes who wrestle, which may put them in close physical contact with an infected person. Vesicular eruptions are often seen on the torso, but can occur in any location where skin-to-skin contact has occurred. Herpetic sycosis is a follicular infection with HSV that causes vesiculopapular lesions in the beard area. It is often caused by autoinoculation from shaving.

HSV infection is one of the most common causes of erythema multiforme ( Figure 8 ), which some patients have with a recurrent HSV infection. The differential diagnosis of HSV-1 infection is presented in Table 1 . Herpes gestationis may present like an HSV infection, but it is an autoimmune disease similar to bullous pemphigoid ( Figure 9 ).

The diagnosis of HSV-1 infection is usually made by the appearance of the lesions and the patient's history. However, if the pattern of the lesions is not specific to HSV, its diagnosis can be made by viral culture, PCR, serology, direct fluorescent antibody testing, or Tzanck test. Viral culture should be obtained from vesicles when possible. The vesicle should be unroofed with a scalpel or sterile needle, and a swab should be used to soak up the fluid and to scrape the base. The swab should be sent in special viral transport media directly to the laboratory (or placed on ice if transport will be delayed). Vesicles contain the highest titers of virus within the first 24 to 48 hours of their appearance (89 percent positive). 9 In general, viral culture for all types of HSV has a sensitivity of approximately 50 percent. 6 Viral isolates usually grow in tissue culture by five days.

PCR is a more sensitive method in the laboratory diagnosis of HSV infection. 4 It is useful for the detection of asymptomatic viral shedding. Direct fluorescent antibody testing may be performed from air-dried specimens, and can detect 80 percent of true HSV-positive cases compared with culture results. 10 Immunoglobulin G antibodies that are type-specific to HSV develop the first several weeks after infection and persist indefinitely. A Tzanck test is difficult to perform correctly without specific training in its use, but it may be done in the office setting by scraping the floor of the herpetic vesicle, staining the specimen, and looking for multinucleated giant cells. Its results do not specify the type of HSV infection, but if done correctly, its sensitivity is 40 to 77 percent for acute herpetic gingivostomatitis. 11

EPISODIC ORAL TREATMENT FOR PRIMARY HERPETIC GINGIVOSTOMATITIS

Oral acyclovir suspension (Zovirax; 15 mg per kg five times per day for seven days) can be used to treat herpetic gingivostomatitis in young children. In one randomized controlled trial (RCT), children receiving acyclovir had oral lesions for a shorter time than children receiving placebo (median of four versus 10 days). The treatment group also had earlier resolution of the following signs and symptoms: fever (one versus three days); eating difficulties (four versus seven days); and drinking difficulties (three versus six days). 12 Viral shedding was significantly shorter in the group treated with acyclovir (one versus five days). 12 Children should be treated symptomatically with oral analgesics and cold, soothing foods such as ice pops and ice cream. Various concoctions of topical anesthetics and other medications have been used to numb the painful ulcers so that children can be kept well hydrated.

EPISODIC ORAL TREATMENT FOR RECURRENT HERPES LABIALIS

In a Cochrane review on the treatment of herpes labialis in patients receiving cancer treatment, acyclovir was found to be effective with regard to viral shedding (median of 2.5 versus 17.0 days); time to first decrease in pain (median of three versus 16 days); complete resolution of pain (9.9 versus 13.6 days); and total healing (median of 13.9 versus 20.7 days). 13 The brief period of viral replication in recurrent herpes labialis lesions suggests short therapeutic regimens should produce good results. In one RCT, 701 patients self-initiated therapy with famciclovir (Famvir; 1,500 mg once [single dose] or 750 mg twice per day for one day [single day]) or placebo within one hour of prodromal symptoms onset. 14 Median healing times of primary (first to appear) vesicular lesions in the famciclovir single-dose, famciclovir single-day, and placebo groups were 4.4, 4.0, and 6.2 days, respectively. 14 Famciclovir showed decreased healing times, with no significant difference between the divided- or single-dose famciclovir treatment groups. 14

In one RCT of recurrent herpes labialis, treatment with oral valacyclovir (Valtrex) plus topical clobetasol (Temovate) was compared with placebo. 15 The patients took oral valacyclovir (2 g twice for one day) and applied clobetasol 0.05% gel (twice per day for three days) at onset of symptoms. There were more aborted lesions in the valacyclovirclobetasol group compared with the placebo-placebo group (50 versus 15.8 percent). Combination therapy reduced the mean maximum lesion size (9.7 versus 54 mm) and the mean healing time (5.8 versus 9.3 days) of classic lesions. 15

EPISODIC TOPICAL TREATMENT FOR RECURRENT HERPES LABIALIS

Topical treatment for herpes labialis is less effective than oral treatment. An RCT of treatment with topical penciclovir 1% cream (Denavir) showed healing was marginally faster in the penciclovir group compared with placebo (4.8 versus 5.5 days). 16 The participants were adults in otherwise good health who had at least three episodes of herpes labialis per year. They applied penciclovir cream or placebo within one hour of the first sign or symptom of a recurrence, and then every two hours while awake for four days. Resolution of symptoms occurred more rapidly in the penciclovir group regardless of whether the medication was applied in the early or late stage. Penciclovir cream applied every two hours while awake reduced median duration of pain from 4.1 to 3.5 days, sped up the healing of classic lesions (e.g., vesicles, ulcers, crusts) from 5.5 to 4.8 days, and did not change median time of viral shedding (median of three versus three days). 16

Docosanol cream (Abreva) is a saturated, 22-carbon, aliphatic alcohol with antiviral activity. It is available without prescription. One RCT of 743 patients with herpes labialis showed a faster healing time in patients treated with docosanol 10% cream compared with placebo cream (4.1 versus 4.8 days), as well as reduced duration of pain symptoms (2.2 versus 2.7 days). 17 More than 90 percent of patients in both groups healed completely within 10 days. 17 Treatment with docosanol cream, when applied five times per day and within 12 hours of episode onset, is safe and somewhat effective.

An RCT of healthy adults with a history of frequent herpes labialis recurrences evaluated treatment with 5% acyclovir cream versus a vehicle control. 18 Participants were told to self-initiate treatment five times per day for four days, beginning within one hour of the onset of a recurrent episode. In study 1, the mean duration of episodes was 4.3 days for patients treated with acyclovir cream and 4.8 days for those treated with the vehicle control. 18 In study 2, the mean duration of episodes was 4.6 days for patients treated with acyclovir and 5.2 days for those treated with the vehicle control. 18

ORAL TREATMENT TO PREVENT HERPES LABIALIS RECURRENCES

Oral acyclovir is effective in suppressing herpes labialis in immunocompetent adults with frequent recurrences. In one RCT, treatment with oral acyclovir (400 mg twice per day) resulted in a 53 percent reduction in the number of clinical recurrences and a 71 percent reduction in virus culture-positive recurrences compared with placebo. 19 The median time to first clinically documented recurrence was 46 days for placebo courses and 118 days for acyclovir courses. 19 The mean number of recurrences per four-month treatment period was 1.80 episodes per patient during placebo treatment and 0.85 episodes per patient during acyclovir treatment. 19

Treatment with oral valacyclovir (500 mg per day) for 16 weeks was compared with placebo in the suppression of herpes labialis in patients with a history of four or more recurrent lesions in the previous year. 20 Results showed 60 percent of persons in the valacyclovir group were recurrence-free throughout the study period compared with 38 percent in the placebo group. The mean time to first recurrence was longer with valacyclovir (13.1 weeks) compared with placebo (9.6 weeks). 20

In a Cochrane review of herpes labialis prevention in patients receiving treatment for cancer, acyclovir was found to be effective in the prevention of HSV infections, as measured by oral lesions or viral isolates (relative risk = 0.16 and 0.17, respectively). 13 There also was no evidence that valacyclovir is more effective than acyclovir. In another study, daily valacyclovir (500 mg per day) and acyclovir (400 mg twice per day) were equally effective in the prevention of recurrent HSV eye disease. 21

An overview of treatments for herpes labialis is provided in Table 2 . 12 – 20

Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-973.

Gibson JJ, Hornung CA, Alexander GR, Lee FK, Potts WA, Nahmias AJ. A cross-sectional study of herpes simplex virus types 1 and 2 in college students: occurrence and determinants of infection. J Infect Dis. 1990;162(2):306-312.

Gilbert S, Corey L, Cunningham A, et al. An update on short-course intermittent and prevention therapies for herpes labialis. Herpes. 2007;14(suppl 1):13A-18A.

Boivin G, Goyette N, Sergerie Y, Keays S, Booth T. Longitudinal evaluation of herpes simplex virus DNA load during episodes of herpes labialis. J Clin Virol. 2006;37(4):248-251.

Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med. 2008;168(11):1137-1144.

Lafferty WE, Coombs RW, Benedetti J, Critchlow C, Corey L. Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med. 1987;316(23):1444-1449.

Chumley H. Conjunctivitis. In: Usatine RP, Smith MA, Chumley H, Mayeaux EJ Jr, Tysinger J, eds. The Color Atlas of Family Medicine . New York, NY: McGraw-Hill; 2009:83.

Mayeaux EJ Jr. Herpes simplex. In: Usatine RP, Smith MA, Chumley H, Mayeaux EJ Jr, Tysinger J, eds. The Color Atlas of Family Medicine . New York, NY: McGraw-Hill; 2009:517.

Spruance SL, Overall JC, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis: implications for antiviral therapy. N Engl J Med. 1977;297(2):69-75.

Chan EL, Brandt K, Horsman GB. Comparison of Chemicon SimulFluor direct fluorescent antibody staining with cell culture and shell vial direct immunoperoxidase staining for detection of herpes simplex virus and with cytospin direct immunofluorescence staining for detection of varicellazoster virus. Clin Diagn Lab Immunol. 2001;8(5):909-912.

Chauvin PJ, Ajar AH. Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management. J Can Dent Assoc. 2002;68(4):247-251.

Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study. BMJ. 1997;314(7097):1800-1803.

Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T. Interventions for the prevention and treatment of herpes simplex virus in patients being treated for cancer. Cochrane Database Syst Rev. 2009;1:CD006706.

Spruance SL, Bodsworth N, Resnick H, et al. Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. J Am Acad Dermatol. 2006;55(1):47-53.

Hull C, McKeough M, Sebastian K, Kriesel J, Spruance S. Valacyclovir and topical clobetasol gel for the episodic treatment of herpes labialis: a patient-initiated, double-blind, placebo-controlled pilot trial. J Eur Acad Dermatol Venereol. 2009;23(3):263-267.

Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA. 1997;277(17):1374-1379.

Sacks SL, Thisted RA, Jones TM, et al.; Docosanol 10% Cream Study Group. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: a multi-center, randomized, placebo-controlled trial. J Am Acad Dermatol. 2001;45(2):222-230.

Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother. 2002;46(7):2238-2243.

Rooney JF, Straus SE, Mannix ML, et al. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann Intern Med. 1993;118(4):268-272.

Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis. 2003;71(3):239-242.

Miserocchi E, Modorati G, Galli L, Rama P. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol. 2007;144(4):547-551.

Continue Reading

More in AFP

More in pubmed.

Copyright © 2010 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions  for copyright questions and/or permission requests.

Copyright © 2024 American Academy of Family Physicians. All Rights Reserved.

• Patient Care & Health Information
• Diseases & Conditions
• Genital herpes

Genital herpes is a common sexually transmitted infection (STI). The herpes simplex virus (HSV) causes genital herpes. Genital herpes can often be spread by skin-to-skin contact during sexual activity.

Some people infected with the virus may have very mild symptoms or no symptoms. They can still able to spread the virus. Other people have pain, itching and sores around the genitals, anus or mouth.

There is no cure for genital herpes. Symptoms often show up again after the first outbreak. Medicine can ease symptoms. It also lowers the risk of infecting others. Condoms can help prevent the spread of a genital herpes infection.

Products & Services

• A Book: Mayo Clinic Family Health Book

Sores associated with genital herpes can be small bumps, blisters or open sores. Scabs eventually form and the sores heal, but they tend to recur.

Most people infected with HSV don't know they have it. They may have no symptoms or have very mild symptoms.

Symptoms start about 2 to 12 days after exposure to the virus. They may include:

• Pain or itching around the genitals
• Small bumps or blisters around the genitals, anus or mouth
• Painful ulcers that form when blisters rupture and ooze or bleed
• Scabs that form as the ulcers heal
• Painful urination
• Discharge from the urethra, the tube that releases urine from the body
• Discharge from the vagina

During the first outbreak, you may commonly have flu-like symptoms such as:

• Swollen lymph nodes in the groin

Differences in symptom location

Sores appear where the infection enters the body. You can spread the infection by touching a sore and then rubbing or scratching another area of your body. That includes your fingers or eyes.

Sore can develop on or in the:

Repeat outbreaks

After the first outbreak of genital herpes, symptoms often appear again. These are called recurrent outbreaks or recurrent episodes.

How often recurrent outbreaks happen varies widely. You'll usually have the most outbreaks the first year after infection. They may appear less often over time. Your symptoms during recurrent outbreaks usually don't last as long and aren't as severe as the first.

You may have warning signs a few hours or days before a new outbreak starts. These are called prodromal symptoms. They include:

• Genital pain
• Tingling or shooting pain in the legs, hips or buttocks

When to see a doctor

If you suspect you have genital herpes, or any other STI , see your health care provider.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

From Mayo Clinic to your inbox

Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview.

Error Email field is required

Error Include a valid email address

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

Thank you for subscribing!

You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.

Sorry something went wrong with your subscription

Please, try again in a couple of minutes

Genital herpes is caused by two types of herpes simplex virus. These types include herpes simplex virus type 2 (HSV-2) and herpes simplex virus type 1 (HSV-1). People with HSV infections can pass along the virus even when they have no visible symptoms.

HSV-2 is the most common cause of genital herpes. The virus can be present:

• On blisters and ulcers or the fluid from ulcers
• The moist lining or fluids of the mouth
• The moist lining or fluids of the vagina or rectum

The virus moves from one person to another during sexual activity.

HSV-1 is a version of the virus that causes cold sores or fever blisters. People may be exposed to HSV-1 as children due to close skin-to-skin contact with someone infected.

A person with HSV-1 in tissues of the mouth can pass the virus to the genitals of a sexual partner during oral sex. The newly caught infection is a genital herpes infection.

Recurrent outbreaks of genital herpes caused by HSV-1 are often less frequent than outbreaks caused by HSV-2 .

Neither HSV-1 nor HSV-2 survives well at room temperature. So the virus is not likely to spread through surfaces, such as a faucet handle or a towel. But kissing or sharing a drinking glass or silverware might spread the virus.

More Information

• Genital herpes: Can you get it from a toilet seat?

Risk factors

A higher risk of getting genital herpes is linked to:

• Contact with genitals through oral, vaginal or anal sex. Having sexual contact without using a barrier increases your risk of genital herpes. Barriers include condoms and condom-like protectors called dental dams used during oral sex. Women are at higher risk of getting genital herpes. The virus can spread more easily from men to women than from women to men.
• Having sex with multiple partners. The number of people you have sex with is a strong risk factor. Contact with genitals through sex or sexual activity puts you at higher risk. Most people with genital herpes do not know they have it.
• Having a partner who has the disease but is not taking medicine to treat it. There is no cure for genital herpes, but medicine can help limit outbreaks.
• Certain groups within the population. Women, people with a history of sexually transmitted diseases, older people, Black people in in the United States and men who have sex with men diagnosed with genital herpes at a higher than average rate. People in groups at higher risk may choose to talk to a health care provider about their personal risk.

Complications

Complications associated with genital herpes may include:

• Other sexually transmitted infections. Having genital sores raises your risk of giving or getting other STI s, including HIV / AIDS .
• Newborn infection. A baby can be infected with HSV during delivery. Less often, the virus is passed during pregnancy or by close contact after delivery. Newborns with HSV often have infections of internal organs or the nervous system. Even with treatment, these newborns have a high risk of developmental or physical problems and a risk of death.
• Internal inflammatory disease. HSV infection can cause swelling and inflammation within the organs associated with sexual activity and urination. These include the ureter, rectum, vagina, cervix and uterus.
• Finger infection. An HSV infection can spread to a finger through a break in the skin causing discoloration, swelling and sores. The infections are called herpetic whitlow.
• Eye infection. HSV infection of the eye can cause pain, sores, blurred vision and blindness.
• Swelling of the brain. Rarely, HSV infection leads to inflammation and swelling of the brain, also called encephalitis.
• Infection of internal organs. Rarely, HSV in the bloodstream can cause infections of internal organs.

Prevention of genital herpes is the same as preventing other sexually transmitted infections.

• Have one long-term sexual partner who has been tested for STI s and isn't infected.
• Use a condom or dental dam during sexual activity. These reduce the risk of disease, but they don't prevent all skin-to-skin contact during sex.
• Don't have sex when a partner with genital herpes has symptoms.

Pregnancy precautions

If you are pregnant and know you have genital herpes, tell your health care provider. If you think you might have genital herpes, ask your provider if you can be tested for it.

Your provider may recommend that you take herpes antiviral medicines late in pregnancy. This is to try to prevent an outbreak around the time of delivery. If you have an outbreak when you go into labor, your provider may suggest a cesarean section. That is a surgery to remove the baby from your uterus. It lowers the risk of passing the virus to your baby.

• Genital herpes: CDC detailed fact sheet. U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/std/herpes/stdfact-herpes-detailed.htm. Accessed Sept. 28, 2022.
• Genital herpes. Sexually Transmitted Infections Treatment Guidelines, 2021. U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/std/treatment-guidelines/herpes.htm. Accessed Sept. 28, 2022.
• AskMayoExpert. Simplex herpes virus (SHV) (adult). Mayo Clinic; 2022.
• Loscalzo J, et al., eds. Herpes simplex virus infections. In: Harrison's Principles of Internal Medicine. 21st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed Sept. 28, 2022.
• Schiffer JT et al. Herpes simplex virus. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Sept. 28, 2022.
• FAQs: Genital herpes. American College of Obstetricians and Gynecologists. https://www.acog.org/Patients/FAQs/Genital-Herpes. Accessed Sept. 28, 2022.
• Dinulos JGH. Sexually transmitted viral infections. In: Habif's Clinical Dermatology. 7th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 31, 2022.
• Symptoms & causes
• Diagnosis & treatment

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

• Opportunities

Mayo Clinic Press

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press .

• Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence
• The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book
• Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance
• FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment
• Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book

5X Challenge

Thanks to generous benefactors, your gift today can have 5X the impact to advance AI innovation at Mayo Clinic.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• BMJ Case Rep

Herpes simplex virus type 1: an atypical presentation of primary infection

Inês medeiros.

1 Paediatrics Department, Hospital de Braga, Braga, Portugal

Cristiana Maximiano

Teresa pereira.

2 Dermatology Department, Hospital de Braga, Portugal

Maria Miguel Gomes

Description.

A 3-year-old female child with personal history of atopic dermatitis presented with confluent vesicular and shallow ulcers pruritic rash surrounded by an erythematous base located to both hands and wrists, with 1-week evolution. She had no fever or other symptoms. There was no personal or family history of herpetic infections. Topical antibiotic, topical corticosteroid and oral antihistaminic were tried with no improvement. Physical examination was unremarkable except for generalised dry skin and lesions in figure 1 . On suspicion of superinfected viral rash or bullous impetigo she was treated with oral amoxicillin and clavulanic acid (concentration of 250 mg/62.5 mg with the dose of 50 mg/kg/day) and topical fusidic acid. One week later, at re-evaluation, there was progression of the rash ( figure 2 ) and the mother reported herpes labialis on the father. At this time, the diagnosis of primary eczema herpetic infection was also considered. Oral acyclovir (20 mg/kg every 6 hours for 5 days) and cefuroxime (30 mg/kg every 12 hours for 7 days) were started, with complete resolution of the lesions after 10 days. PCR assay of lesion’s swab was positive for herpes simplex virus (HSV) type 1 and bacterial culture was negative.

Grape-like clustered shallow ulcers in the dorsal surface of the left hand.

Confluent vesicles and shallow ulcers with bilateral localisation in both hands, grouped in the left hand and disseminated in the right hand.

HSVs cause a variety of illnesses, depending on the anatomic site where the infection is initiated, the immune state of the host and whether the symptoms reflect primary or recurrent infection. Common infections involve the skin, eye, oral cavity and genital tract. Infections tend to be unilateral, mild and self-limiting, except in the immunocompromised patient and newborns. 1 2

The authors want to emphasise the fact that the primary HSV infection can present in atypical forms, in which the lesions may be generalised, symptomatic, severe and with bilateral involvement. Therefore, this diagnosis should be considered in the differential diagnosis of other vesiculobullous diseases 3 .

Learning points

• Acute herpetic gingivostomatitis is the most common clinical presentation of herpes simplex virus (HSV) primary infection in children aged 6 months to 5 years.
• Eczema herpeticum is a rapid dissemination of an HSV infection over the eczematous atopic skin, prone to superinfection with Staphylococcus aureus or Streptococcus pyogenes .
• HSV PCR assay is the most sensitive method to confirm HSV infection.

Contributors: IM collected the data, wrote the manuscript and reviewed the literature. CM collected the data and reviewed the literature. TP and MMG did the critical review of the manuscript.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared

Patient consent: Parental/guardian consent obtained.

Provenance and peer review: Not commissioned; externally peer reviewed.

A review of HSV pathogenesis, vaccine development, and advanced applications

• Open access
• Published: 29 August 2024
• Volume 5 , article number  35 , ( 2024 )

Cite this article

You have full access to this open access article

• Lan Bai 1 , 2 ,
• Jiuzhi Xu 2 , 3 ,
• Linghui Zeng 4 ,
• Long Zhang 1 , 5 , 6 &
• Fangfang Zhou 4 , 7  

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Avoid common mistakes on your manuscript.

Introduction

The herpes simplex virus (HSV), a highly prevalent human pathogen with a global seroprevalence of 66%, comprises type 1 (HSV-1) and type 2 (HSV-2), primarily linked to orofacial and genital lesions respectively [ 8 , 9 ]. HSV infections are ubiquitous and covert, silently targeting mucosa and skin of all ages, and remaining latent in neurons for life. Approximately 80% of patients remain asymptomatic during the lytic infection, which leads to the narrow treatment window often being missed and the virus being unintentionally transmitted to partners or neonates, further exacerbating its spread [ 11 , 12 , 13 ]. Annually, approximately 14,000 neonatal infections worldwide originate from infected genital secretions during birth, leading to severe conditions such as neonatal encephalitis, pneumonia, and hepatitis, resulting in significant morbidity and mortality [ 14 ]. Unfortunately, HSV significantly elevates the risk of human immunodeficiency virus (HIV) infection by 3-4 times by eliciting an immune response within the genital tract that increases CCR5 receptor expression on CD4+ T cells, a key factor associated with HIV transmission [ 15 , 16 ]. HSV is also implicated in various cancers like cervical squamous cell carcinoma and adenocarcinoma, oral cancer and prostate cancer, as well as age-related disorders such as type 2 diabetes and neurodegenerative diseases [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ].

To date, there are no available cures or vaccines against HSV infections, making combating the disease and limiting its spread a challenge. However, medications such as acyclovir, valacyclovir, and ganciclovir have been widely used to control the symptoms, such as reducing viral shedding and shortening symptom duration [ 29 ]. Nevertheless, these only provide temporary relief as outbreaks can recur due to viral reactivation [ 30 , 31 ]. Over the past few decades, numerous studies have been conducted to develop a vaccine to prevent or treat HSV infections, which would also potentially decrease HIV and human papilloma virus (HPV) infections, yet an ideal vaccine candidate remains elusive [ 16 , 32 ]. This dilemma primarily arises from the intricate nature of HSV's pathogenesis and immune evasion mechanisms, which employ diverse pathways to evade host antiviral immune responses, presenting formidable challenges in identifying effective vaccine targets capable of eliciting and maintaining a robust immune response [ 15 , 33 , 34 ].

Nevertheless, looking at both sides of the coin, HSV's unique biological characteristics not only hinder profound research and vaccine development but also show immense promise as a versatile tool in clinical and scientific research. To be specific, HSV boasts a robust genetic load capacity, which endows it with potential applications in oncolytic virotherapy, gene therapy, and biological imaging [ 10 , 35 , 36 , 37 , 38 , 39 ]. Its neurotropism is crucial, enabling it to play a central role in the investigation of neuronal disorders [ 40 , 41 ]. HSV has also been utilized in vaccine carrier development and disease modeling. However, despite its vast potential for applications, many inherent risks and challenges persist, such as targeting and gene expression regulation abilities [ 36 , 43 ]. Thus, continued research into HSV is essential for gaining a comprehensive understanding of the virus, addressing existing limitations, and advancing the development of vaccines and applications.

In this review, we focus on HSV pathogenesis, encompassing biological characteristics, lytic and latent infections, reactivation, and virus-host immune interactions, with the aim of providing a thorough overview and in-depth insights that will contribute to the advancement of vaccine development for disease control and HSV-based tools. Additionally, we examine the recent progress in vaccine candidates and potential applications of HSV-based biological tools, highlighting their successes and challenges, with the aim of contributing to achieving control over HSV infection and harnessing its full potential as a versatile tool.

Pathogenesis of HSV

Structural and biological characteristics.

HSV is a double-stranded, DNA-enveloped virus. The DNA core is enclosed within an icosahedral protein capsid comprising 162 capsomeres that form a viral particle. The particle is further surrounded by a protein-rich unstructured matrix called a tegument, which contains several proteins associated with viral replication and immune evasion (VP16, UL36, and VP22). Enveloping the tegument is a lipid bilayer membrane decorated with 13 branched glycoproteins, including glycoproteins B, C, D, and E, that play crucial roles in viral invasion and immune evasion [ 44 , 45 , 46 , 47 , 48 ].

The HSV-1 genome consists of approximately 150 kilobase pairs (kbp); however, 284 open reading frames (ORFs) have recently been defined, which contradicts the previous results of 80 ORFs [ 49 ]. This significant difference underscores the immense complexity of the HSV genome and protein expression, posing significant challenges in understanding its pathogenesis and developing effective vaccines. Nevertheless, this also hints at the immense genetic load capacity of the HSV genome. The viral mRNA is synthesized by sequential transcriptional cascades under the regulation of viral factors, with the participation of the host cell RNA-polymerase II. HSV genes are categorized into three groups based on their expression order: immediate early genes (IE or α genes), early genes (E or β genes), and late genes (L or λ genes) [ 50 , 51 ]. IE genes are the first genes whose expression is regulated by tegument protein VP16. The products of IE genes are closely associated with lytic viral and latent infections. For instance, ICP0 and ICP4 play important roles in viral replication and expression of the E and L genes. E genes encompass β1 and β2 proteins, with β2 proteins mainly being responsible for viral nucleic acid metabolism, including thymidine kinase and DA polymerase. L proteins comprise viral structural proteins, such as glycoproteins, capsid proteins, and endometrial proteins, which are integral to viral attachment, entry, and antigenicity [ 52 ].

Lytic infection

Host-cell entry.

Primary infections typically target the mucosal epithelium, where many progeny are produced and released through cell lysis. Host cell entry mainly involves two pathways: post-attachment fusion (Fig. 1 ) and endocytosis and phagocytosis-like uptake, both of which involve multiple viral glycoproteins. During post-attachment fusion, the virus rides along the filopodia surface of the target host cell, facilitated by the binding of glycoproteins B and/or C (gB and/or gC) to heparan sulfate proteoglycans (HSPGs). This allows the virus to reach the cell surface, where viral glycoprotein D (gD) attaches to one of its specific receptors, thereby marking the attachment step [ 9 , 20 ]. The reported gD cellular receptors fall into three classes: herpes virus entry mediator (HVEM), nectin-1, nectin-2, and 3-O-sulfated heparan sulfate (Table 1 ). They are expressed in different cell types and act on various viral species [ 20 , 28 , 53 ]. Filopodia, key structures on various cell surfaces, express HSPG, increasing the likelihood of HSV attachment and enhancing infectivity [ 54 , 55 , 56 ]. Once attachment occurs, a signal is relayed to the glycoprotein H-L complex (gH-gL), activating gH and triggering a conformational change in the fusion gB from its pre-fusion to post-fusion state. Activated gB is inserted into the cell membrane, and facilitates the fusion of cells and viral membranes, followed by the creation of a pore in the cell membrane, which allows the viral capsid to enter the cytoplasm by refolding [ 9 , 57 , 58 , 59 ]. Other studies have shown that gB initiates membrane fusion by binding to its receptors [ 54 ]. The gB receptors have three types: paired immunoglobulin-like type 2 receptor-α, an inhibitory receptor located on macrophages, dendritic cells (DCs), and monocytes; a myelin-associated glycoprotein present on glial cells; and non-muscle myosin heavy chain II found on human tissues (Table 1 ). Alternatively, HSV can enter host cells via endocytosis and phagocytosis-like uptake. HSV specifically binds to the gD receptor localized in the endosome, activates Rho GTPase, and rearranges the cytoskeleton, ultimately leading to fusion with the endosomal membrane [ 54 , 60 ].

Host cell entry and transmission of HSV. (1) HSV gD interacts with a specific cellular receptor, initiating a cascade that activates gH and gB (not shown). (2) gB leads to fusion at the plasma membrane. (3) The capsid, accompanied by tegument proteins, is released into the cytoplasm, where it traverses to the cell nucleus along microtubules, which is facilitated by the interaction between UL36 and motor proteins. Subsequently, the linear DNA is released into the nucleus and converted into a circular genome. (4) Meanwhile, tegument protein VP16 detaches from the capsid and independently enters the nucleus, where it starts the transcription of IE genes by recruiting host cell factors. (5) The IE genes are translated and participate in the transcription of E genes. (6-7) The E genes are translated and take part in the replication of the viral genome and start transcription of L genes. (8) Once a sufficient number of viral genome copies are attained, the products of the L genes aid in the process of DNA encapsidation. (9) The mature virus leaves the nucleus via an envelopment-deenvelopment process, acquiring tegument and envelope (not shown) prior to cellular egress. (10-11) Two major modes of HSV transmission, a virion within a vesicle traffics either to the cell surface and extracellular space, for CFR to infect neighboring or distant cells by recognizing specific receptors, or to the cell-cell junctions, for CCS to target adjacent cells via receptors or other factors, for release by exocytosis. CCS, cell-cell spread; CFR, cell-free release

As previously stated, filopodia formation and HSPG play crucial roles in HSV reaching the cell surface, gD mediates viral attachment or direct membrane fusion, and the heterodimer gH-gL and viral fusion gB are a set of core entry glycoproteins that are conserved in all herpes viruses. In summary, these proteins are required for cell entry. Blocking the virus at the entry step is a beneficial and broad strategy for developing vaccines and antiviral drugs, and several types of HSV substances targeting these targets have been developed, such as anti-HSPG peptides, anti-HSV.

antibodies, vaccines targeting glycoproteins, and inhibitors [ 54 ]. However, it is necessary to uncover the underlying cellular and molecular mechanisms of HSV infection and filopodia generation to better understand viral pathogenesis and promote the development of novel therapeutic strategies and more effective viral tools.

Genome expression

After the viral capsid and tegument enter the target cytoplasm, inner tegument proteins collaborate with host actin and myosin to facilitate the retrograde transport of the viral capsid along microtubules towards the nuclear pore, where the viral genome is released into the nucleus through rearrangement of the capsid proteins. Upon nuclear entry, viral DNA is promptly coated with histones and cellular repressors, serving as anchors for the assembly of nuclear domain 10 (ND10) bodies, which silence viral DNA. To fully express its function, HSV must overcome host suppression. Remarkably, the outer tegument proteins VP16, VP22, and pUL36 independently migrate to the nucleus before the genome, initiating viral DNA expression [ 47 , 51 , 61 , 62 , 63 , 64 , 65 , 66 ]. As mentioned above, viral genes are expressed in a cascade because of sequential derepression, evolved to maximize viral yield while minimizing host interference with viral DNA and protein synthesis, viral assembly, and elimination from the infected cells [ 67 ].

IE genes are derepressed when VP16 recruits host cell factor 1 (HCF1), octamer binding protein 1 (Oct-1), and lysine -specific demethylase 1 (LSD1) to their promoters. This recruitment initiates the transcription of IE genes, including ICP0 , ICP4 , ICP22 , and ICP27 , via the cellular transcriptome (Fig. 2 a) [ 68 , 69 , 70 ]. Moreover, the E and L genes are suppressed by ND10 bodies and the HCLR repressor complex, which is composed of histone deacetylases (HDAC1 or HDAC2), Co-RE1 silencing transcription factor (CoREST), LSD1, and REST. ICP0, however, disrupts this repression mechanism by binding to CoREST and displacing HDAC, leading to the release and transcription of E and L genes. Notably, ICP0, which possesses RING-finger E3 ubiquitin (Ub) ligase activity, can also degrade ND10 bodies (Fig. 2 b,c) [ 71 ]. To express genes, viral DNA must be derepressed by modification of repressive histones, cellular repressors, and ND10 coating the viral DNA; VP16 and ICP0 are two key viral players.

Genome expression. a The linear viral DNA is released into the nucleus and is promptly silenced by histones, HCLR repressor, and ND10 bodies. b The tegument protein VP16 recruits host factors HCF1, Oct-1, and LSD1 to their promoters to initiate the transcription of IE genes, including ICP0, ICP4, ICP22, and ICP27. c The IE protein ICP0 disrupts HCLR repressor by binding to CoREST and displacing HDAC, and degrades ND10 bodies via RING-finger E3 ubiquitin ligase activity, thereby leading to the releases and transcription of E and L genes. HCF1, host cell factor 1; Oct-1, octamer binding protein 1; LSD1, lysine specific demethylase 1; HDAC, histone deacetylase; CoREST, Co-RE1 silencing transcription factor; ND10, nuclear domain 10

ICP0 in the cytoplasm not only directly modulates genome expression but also facilitates viral replication by blocking host responses, such as the inactivation of IRF3 [ 72 ]. Furthermore, studies have revealed that pUL16 and pUL21 interact with nuclear pore complexes to interfere with capsid docking, which may prevent the production of progeny virions [ 73 ]. Currently, no antiviral drugs targeting ICP0, VP16, VP22, or UL21 exist. Nevertheless, studying these targets from diverse perspectives is crucial for enhancing our understanding of their mechanisms and facilitating the development of vaccines. Additionally, it aids in the precise regulation of exogenous gene expression during gene therapy.

Transmission

Progeny virions egress from the host cell and continue to infect new target cells via two pathways: cell-cell spread (CCS) and cell-free release (CFR) [ 74 , 75 , 76 , 77 ]. In CCS, viral particles are directly delivered to the cellular junctions to target adjacent cells (Fig. 1 ). The CCS tends to infect highly polarized cells, such as epithelial cells, as it guards virions against neutralizing antibodies and other soluble immunological factors. The highly directed nature of CCS likely enhances infection efficiency [ 74 , 78 ]. In contrast, CFR involves the release of viral particles into the extracellular space, allowing them to travel and infect neighboring or distant cells by recognizing specific receptors (Fig. 1 ). CFR channels are critical for viral transmission between distant cells and hosts. Nevertheless, similar to other numerous enveloped viruses, HSV primarily relies on the efficiency and protective nature of CCS to disseminate the infection [ 79 ].

Although the precise mechanism of HSV transmission among cells remains unknown, studies have shown that several viral and host proteins are required [ 80 , 81 , 82 ]. Once the viral particle attains infectivity, that is, the nucleocapsid is enveloped in a vesicle, the vesicle will signal the cell periphery, either to the cell-cell junction for CCS or to the cell surface for CFR, where the mature virion is released through exocytosis [ 79 ]. In CCS, the progeny are released into the cell-cell junction, facilitating efficient interaction with host entry receptors. Nectin-1, a major entry receptor for gD, accumulates at these junctions, thereby promoting CCS. Notably, nectin-1 also functions as a host-adhesion transmembrane protein that mediates cellular adhesion (Fig. 1 ). This suggests that the virus may exploit these host proteins as binding receptors to infect adjacent cells [ 53 ]. In addition, several glycoproteins and tegument proteins have been reported to play a role in CCS. For example, the glycoproteins E and I (gE and gI, respectively) promote virion delivery [ 79 ]. Deletion of amino acids 167–244 in pUL51 or ablation of pUL7 expression hinder the concentration of gE at the junctional surfaces of Vero cells [ 80 ]. In the absence of gC, progeny virions bind more tightly to infected cells, indicating that gC facilitates virion detachment from infected cell surfaces. Consequently, gC also enhances the release of cell-free progeny virions at the end of the infectious cycle [ 83 ]. Similarly, glycoproteins K, M, and N (gK, gM, and gN) and tegument proteins UL11, UL16, and VP22 also participate in the transmission mechanism [ 20 , 79 ]. In contrast, in CFR, the progeny traverse the plasma membrane via host-directed pathways involving Rab6a, Rab8a, and Rab11 and are then expelled into the extracellular environment through exocytosis [ 79 ]. Although certain viral and cellular factors have been implicated in CFR, the potential mechanisms remain poorly understood. One such viral factor is ICP27, as evidenced by the decreased CFR observed in ICP27 mutants [ 84 ]. Other factors, such as gC and host protein tyrosine phosphatase, are important for the spread of HSV-1 CFR [ 81 ]. ICP27-gC forms a regulatory axis that induces CFR specifically in tissues linked to reactivation, drawing parallels from the behavior of human cytomegalovirus, varicella-zoster virus, and Marek’s disease virus [ 79 ]. Furthermore, CFR and CCS engage in significant competition during vesicular formation and trafficking, as evidenced by the unusually high levels of CFR exhibited by the CCS-deficient gE mutant [ 80 ].

Recently, HSV-1 was reported to employ extracellular vesicles (EVs) for packaging and delivering viral components or infectious virions, significantly enhancing its transmission efficiency [ 85 , 86 ]. HSV-1 hijacks the cellular vesicular secretion system and promotes EV secretion from infected cells. Previous studies have revealed that non-infectious EVs secreted by HSV-1-infected cells possess antiviral effects against HSV-1 due to their containment of host-restrictive factors, including STING, CD63, and Sp100 [ 87 , 88 , 89 ]. However, a recent study showed that Oct-1, a nuclear-localized transcription factor that initiates genome transcription, is packaged in non-virion-containing EV and exported from HSV-1- infected cells, which is then immediately transported into the nucleus of recipient cells to promote the subsequent round of HSV-1 infection [ 90 ]. EV-associated Oct-1 can enhance viral dissemination, and underline the heterogeneous nature and complexity of these non-infectious double-lipid particles in the HSV life cycle.

Determining how these cellular and viral factors modulate the CCS and CFR is important. Blocking the spread of viruses between cells and hosts by targeting CCS or CFR can greatly reduce viral transmission, alleviate HSV diseases, and prevent serious inflammatory complications and clinical and subclinical symptoms. The efficient transmission of HSV is of paramount importance for its utilization as an oncolytic virus in tumor therapy and as a tracer.

Latent infection

Although most viruses are cleared by immune responses induced by lytic infection, a portion can escape host immunity, and access the nucleus of sensory neurons, and establish latent infection. HSV-1 commonly resides latently in the trigeminal ganglion (TG), whereas HSV-2 remains latent in the dorsal root ganglia (DRG). Currently, the molecular mechanisms of HSV latent infection are not clear, but three urgent issues need to be understood, as outlined below, to inform the development of antiviral drugs or vaccines.

First, what causes HSV to undergo latent infection? However, this topic remains largely unexplored. Available data suggest that the choice between latent and lytic infections is a stochastic process spanning several days rather than an instant decision upon HSV-1 entry into the TG from the cornea. The initial step towards establishing a latent infection, which is silencing, occurs very early, possibly during retrograde transport to neurons. Latency-associated transcripts (LATs) and microRNAs (miRNAs) are key factors in establishing latency and accumulate over a prolonged period [ 68 ]. In essence, the decision to develop a latent infection occurs early and is regulated by a combination of various factors rather than a singular event.

Second, the mechanism by which HSV invades neurons remains unclear. There are several assumptions regarding neuron entry. It is widely accepted that the axon terminus near the peripheral epithelial cells is the initial site of HSV-1 attachment in neurons (Fig. 3 ) [ 91 ]. However, some studies have suggested that HSV-1 directly enters the cell body via membrane fusion [ 61 ]. Other studies suggest that HSV-1 enters neurons through a pH-independent fusion process between its envelope and the neuronal plasma membrane [ 92 ]. In contrast, studies have shown that nectin-1 is the main receptor in neurons, facilitating receptor-dependent membrane fusion and entry into epithelial cells [ 93 , 94 ].

Establishment of HSV latency and reactivation in neurons. After primary infection in the epidermis, HSV enters sensory nerves innervating the skin or mucosa, undergoes retrograde axonal transport to reach the trigeminal ganglion, where it establishes a lifelong latent infection. The capsid containing pUL36 and other inner tegument proteins travels to the nucleus independently from tegument proteins like VP16. This process, together with histones and histone-modifying enzymes within nucleus, leads to DNA silencing. Conversely, the LAT gene sustains transcription and accumulation. Upon reactivation, HSV replicates and travels either via anterograde axonal transport to the peripheral epidermis, causing recurrent herpes, or retrograde axonal transport to the central nervous system, potentially leading to encephalitis or maintaining latency. CNS, central nervous system; DRG, dorsal root ganglia

As the virus and tegument proteins enter the neurons, the outer tegument proteins dissociate into the cytoplasm, whereas the inner tegument proteins (VP1/2, UL36, and Us3) travel together with the nucleocapsids along nerve fibers to the nucleus of sensory neurons by interacting with the actin cytoskeleton (Fig. 3 ) [ 92 ]. Now, a pivotal question arises: What mechanism does the HSV rely on for its movement? Pegg found that the pUL36 protein can “hijack” dyneins and kinesins, causing them to leave epithelial cells and enter neural cells, thereby enabling HSV-1 transport from the cytoplasm to the nucleus along the meridian axis [ 95 ]. Rickard and Sollars demonstrated that pUL37 is also essential for the virus to move along nerve fibers, and mutated viruses with modified pUL37 region 2 (R2) cannot penetrate deep into the nervous system, but instead become stuck at the end of the nerve [ 96 ].

Based on these results, there is a new idea for the development of HSV vaccines against latent infections. The effectiveness of an R2-modified HSV-1 live virus vaccine against HSV-2 infection in guinea pigs was evaluated, exhibiting remarkable superiority. The release time of HSV was shortened from 29 days to approximately 13 days, and HSV-2 was undetectable in the neurons. Simultaneously, the neutralizing antibody level was three-fold higher than that of the other candidate vaccines [ 96 ]. The R2 vaccine can block HSV entry into the nervous system, thereby avoiding latent infection and neurological complications, which has significant implications for future vaccine development efforts.

Lastly, how does HSV establish and sustain a latent infection? The nature of latent infection is to maintain viral DNA silencing and block the expression of a large number of genes. HSV DNA is known to be silenced in heterochromatin during latent infection, and according to current reports, the reasons may be related to the following aspects. First, owing to the absence of HCF1 and VP16 in the neuronal nucleus, viral DNA undergoes gradual silencing by histones and histone-modifying enzymes within the nucleus, leading to heterochromatin. Some studies have indicated that HCF1 and VP16 are retained in the axons or cytoplasm, preventing their translocation to the neuronal nucleus to overcome heterochromatin and initiate transcription. Another hypothesis is that the distinctive neuronal architecture leads to the inefficient axonal transport of virion-associated regulatory factors [ 97 , 98 , 99 , 100 ]. Second, host immunity plays an important role in establishing and maintaining latency. Knipe and Sodroski discovered that interferon-inducible protein 16 (IFI16) restricts gene expression and replication of a nuclear DNA virus by maintaining or preventing the removal of repressive heterochromatin [ 101 ]. This study defines the impact of nuclear interferon-stimulated genes (ISGs) and provides the foundation for future antiviral strategies related to nuclear epigenetic silencing [ 101 ]. Additionally, the reactivation rate of latent infection in the central nervous system (CNS) is relatively low, possibly because of the robust immune response against HSV, which is exacerbated by the immune surveillance of microglia and astrocytes, which express a range of toll-like receptors (TLRs) [ 102 ]. Moreover, HSV latency in the human TG is related to T-cell accumulation, specifically the persistence of CD8+ T cells in the ganglia, which is likely triggered by parenchymal cells [ 103 ]. Third, there is a consensus that a neuron-specific promoter in the viral genome drives the expression of LATs, which play a major role in enhancing latency reactivation because viruses lacking LAT reduce latency and reactivation [ 104 ]. During latency, LAT produces multiple miRNAs, and two small non-coding RNAs (sncRNAs) [ 71 , 105 ]. These miRNAs can interfere with viral and cellular gene expression, and several HSV-1 miRNAs can suppress the expression of key lytic regulatory factors, such as ICP0, ICP4, and ICP34.5 [ 106 ]. This suggests that miRNAs stabilize latency by mitigating the cytotoxic effects of spurious viral protein expression levels [ 107 , 108 ]. miRNAs are also likely to target multiple host mRNAs, thereby altering the neuronal environment or suppressing antiviral responses. For example, MiR-138 can simultaneously regulate ICP0, Oct-1, and FOXC1 in the host to inhibit the expression of viral lytic genes, thereby creating favorable conditions for HSV latency [ 89 ]. Neuronal MiR-9 can facilitate HSV epigenetic silencing and latency by suppressing Oct-1 and Onecut genes, as the nonspecific binding of Onecut with viral genes effectively decreases viral heterochromatin and increases the accessibility of viral chromatin [ 109 ]. The sncRNAs not only have anti-apoptotic activity but also induce HVEM overexpression by activating its promoter [ 54 , 110 ]. HVEM plays a role in HSV latency and reactivation by controlling apoptosis and T cell activation and independently binding to gD [ 111 , 112 ]. Overall, these results suggest that LAT helps establish and maintain HSV's long-term latent infection in the host by preventing neuronal apoptosis and suppressing host immune responses [ 113 ]. Nevertheless, some studies have found that LAT-mutant viruses can promptly achieve latency, albeit with a reduced number of neurons overall and fewer neurons harboring the virus, indicating that LAT may not be the sole determinant of latency or neuronal survival [ 114 , 115 ]. Finally, HSV may express non-coding RNAs such as LATs and miRNAs, which are the only abundant viral gene products during latent infection. However, one study has reported that ICP0 is expressed and regulates viral chromatin to optimize latent infection during the establishment and maintenance of latent infection in mice [ 116 ]. Given its dual role, ICP0 may be a viable target for antivirals designed to combat both lytic and latent infections.

Although numerous hypotheses exist regarding the establishment and maintenance of latent HSV infections, the molecular mechanisms underlying neuronal latency remain unclear. One such controversial topic is whether neurons serve as immunologically privileged sites for HSV, enabling the virus to evade host antiviral responses. The latency of HSV is a complex phenomenon, either active or passive, resulting from either the host immune system successfully suppressing the virus from reaching nerve cells, or the virus actively entering a resting state within these cells to evade antiviral immunity. Furthermore, the nature of latency remains unclear, whether instantaneous or continuous, involving questions about whether low-level virus production persists and whether accumulated LAT and other products can disseminate to neighboring cells, thereby retaining infectivity. These questions can only be answered by relying on research. Hopefully, the mechanisms can be fully understood, and breakthroughs can be found to block HSV latency infection in neurons or virus recurrence.

Reactivation

Sporadic reactivation events of latent infections occur within the host’s lifetime, particularly in immunodeficient individuals. These reactivation events exhibit remarkable heterogeneity, even within a single individual, in terms of position, intensity, and duration. Typically, the progeny virus travels to the site of primary infection or the neural system, potentially leading to viral shedding and transmission to other tissues or hosts. In some cases, it can initiate productive infections in the brain, resulting in encephalitis if they find their way to the CNS (Fig. 3 ) [ 54 , 79 , 117 , 118 , 119 ]. Currently, the mechanisms by which host and viral factors affect the HSV latent-lytic switch are partially understood. The nature of HSV reactivation involves extensive chromatin reorganization modulated by various factors to ensure adequate levels of viral gene expression for replication. Additionally, the virus must overcome antagonistic host responses to successfully transition from a latent to an active state. The broadly accepted view is that reactivation events are triggered by diverse stress signaling pathways, which can alter the silencing of histone modifications and initiate the transcription of viral genes [ 120 , 121 ].

However, what are the stresses, and how do stress-signaling pathways trigger HSV reactivation? First, stress (acute, episodic acute, or chronic), fever, UV light, and heat stress can elevate the frequency of reactivation in humans by activating the glucocorticoid receptor (GR) [ 122 ]. GR exerts anti-inflammatory and immunosuppressive effects by inhibiting the transcriptional activity of protein 1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This mitigates T cell activation, limits T helper subsets expansion, reduces T-cell co-stimulation, dampens innate immune and pro-inflammatory responses, and ultimately hinders the spread of viruses to peripheral cells and tissues [ 123 , 124 , 125 ]. Additionally, approximately 50% of TG sensory neurons express the GR, indicating that GR activation can directly induce reactivation from latency by stimulating viral gene expression [ 122 , 126 ]. Second, the GR and specific stress-induced cellular transcription factors stimulate viral promoters, driving the expression of key viral transcriptional regulators such as ICP0, ICP4, ICP27, and VP16 [ 122 ]. ICP0 is a protein normally involved in reactivation and is rarely expressed during latent infection. Once latent infection is broken and reactivation begins, ICP0 performs epigenetic regulation of the viral genome and promotes viral replication. ICP0 inhibits the host immune defense and interacts with the Ub pathway to foster an environment conducive to lytic infection and reactivation of viral genomes from latency, relying on its RING finger E3 ubiquitin ligase activity [ 127 ]. ICP0 also disrupts ND10 structure and dissociates HDAC 1 and 2 from CoREST/REST to relieve repression, as mentioned in “Genome expression” [ 128 , 129 ]. VP16 binds to the promoters of IE genes to initiate transcription, and concurrently, ICP0 and ICP4 are expressed as IE proteins, further stimulating the expression of E and L genes [ 68 , 122 , 130 ]. Third, HSV reactivation is caused by the loss of trophic support and the need to find a new foothold. Many cell types secrete nerve growth factor (NGF), the first identified neurotrophic factor that aids in neurite outgrowth, thereby facilitating HSV transmission and infection [ 131 , 132 , 133 ]. HSV-1 reduces the repulsive effect of epithelial cells on neurite outgrowth, particularly in the presence of NGF, whereas HSV-2 gG increases neurite outgrowth, thereby facilitating the spread of HSV to neurons [ 133 , 134 , 135 ]. Studies have demonstrated that applying anti-NGF antibodies to the eyes of rabbits with latent infection results in viral shedding, which aligns with increased reactivation [ 136 ]. Finally, host signaling pathways are vital in reactivation. Notably, during a de novo infection, cellular stress conditions exert a prolonged impact on neurons or the viral genome, effectively enhancing the reactivation potential. As an example, the c-Jun signaling pathway commences its regulatory function during the initial HSV-1 infection. It not only boosts the reactivation capacity by adjusting latency but also directly propels HSV-1 towards a fully reactivated state. However, the precise mechanism behind how the viral genome or neurons retain a memory of prior cellular stresses remains unclear [ 137 , 138 ]. Furthermore, single-cell sequencing (scRNA‐seq) of reactivated neurons reveals that DNA damage–inducible 45 beta (Gadd45b), a host stress sensor, functions as a novel neural determinant for HSV-1 reactivation. Its subcellular localization correlates with ICP 4 expression, potentially serving as a predictive marker for successful reactivation [ 139 ].

Another issue worth discussing is the factors influencing the heterogeneity of HSV reactivation events. The prevailing assumption is that the degree of reactivation is positively correlated with the number of viruses invading during lytic infection and the quantity of latent viral DNA in nerve cells, which may be due to the high latency and relatively high reactivation potential and proportion [ 97 , 140 ]. However, several studies have implicated host immune cells in playing a significant role in the reactivation of HSV-2 within the epithelium [ 141 ]. For example, HSV-2-specific tissue-resident memory CD8+ T cells (TRMs), a subset of CD8+T cells, are crucial for controlling viral reactivation and act as rapid responders to prevent reinfection or reactivation [ 142 , 143 , 144 ]. However, TRMs are not uniformly distributed in tissues, but rather clustered in hetero-dispersed aggregates at the dermal-epidermal boundary. Occasionally, they may not be well positioned to promptly contain the emergence of HSV-2, allowing latent viruses in different locations to evade immune control with varying probabilities, leading to heterogeneity [ 145 ]. The strength and duration of epithelial reactivation events are primarily determined by the temporal and spatial limitations placed on TRMs in containing each reactivation [ 79 ]. Moreover, the concentration of CD8+ T cells in the genital mucosa reliably predicts the duration and severity of viral reactivation, consistent with the recurrence tendency in immunodeficient individuals [ 141 ].

For every HSV genome that generates an infectious progeny, a greater number will likely recur but fail at some point. As viruses strive to overcome these reactivation obstacles, viral activity increases, and the likelihood of a robust counter-response from the host rises and progresses to each successive stage. The competition between the virus and the host revolves around maximizing viral production while carefully gauging the host’s capacity to support critical processes, such as DNA replication, virion synthesis, or dissemination to epithelial cells, to prevent the elimination of infected neurons without producing new viruses. These studies have identified some cellular factors, viral regulatory proteins, and signaling pathways that regulate reactivation, and further research is imperative to delve deeper into these mechanisms. Such explorations may reveal potential drug targets or novel therapeutic strategies aimed at reducing the frequency of reactivation due to latency and potentially new application opportunities.

Host immune responses and virus immune evasion

Upon infection, innate immune responses are induced by viral antigens, serving as the first line of defense against HSV while fostering the emergence of adaptive humoral and cellular responses for long-term immunity. Nevertheless, certain viruses skillfully evade antiviral immune responses, invading and replicating successfully and establishing latency and reactivation [ 141 ]. HSV constantly competes for host immunity, apparently winning because the virus has successfully established a complete lifecycle. Consequently, exploring HSV immune evasion strategies holds immense significance, and it is worth comprehending the intricate immune interplay between HSV and the host, paving the way for the development of an effective vaccine capable of eliciting a robust immune response.

Innate immunity

The innate immune system induces the initial response to HSV infection [ 15 ]. Host cells sense invading viruses via cellular pattern recognition receptors (PRRs) to elicit antiviral innate immune defense. PRRs can be generally categorized into several distinct families, including TLRs, RIG-like receptors, NOD-like receptors, C-type lectin receptors (CLRs), AIM2-like receptors, and cyclic GMP-AMP synthase (cGAS). These PRRs recognize a wide range of pathogen-associated molecular patterns derived from bacteria, viruses, fungi, and protozoa, as well as danger-associated molecular patterns. PRRs can recognize nucleic acids. Among them are DNA sensors, such as endosomal TLR9, cytosolic absent in melanoma 2 (AIM2), IFI16, DNA-dependent activator of interferon-regulatory factors (DAI), and cGAS. RNA sensors include TLR3, TLR7, TLR8, cytosolic retinoic acid-inducible gene I(RIG-I), melanoma differentiation-associated protein 5, NLR family pyrin domain containing 3, and nucleotide-binding oligomerization domain-containing protein 2. TLR2 recognizes viral glycoproteins [ 146 ]. Once these antigens are sensed, PRRs activate their adaptors, downstream interferon regulatory factors (IRFs), and NF-κB, leading to the expression of cytokines, chemokines, major histocompatibility complex (MHC), and co-stimulatory molecules to interfere with viral replication. Notably, type I interferons (IFN-α and IFN-β), a subgroup of cytokines, induce the expression of multiple ISGs, thereby creating an antiviral state in infected and surrounding cells, which blocks viral infection and limits its transmission, leading to an antiviral response by guiding IFN-responsive genes on adjacent cells to bind to the IFNα/β receptor and activate the JAK-STAT pathway to inhibit viral replication [ 101 , 147 , 148 ]. In addition, PRRs can trigger signal transduction and induce cellular processes, such as phagocytosis, autophagy, cell death, and inflammasome activation. These processes collaborate with the innate immune response to create a comprehensive network of antiviral host defense mechanisms (Fig. 4 ) [ 146 ].

The host innate immunity and immune evasion mediated by HSV. TLRs, located at both the plasma membrane and endosomes, sense different ligands such as viral dsRNA, dsDNA, and glycoproteins. RLRs such as RIG-I and MDA5 detect RNA structures, and the cGAS-STING pathway senses dsDNA. They all activate IRF3 or NF-κB, inducing IFN-I and inflammatory cytokines. IFN-I stimulates ISG expression via the JAK-STAT pathway to limit HSV. NLRs such as AIM2 and DAI recognize dsDNA and lead to apoptosis and autophagy. The IFN-I, inflammatory cytokines, cellular responses and ISGs are induced for antiviral immunity, but HSV proteins highlighted in the red box can hijack multiple downstream steps of these signaling pathways, effectively suppressing these immune reactions. CBP, CREB-binding protein; P, phosphate

However, to ensure long-term survival and generate significant progeny from infected cells, HSV employs diverse countermeasures, encompassing transcription shutoff, protein degradation, interaction competition, and enzymatic activity disruption, all of which involve multiple viral proteins, particularly IE proteins, tegument proteins, and other functional proteins, to evade host antiviral responses (Fig. 4 ) [ 52 ]. For instance, in the STING pathway, the HSV-1 UL37 tegument protein targets cGAS by deamidating an asparagine residue, thereby limiting the synthesis of cGAMP. Additionally, UL41 degrades cGAS via RNase activity, effectively evading the cGAS/STING-mediated DNA-sensing pathway [ 149 , 150 ]. Furthermore, the downstream events of the cGAS-STING and DAI-STING are shared, which can be inhibited by the serine protease activity of HSV-1 UL24 to impair NF-κB activation [ 151 ]. In the TRAF3-TBK1-IRF3 pathway, UL36, a ubiquitin-specific protease, deubiquitinates TRAF3, thereby hindering stimuli-induced IRF3 dimerization and nuclear translocation, ultimately inhibiting IFN-β transcription [ 152 ]. Moreover, VP24 targets TBK1, hampering IRF3 phosphorylation, leading to the impairment of IFN-I generation and subsequent repression of ISGs in infected and nearby cells [ 153 , 154 ]. As for RIG-I, the viral kinase Us3 specifically phosphorylates RIG-I, effectively blocking downstream signaling [ 155 ]. In addition, UL37 directly blocks the function of RIG-I by deamidating its helicase domain, a crucial component for sensing dsRNA products [ 156 ]. Myeloid differentiation primary response 88 (MyD88) is triggered by both TLR2 and TLR9, leading to the activation of NF-κB and type-1 IFN. ICP0, independently of other viral factors, effectively blocks the downstream signaling of MyD88 and reduces the levels of both MyD88 and its adaptor-like protein (Mal) through its E3 Ub ligase activity and cellular proteasomes [ 157 , 158 ]. Conversely, ICP27 modulates the STAT-1 pathway by disrupting STAT-1 phosphorylation and nuclear accumulation [ 159 ]. Additionally, HSV-1 suppresses the activity of antiviral restriction factors by manipulating peptidylarginine deiminases (PADs). For example, HSV-1 infection enhances the citrullination of IFIT1 and IFIT2, which are induced by IFN and play crucial roles in antiviral and immunomodulatory responses [ 160 ]. In contrast, HSV interferes with cellular responses, as exemplified by ICP34.5, which binds to Beclin-1 and inhibits Beclin-1-dependent autophagy, a crucial antiviral mechanism, particularly within the nervous system [ 161 ].

During HSV infection, PRRs dynamically detect a range of molecular patterns throughout the viral life cycle, including the DNA genome, transcription-derived RNA species, unmasked cellular RNA, proteins, and peptides. This triggers innate immune signaling. Strategies that interfere with these manipulations could lead to novel antiviral therapies, and immune modulatory-deficient HSV mutants offer promising candidates for vaccines and oncolytic viral strains, further emphasizing the translational value of basic research. Notably, while PRRs recognize various viral components to induce type-1 IFN and thereby limit viral infection, they may also contribute to exacerbated inflammatory responses, such as brain inflammation and corneal infectious blindness [ 162 ]. Therefore, managing appropriate levels of inflammation or immunity is a crucial consideration for the future development of strategies targeting HSV and its associated complications.

Adaptive immunity

Unlike the innate immune system, adaptive immunity (humoral and cell-mediated responses) targets the pathogen and is more sophisticated, conferring enduring protection and playing a pivotal role during the early stages of infection, latent infection, and reactivation via CD4 and CD8 T cells in the genital tissue [ 163 , 164 , 165 ]. Upon HSV infection, DCs process viral antigens and migrate to the lymph nodes to present these antigens to activate T cells. During HSV infection, macrophages also contribute to the processing of HSV antigens and presentation to T cells. Moreover, the M1/M2 macrophage balance may influence HSV-induced cytokine production and eye disease in mice [ 166 ]. HSV-specific T cells are found in both active and healed lesions as well as in infected sensory human ganglia [ 121 ]. CD4+ T cells are mainly involved in primary infection, whereas CD8+ T cells contribute significantly to immune responses during latent genital herpes infection and recurrence, which is supported by the fact that the depletion of CD8+ T cells results in higher reactivation rates [ 167 , 168 ]. Activated CD4+ T cells flow into the genital tissue in a CCR5-CCL5-dependent manner, peaking 1 week after infection. They orchestrate the anti-HSV adaptive immune response and assist B cells in antibody production. HSV-specific CD8+ T lymphocytes produce numerous cytolytic molecules that eliminate infected cells through cytotoxic T lymphocyte responses and release IFNs in response to viral antigens [ 121 ]. Although CD8+ T cell infiltration into vaginal tissue is limited under homeostatic conditions, TRMs respond quickly to HSV recurrence in an IFN-γ dependent manner, constituting the primary immune response in recurrent human infections [ 141 , 166 , 169 , 170 ]. Moreover, MHC class 1 and T cell receptor engagement occur at the contact region between neurons and memory CD8+ T cells (Fig. 5 a) [ 171 ]. However, CD8+ T cells did not respond to LATs. TRMs exhibit uneven distribution in tissues and, in certain instances, fail to contain the virus promptly [ 169 , 170 , 172 , 173 , 174 ]. Consequently, the virus can seize this opportunity to evade immune surveillance, leading to reactivation and transmission [ 145 ]. Moreover, studies of herpes keratitis and herpetic stromal keratitis have shown that Tregs play a beneficial role in minimizing viral immunological lesions. By inhibiting the proliferation of CD4 and CD8 T cells and suppressing the release of inflammatory cytokines and chemokines such as IL-2, IL-6, and CCL3, Tregs mitigate the generation, migration, and harmful effects of pathogenetic T cells on the cornea [ 166 , 175 ].

The host adaptive immunity and immune evasion mediated by HSV. a DC processes viral antigens and migrates to draining lymph nodes to present these antigens to activate CD8 T and CD4 T cells, thereby triggering both humoral and cellular responses. CD4 T cells produce Th1 cytokines that stimulate CD8 T cells, inducing CTL to eliminate infected cells, and Th2 cytokines can aid in the differentiation of B cells, leading to antibody production. Memory T cells continuously monitor HSV-infected neurons, and are ready to respond to reinfection. Meanwhile, memory B cells can produce a wide range of virus-specific antibodies, effectively limiting the potential for reinfection. However, HSV proteins such as ICP22 and ICP47, highlighted in the red box, can reduce MHC levels and inhibit the activation of T cells, thereby suppressing adaptive immunity. b gC can inhibit the complement system by binding to C3b. Since gE functions as a FcγR and binds with IgG, C1q cannot bind to gE, thus suppressing the complement system, and the virus-specific antibodies cannot recognize HSV and NK cells, resulting in suppression of antibody responses and ADCC. DC, dendritic cell; NK, natural killer cells; ADCC, antibody-dependent cell-mediated cytotoxicity

In addition to the escape time window of the host immune system, HSV has evolved various immune escape mechanisms to avoid clearance and subsequent recurrence. For instance, HSV employs ICP47, which targets transporters linked to antigen processing in the endoplasmic reticulum. This leads to reduced antigen presentation on MHC-I molecules by DCs. ICP47 impedes antigen translocation to this organelle, preventing the loading of viral antigenic peptides onto MHC-I molecules [ 176 ]. HSV can also reduce the capacity of DCs to activate T-cells through ICP22, which binds to the CD80 promoter and downregulates the expression of the co-stimulatory molecules CD80 and CD86 on the cell surface [ 48 , 177 , 178 ]. Reports indicate that both HSV-1 and HSV-2 can inhibit autophagosome formation in DC, interfere with cellular degradation processes, affect antigen presentation to CD8+ T cells, and hinder DC migration from infected tissues to the corresponding lymph nodes, likely reducing the efficacy of DC in activating CD4+ and CD8+ T cells at this site (Fig. 5 a) [ 48 , 179 , 180 , 181 , 182 ]. In addition, HSV protects infected cells from natural killer (NK) cell-mediated apoptosis by inhibiting the release of cytotoxic molecules from NK cells [ 183 , 184 ]. Overall, these findings support the theory that HSV has developed multiple mechanisms and strategies to undermine the functions of DCs, NK cells, and T cells and potentially negatively affect host adaptive immune responses [ 154 ].

Another important immune escape mechanism is the restriction of the immune response by HSV gC and gE. gC can bind to complement component C3b, thereby blocking complement component C5 and properdin to activate the alternative and classical complement signaling pathways, respectively. Consequently, this mechanism prevents the formation of a membrane attack complex that lyses infected cells and impairs the ability of B and T cells to enhance immunity [ 185 , 186 , 187 , 188 ]. In addition, the Fc domain of gE functions as an IgG Fc receiver (FcγR), which binds to IgG and blocks antibody-dependent cell- mediated cytotoxicity and C1q binding [ 33 , 189 ]. Notably, the FcγR of gE can block antibodies against HSV and many other viruses, exerting a broad inhibitory effect on all immune pathways associated with Fc, thus elevating the risk of infection with various pathogens and predisposing to immune-related diseases (Fig. 5 b). However, it is interesting to note that the vaccine targeting gC2/gD2/gE2 has achieved phased success, with gD2 blocking viral entry and gC2 and gE2 blocking immune evasion, suggesting its outstanding potential in the fight against HSV infection [ 32 ].

In summary, although HSV invasion can induce host innate and adaptive immunity and cellular responses to eliminate or restrict HSV replication and transmission, sophisticated countermeasures have been devised to neutralize these anti-immune responses, thereby ensuring long-term survival and replication. Consequently, continually refining and consolidating our comprehension of these mechanisms to enhance our understanding of HSV-host interactions in immune responses is imperative. This will pave the way for the development of innovative antiviral strategies, vaccines, and oncolytic viruses.

Progress in HSV vaccine development

As described above, the biological complexities, pathogenesis, and immune evasion mechanisms of HSV infection are profound, leading to complex clinical symptoms and posing significant challenges to the development of antiviral drugs and vaccines. The FDA has not approved genital herpes vaccines despite 75 years of effort, including attenuated live, nucleic acid, inactivated, subunit, genetically engineered live virus, and synthetic peptide vaccines [ 190 ]. The majority of vaccine candidates have fallen short in clinical stage I/II or even preclinical research, with only a minority advancing to phase 3 trials, yet none have achieved the desired level of efficacy [ 50 , 191 ]. With regard to the development of HSV vaccines, given our knowledge of the pathogenesis of the virus, an effective vaccine would likely stimulate innate and adaptive immunity, encompassing both humoral and cellular responses, which are mainly determined by antigens and adjuvants selected as immunogens. However, based on the outcomes of various vaccine candidates tested in animals and humans using diverse platforms, antigens, and adjuvants, the failed vaccines may have overlooked antigens crucial for eliciting and maintaining a robust immune response despite several antigen screening processes [ 15 ].

Although these candidate vaccines have only generated partial success, each vaccine offers unique advantages and disadvantages, which are summarized below and serve as a valuable reference for future vaccine development efforts (Table 2 ). HSV vaccines can be classified as prophylactic or therapeutic based on the characteristics of the viral infection. Prophylactic vaccines are aimed at healthy individuals and are designed to establish a defensive barrier on the skin and mucous membranes to prevent viral invasion. The primary objective was to target the initial HSV infection and prevent the formation of latent infections. A successful prophylactic genital herpes vaccine should accomplish the following: prevent both clinical disease and subclinical infection, reduce the risk of inadvertent transmission to non-vaccinated partners (both males and females), maintain durable immune protection against HSV invasion and latency, provide cross-protection against both HSV-1 and HSV-2 genital infections, and effectively prevent maternal and neonatal herpes infections following female immunization [ 190 , 191 , 192 ]. Conversely, therapeutic vaccines are intended for the population already infected with the virus, aiming to alleviate clinical symptoms, prevent disease progression, and even suppress herpes recurrences. Simultaneously, it should have long-term effectiveness for both sexes, provide cross-protection against both HSV-1 and HSV-2 and be suitable for individuals of all ages.

Currently, subunit vaccines targeting viral glycoproteins are being extensively studied. These glycoproteins, especially gD, block cell entry, followed by gB, gC, and gE, and are often combined with various adjuvants to enhance immunity and prevent host cell entry and cell-to-cell transmission [ 193 , 194 , 195 , 196 ]. Unfortunately, some vaccines that have been proven to be effective in animal models have recently been discontinued owing to their failure in human clinical trials. A study sponsored by GlaxoSmithKline revealed that the gD2 vaccine, administered with MPL and alum as adjuvants, showed a high efficacy of 74% in HSV-1/HSV-2 seronegative women but was not efficacious in HSV-1 seropositive and HSV-2 seronegative women. It was not effective in men regardless of their serological status, raising concerns about sex differences in vaccine efficacy [ 191 , 197 ]. To further assess its efficacy in women, the Simplirix vaccine was evaluated in a group of young women aged 18–30 years who were seronegative for HSV-1 and HSV-2. The vaccine exhibited efficacies of 58% against HSV-1 and 20% against HSV-2 [ 198 ]. The reason this finding differs from the previous studies may be the difference in the studied populations, as the attack rates of HSV-2 genital disease in prior studies were high among uninfected women in discordant couples and were significantly reduced by the vaccine. Regarding the gD2 vaccine, significant protection against HSV-1 infection, but not HSV-2, may be due to low-dose infection of HSV-1, as gD1 and gD2 amino acids share 89% homology [ 198 ]. The gD2 and gB2 subunit vaccines adjuvanted with MF59 can induce high levels of HSV-2 specific neutralizing antibodies in HSV-2 seronegative discordant couples and HSV-2 seronegative couples at sexually transmitted disease clinics; however, the overall efficacy for preventing HSV-2 infection was only 9% [ 199 ]. Although gD can elicit human immune responses and extensive research has been conducted on vaccines incorporating gD along with diverse adjuvants and platforms, these efforts have yielded only partial success. The limited effectiveness of existing vaccines targeting gD and/or gB can be attributed to the lack of a potent antigen [ 200 ]. HSV encodes a plethora of genes capable of immune evasion, which complicates vaccine development.

Recently, a trivalent subunit vaccine of gD2/gC2/gE2 administered with CpG and alum as adjuvants showed significant immune responses and protection in rhesus macaques and female guinea pigs, in which gD2 blocked viral entry, whereas gC2 and gE2 suppressed immune evasion [ 32 ]. In rhesus macaques, vaccine-induced plasma and mucosal-neutralizing antibodies stimulated CD4+ T cell responses and exhibited a remarkable efficacy of 97% against HSV-2 [ 32 ]. Similarly, in guinea pigs, the efficacy against acute disease and recurrent genital lesions reached 97%, showing both preventive and therapeutic effects and preventing the shedding of replication-competent viruses [ 32 ]. Combined with the unique advantages of mRNA vaccines, BNT163, a trivalent mRNA vaccine for gD2/gC2/gE2 encapsulated in lipid nanoparticles, was developed by BioNTech [ 201 , 202 ]. BNT163 exhibited significant immunogenicity and efficacy in mice and guinea pigs. The efficacy against clinical and subclinical infections reached 63/64 and 8/10 in mice and guinea pigs, respectively, significantly reducing the risk of transmission to partners and newborns. Immunological assays showed that the trivalent mRNA vaccine was superior to the trivalent proteins in stimulating serum and vaginal IgG antibodies, serum neutralizing antibodies, and antibodies targeting crucial gD2 epitopes involved in entry and cell-to-cell spread, CD4+ T cell responses, and T follicular helper and germinal center B cell responses in mice [ 203 ]. Second, BNT163 showed long-term protection in guinea pigs and mice, lasting approximately 8 months and 1 year, respectively. This durable protection is likely attributable to the generation of high neutralizing titers and a robust B-cell immune memory that persists for up to a year [ 204 ]. Third, the mRNA vaccine also generated cross-reactive antibodies against vaginal HSV-1 infection and latent infection, resulting in complete protection from death and genital disease in all mice infected with HSV-1 (54/54, 100%) and HSV-2 (20/20, 100%) and prevented HSV DNA from reaching the dorsal root ganglia in a high proportion of mice infected with HSV-1 (29/30, 97%) and HSV-2 (10/10, 100%). Overall, BNT163 provides comprehensive protection against HSV-1 and HSV-2 genital herpes in animals, making it a promising candidate for further development [ 193 , 205 ]. Finally, a study involving female mice immunized before mating and newborns infected intranasally with HSV-2 suggested that the efficacy of mRNA and protein vaccines in newborns was 117/120 and 154/160, respectively. Both vaccines induced comparable IgG binding and neutralizing antibody levels in mothers and newborns, successfully protecting first- and second-litter newborns from disseminated infections based on virus titers in multiple organs [ 206 ]. Collectively, these four aspects underscore the ability of trivalent mRNA vaccines to effectively prevent genital herpes. Based on animal models, BNT163 is currently the closest to an ideal vaccine, and a clinical trial is being conducted by BioNTech. The success of both trivalent subunit and mRNA vaccines further underscores the significance of multiple vaccine antigens, particularly those related to immune escape, for inducing and maintaining effective immune responses during the development of an HSV vaccine.

Other candidate HSV vaccines exist that have demonstrated partial success and require further investigation. One such vaccine, HerpV, is a recombinant human heat shock protein 70 polyvalent peptides complexed with 32 synthetic HSV-2 peptides, adjuvanted with QS-21. In a phase 1 trial, HerpV elicited HSV-2-specific CD4+ and CD8+ T cells and reduced HSV-2 shedding by 15% following initial vaccination [ 207 , 208 ]. Another vaccine, GEN-003, comprises two recombinant T-cell antigens: an internal fragment of ICP and a transmembrane deletion mutant of gD2 with a matrix-M2 adjuvant and a saponin-based lipid particle. The vaccine significantly reduced viral shedding (approximately 40%) and lesion rates while stimulating humoral and cell-mediated antigen-specific immune responses. However, GEN-003 has been acquired by another company [ 209 , 210 ]. Moderna predicts that mRNA-1608 can inhibit HSV-2 genital herpes and provide cross-protection against HSV-1, with clinical trials already underway. Another strategy is the live attenuated HSV vaccine, which specifically deletes genes to limit infection and replication while maintaining immunogenicity and induces extensive immune responses by supplying a wider range of antigens. The COR-1 vaccine, a gD2 codon-optimized DNA vaccine, demonstrated both cellular and humoral responses in murine models and reduced viral shedding in humans [ 209 ]. The VC2 vaccine, which contains HSV with partial deletions in the gK and UL20 genes, prevents HSV from entering the neuronal axons [ 211 ]. This vaccine reduces acute and recurrent HSV-2 disease, viral shedding, and the amount of virus detected in neurons [ 96 , 212 , 213 ]. However, modifying the virus may carry risks, such as reducing immunogenicity or enhancing virulence [ 96 ].

The ongoing clinical and preclinical vaccine efforts are dependent on the present comprehension of HSV biology and immunopathogenesis within host cells [ 214 ]. According to nearly 80 years of HSV vaccine development, most vaccines are primarily constrained by the identification of vaccine antigens capable of effectively inducing and sustaining robust immune responses, encompassing both humoral and cellular immunity [ 215 ]. The promise lies in subunit and mRNA vaccines, which provide a gateway to present the immune system with complex antigenic compositions, potentially including T cell and B cell epitopes. Furthermore, the combination of subunit vaccines with specific adjuvants and vaccine formats has introduced a novel approach for exploring future options in HSV vaccination. The next challenge concerns the vaccine development technology itself, particularly mRNA vaccines and LNP delivery systems. mRNA vaccines possess numerous unique advantages and have demonstrated superior efficacy compared to subunit vaccines, pointing to a promising pathway. Another obstacle is likely the absence of ideal animal models, as guinea pigs and mice currently used cannot comprehensively evaluate the effectiveness of HSV vaccines against lytic, latent, and reactivation infections. Therefore, constructing an ideal animal model is a critical priority for the future. Alongside these limitations, we also face additional challenges, including viral culture systems, injection methods, and adjuvant use, which indicate the direction of our future efforts.

Application prospects of HSV

Oncolytic virotherapy.

Oncolytic viruses (OVs) are a promising emerging class of anticancer immunotherapies that use replication-competent viruses to specially target and lyse tumor cells. During this process, the virus and tumor antigens recruit more immune cells, boosting the elimination of residual tumor cells and enhancing immune cell infiltration to reshape the tumor microenvironment [ 216 , 217 ]. To enhance the tumor selectivity of OVs, improve their replication efficiency, minimize pathogenicity, and bolster immunogenicity, they usually are genetically engineered through the deletion or modification of viral genes, modification of virus surface proteins, insertion of tumor specific promoters into the genome, or fusion of tumor cell specific antibodies [ 216 , 218 ].

Currently, HSV is a widely used OV in clinical practice. It possesses several features that favor its use for oncolytic virotherapy (Fig. 6 a). First, HSV-1 demonstrates potent infectivity, completing its replication cycle within 10 h and rapidly releasing a multitude of progeny viruses. This efficiency surpasses that of other common viruses, such as adenoviruses. Additionally, CCS promotes the efficient spread of these progeny viruses within tumors, resulting in effective tumor clearance or shrinkage. Second, HSV infection stimulates the secretion of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, and IFN from tumor cells, thereby attracting more antigen-presenting cells (APCs) and activating T cells. As tumor cells lyse, viral and tumor antigens are released, further activating the host immune system. As a substantial influx of T cells is attracted to the tumor site, their infiltration within the tumor microenvironment is significantly strengthened, ultimately leading the transformation of “cold” tumors into “hot” ones. RNA sequencing (RNA-seq) has identified Visfatin in the responsive tumors following OV treatment. Visfatin promotes the antitumor efficacy of OV by remodeling the tumor microenvironment, specifically by enhancing CD8+ T cell and DC cell infiltration and activation, repolarizing macrophages towards the M1 like phenotype, and reducing Treg cell numbers [ 219 ]. This enhances the anti-tumor effects and treatment durability and provides immune-mediated tumor-killing therapy for patients unresponsive to inhibitor immunotherapy. Third, its ability to infect almost all cells, including immune and nerve cells, indicates its unique potential to induce strong immune responses and penetrate the blood-brain barrier, making it useful for treating neurological diseases. Studies have shown that oncolytic HSV-1 is effective against CNS cancers, such as glioblastoma, improving patient survival and quality of life. Finally, HSV-1 can effectively infect various experimental animals, making it highly suitable for preclinical in vivo studies [ 218 , 220 , 221 , 222 ].

The applications of HSV. a HSV serves as an oncolytic virus to selectively infect, replicate, and lyse tumor cells. OV also eliminates distant and uninfected tumor cells via releasing progeny virions. Meanwhile, OV induces immune responses to amplify anti-tumor activity. The infected tumor cells release cytokines like type I IFNs, DAMPs, PAMPs, as well as viral and tumor antigens, which aid in maturing and recruiting antigen-presenting cells (APCs), inducing and activating tumor specific T cells and NK cells, to enhance immune responses. b HSV acts as a viral vector while also contributing to immune therapy. It introduces tumor antigens into DC as an anti-tumor vaccine, the DC also assists in the activation and expansion of tumor-specific cells to enhance immune responses. It also introduces CAR into T cells to generate CAR-T cells, enhancing the targeting of tumor cells. In addition, the expression of checkpoint inhibitors like PD1 antibodies by HSVs helps in blocking PDL1, leading to antitumor activity. c HSV acts as a viral vector carrying extra-functional genes to the mutant cell to restore its function by the expression of functional proteins. d HSV also carries gene editing systems like CRISPR/Cas to engineer genes, which can be used in the construction of disease models and anti-tumor therapy. e Due to its neurotropism, HSV can act as an imaging and tracing tool for neuroscience. It can be attached to a GFP anterograde transneuronal tracer. OVs, oncolytic viruses; IFNs, interferons; DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; APC, antigen-presenting cells; NK, natural killer cells; DC, dendritic cell; CAR, chimeric antigen receptors; CAR-T, chimeric antigen receptor T-cell immunotherapy; ICT, immune checkpoint therapy

Recently, clinical trials have witnessed encouraging advancements in oncolytic viral therapies using HSV-1 (Table 3 ). T-VEC, the first OV product approved as a drug in Europe and the USA in 2015, is used to treat melanomas that cannot be completely removed surgically [ 220 ]. T-VEC is a second-generation oncolytic HSV-1 with deletions of ICP34.5 and ICP47 and the incorporation of human GM-CSF. These strategies bolster cancer-targeting replication, minimize virulence, hinder replication in healthy cells, and enhance antigen presentation and anti-tumor immunity. Studies have indicated that combining T-VEC with checkpoint inhibitors, such as Yervoy and Keytruda, gives a remarkable response rate of 62%, with most patients experiencing > 50% tumor reduction and exhibiting good tolerance and high efficacy. Furthermore, Teserpaturev/G47△ is a third-generation recombinant oncolytic HSV-1, with the deletion of ICP34.5 and ICP47 and the inactivation of ICP6. Owing to its high efficiency and specificity in humans, it was globally recognized as the first OV drug for glioblastoma treatment [ 221 ]. CAN-3110, an oncolytic herpes virus (oHSV), has demonstrated a significantly enhanced replication ability and glioblastoma treatment effectiveness in clinical trials [ 223 , 224 ]. Furthermore, T3011, a recombinant oncolytic HSV-1 with insertion of IL-12 and PD1 and deletion of one copy of ICP34.5 to enhance anti-tumor activity and safety, was manufactured by ImmVira. Recent clinical data have suggested that intratumoral injection of MVR-T3011 (MVR-T3011 IT) combined with pembrolizumab is safe and tolerable and has the potential to modify the tumor microenvironment and overcome immune tolerance in malignant tumors. Additionally, BS006, a new oncolytic HSV equipped with bispecific antibody (BsAb) molecules targeting PDL1/CD3 (oHSV2-PDL1/CD3-BsAb) for human malignancies, has been approved for the initiation of phase 1 clinical trials. As a globally pioneering oncolytic viral drug, BS006 is expected to provide new treatment options for patients with cancer [ 225 ]. Other promising oHSV products, including VG161, OrienX010, and GM-GSF, are also in the pipeline [ 226 , 227 , 228 ].

Gene and immune therapies

HSV has significant potential as a gene therapy vector owing to several key advantages. First, their strong genetic load capacity enables them to carry complex regulatory elements and a wide range of exogenous genes. Second, HSV demonstrates efficient transduction in various cell types. Third, its ability to evade host immunity facilitates repeated administration while minimizing immune toxicity. Finally, its lack of integration with the host genome ensures that it remains non-oncogenic [ 218 , 220 , 229 , 230 ].

HSV vectors can correct defective genes by transmitting normal genes, thereby offering a potential therapeutic strategy for hereditary diseases (Fig. 6 c). For instance, cystic fibrosis, a genetic disease caused by mutations in the CFTR gene, leads to dysfunctional or absent CFTR proteins and accumulation of mucus in the lungs, resulting in persistent lung infections and progressive lung deterioration. KB407, a modified HSV-1 vector, effectively carries two copies of the CFTR to respiratory cells in the lungs, providing a treatment option for all patients with cystic fibrosis, regardless of their specific genetic mutation. Similarly, dystrophic epidermolysis bullosa, a rare genetic blistering disease caused by mutations in COL7A1 -the gene encoding type VII collagen (C7), leads to absent or dysfunctional anchoring fibrils and disrupts the adhesion of the epidermis to the dermis [ 231 ]. B-VEC, a replication-defective HSV-1 vector designed to restore functional C7 protein through the delivery of functional COL7A1 , can treat wounds in patients 6 months or older with dystrophic epidermolysis bullosa caused by COL7A1 mutations (Table 4 ) [ 39 , 232 , 233 ].

In addition to gene therapy for hereditary diseases, HSV vectors exhibit significant potential for immunotherapy (Fig. 6 b). They can carry specific genes or drugs to directly infect target cells and release therapeutic substances, thereby enabling more comprehensive or personalized tumor treatment strategies. For instance, HSV can deliver immune-stimulating or anticancer genes to tumor cells, activate the immune system, induce apoptosis, and inhibit tumor cell proliferation. Furthermore, HSV can introduce chimeric antigen receptors (CARs) into T cells, enhancing their ability to recognize specific tumor antigens. Additionally, HSV vectors carrying genes that regulate the tumor microenvironment facilitate CAR T-cell targeting and tumor infiltration. The combination of HSV vectors and CAR-T cells has demonstrated promising therapeutic effects and offers new strategies for tumor immunotherapy. Furthermore, T cells express checkpoint inhibitor antibodies against HSV that block PDL1 or CTLA4, resulting in anti-tumor activity [ 222 , 224 , 234 , 235 ].

Remarkably, HSV vectors can also transport nerve growth factors or other therapeutic proteins across the blood-brain barrier to the damaged nervous system, owing to their neurotropism. In autoimmune neurological diseases, such as multiple sclerosis, HSV carriers can effectively deliver anti-inflammatory factors or immune modulators to alleviate inflammatory responses. Moreover, HSV-1 has the potential to carry endogenous enzymes involved in dopamine synthesis and therapeutic genes that protect neurons, thus restoring the functionality of cells damaged in Parkinson’s disease [ 236 ].

Vaccine development and disease modeling

HSV, as a versatile tool carrier, is applied in various fields, including vaccine development and disease modeling. Through genetic engineering, HSV can express antigens specific to multiple viruses or bacteria, offering a novel method for concurrent vaccination against diverse pathogens. Its unique ability to infect both immune and nerve cells provides significant advantages for immune activation and neurological disease research. In the context of tumor vaccines, HSV vectors are used to deliver genes encoding tumor-specific antigens, such as DCs, eliciting robust immune responses that lead to effective tumor immunotherapy and long-lasting immune memory to prevent tumor relapse (Fig. 6 b). Multiple vaccinations can further amplify the immune response and enhance the treatment and prevention outcomes. In addition, HSV carriers can be used to deliver Aβ vaccines, aiding in the prevention of brain Aβ plaque formation and clearance, thus providing a therapeutic approach for neurological conditions like Alzheimer’s disease [ 222 , 237 , 238 ].

As a gene vector, HSV can be used to construct disease models by expressing or knocking out specific genes. For example, HSV vectors can introduce mutated genes into neurons in animal models by carrying gene editing systems, such as CRISPR/Cas, to simulate the pathogenesis of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease (Fig. 6 d). By carrying tumor-related or therapeutic genes, HSV can also induce tumorigenesis and assess the efficacy of tumor treatments in vivo. These models facilitate the study of tumor etiology, tumor cell biology, and tumor-immune system interactions, paving the way for innovative tumor diagnosis and treatment approaches. Additionally, HSV serves as a model for investigating viral infections and immune responses. By genetically modifying HSV vectors, researchers can introduce specific mutations or deletions to study virus-host interactions, viral replication and transmission mechanisms, and host immune reactions to viral infections. This modeling approach enhances our understanding of the pathological processes underlying viral infections and lays the foundation for the development of antiviral medications and vaccines [ 41 , 239 ].

Biological imaging and tracing

The ability to carry a larger genetic payload and efficiently amplify the host HSV-1 makes it a potentially powerful tool for imaging and tracing. Their neurotropic nature provides valuable insights into neuroscience (Fig. 6 e) [ 10 , 240 , 241 , 242 ]. The HSV-1 strain H129, with the unique feature of predominantly anterograde transneuronal transmission, represents a promising anterograde neuronal circuit tracer for mapping output neuronal pathways (Table 5 ). Over the years, the H129-derived anterograde tracing toolbox has expanded significantly, encompassing both polysynaptic and monosynaptic tracers labeled with various fluorescent proteins. These tracers have been instrumental in neuroanatomical studies that have revealed numerous critical neuronal circuits. One example is H129-G4, a polysynaptic tracer notable for its bright labeling intensity, which makes it ideal for mapping output networks. It stands out as the only anterograde transneuronal tracer compatible with fluorescence micro-optical sectioning tomography, enabling the decoding of whole-brain projections and neuronal morphology within a specific brain region. Nevertheless, it has limitations, such as a lack of starter cell specificity, potential retrograde labeling, and high toxicity. Another tracer, H129-dTK-tdT, is an anterograde monosynaptic tracer suitable for both specific and nonspecific tracing of starter neurons. However, it exhibits low labeling intensity and relatively high toxicity to starter neurons and requires immunostaining for visualization [ 4 , 243 ].

Although HSV-based biological imaging and tracing tools play a vital role in neuroscience, several concerns have arisen regarding these strategies. First, a prevalent issue with most current trans-neuronal tracers is whether they are strictly transmitted through synapses. The synaptic gap typically measures 20 nm; however, the average diameter of the H129 virion is approximately 200 nm, raising questions about how such a large viral particle can traverse such a narrow space [ 40 , 76 ]. Second, the high toxicity and biological complexity of HSV often result in severe neuronal dysfunction or even death, posing a significant challenge [ 6 ]. Third, the large genome size of HSV-1 complicates DNA manipulation [ 244 ]. Further research characterizing HSV virology is imperative to optimize and develop novel HSV-based biological imaging and tracing tools.

Despite the vast potential of HSV as a tool carrier, it is crucial to approach its practical applications cautiously, owing to the inherent risks and challenges. First, HSV retains certain biosafety hazards even after modifications to reduce toxicity. Specifically, novel oHSVs that feature multigene mutations and are armed with specific foreign genes necessitate further research and investigation to enhance both their safety and efficiency. Furthermore, HSV tracers that possess strong toxicity have the potential to damage infected neurons, thereby preventing them from performing functional mapping. Second, the complexity of the HSV immune escape mechanism may alter the host immune response, possibly triggering inflammation and other complications. As for oHSV, it is necessary to find ways to diminish antiviral immunity while enhancing the virus's ability to trigger robust antitumor immunity. Third, the prolonged presence and replication of HSV vectors within the body could pose risks, such as gene mutations or cellular transformations. Additionally, the safety, stability, and targeting capabilities of the tool carriers have limitations. Although HSV exhibits neurotropism and dermatotropism, the HSV vector may infect target cells and other non-target cells, leading to nonspecific gene expression or adverse reactions. Therefore, improving the targeting ability of HSV vectors remains an important challenge in gene therapy. Finally, the key to tool vectors is the precise expression of target genes. However, currently, it is not possible to fully control the gene expression level and duration of HSV vectors in vivo, which may affect treatment efficacy and safety. In summary, although HSV has broad application prospects as an oncolytic virus and in gene therapy, it has many limitations. To overcome these limitations, it is necessary to continue in-depth research on the biological characteristics, pathogenesis, and interaction mechanisms between HSV and the host to better control its targeting and gene expression regulation ability in vivo and develop wider applications.

Conclusions and perspectives

HSV, a lifelong disease affecting a large number of people of varying ages globally, is characterized by its complex pathogenesis. This review comprehensively discusses HSV's biological characteristics, infection cycle, and host-virus immune interplay. Notably, HSV serves as a “double-edged sword.” Its intricate pathogenesis and immune evasion have caused unprecedented disasters in humans, resulting in widespread and severe global infections, while hindering vaccine development.

Conversely, HSV remains a promising biological tool vital for disease and scientific research. This review highlights the recent advancements in HSV vaccine development and HSV-based tool applications, discussing their successes and challenges to guide future research.

Even though diverse strategies have been attempted, no ultimate cure or vaccine is yet available. The situation is mainly due to the intricate nature of HSV's pathogenesis and immune interplay, which acts as a significant obstacle to the comprehensive and profound understanding of the virus, thereby limiting the development of vaccines. To be specific, several vaccines face challenges, including a narrow therapeutic spectrum and limited effectiveness, which are constrained by the difficulty in identifying vaccine antigens capable of effectively inducing and maintaining robust immune responses. In addition to vaccine antigens, however, several limiting factors exist in vaccine development, such as viral culture systems, animal models, injection methods, and adjuvant use. Furthermore, as mentioned earlier, mRNA vaccines are a promising avenue because of their distinctive advantages, with initial studies of trivalent mRNA vaccines demonstrating superior efficacy compared to subunit formulations.

Despite these challenges, HSV has emerged as a promising biological tool due to its unique characteristics that play a pivotal role in disease and scientific research. As an OV, it effectively lyses tumor cells and recruits immune cells for anticancer therapy. Additionally, HSV serves as a versatile viral carrier, capable of transporting various foreign genes or therapeutic agents for gene and immune therapies. Equipped with marker genes, HSV functions as an imaging tool for enhanced visualization and tracking, particularly in neuroscience. However, practical applications involve numerous potential biological risks, including challenges in targeting specificity, gene expression stability, viral toxicity, lifelong latent infections, and achieving high precision during in vivo genome engineering. In summary, developing an effective vaccine and overcoming the limitations in its applications is a daunting task, and further research is urgently needed to comprehensively and deeply understand HSV.

Future advancements in HSV's life cycle, protein interactions, and immune evasion mechanisms will pave the way for effective HSV vaccines to prevent or mitigate infections. This includes identifying optimal antigens, overcoming technical hurdles in vaccine design and delivery, and assessing the efficacy and safety of candidate vaccines in clinical trials. Furthermore, this knowledge will also aid in optimizing HSV-based viral vectors for gene therapy by enhancing targeting specificity, maintaining stable gene expression, minimizing viral toxicity, and achieving high precision during in vivo genome engineering. HSV's oncolytic potential can be boosted by enhancing its tumor selectivity, immune response induction, and developing combination therapies with other immunomodulatory agents. Moreover, HSV's potential as a neuroimaging tool can be augmented by developing more sensitive and specific marker genes, improving imaging resolution, and expanding the scope of neurological disorders that can be studied. In summary, HSV research holds great promise for both addressing public health challenges and advancing scientific knowledge. By addressing the current limitations and exploring new research avenues, we can gain control over HSV infection and harness its full potential as a tool for improving human health.

Availability of data and materials

Not applicable.

Lo LC, Anderson DJ. A Cre-Dependent, Anterograde Transsynaptic Viral Tracer for Mapping Output Pathways of Genetically Marked Neurons. Neuron. 2011;72(6):938–50. https://doi.org/10.1016/j.neuron.2011.12.002 .

Article   PubMed   PubMed Central   CAS   Google Scholar  

Montgomery RI, Warner MS, Lum BJ, Spear PG. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell. 1996;87(3):427–36. https://doi.org/10.1016/S0092-8674(00)81363-X .

Article   PubMed   CAS   Google Scholar  

McGovern AE, Davis-Poynter N, Rakoczy J, Phipps S, Simmons DG, Mazzone SB. Anterograde neuronal circuit tracing using a genetically modified herpes simplex virus expressing EGFP. J Neurosci Methods. 2012;209(1):158–67. https://doi.org/10.1016/j.jneumeth.2012.05.035 .

Article   PubMed   Google Scholar  

Zeng WB, Jiang HF, Gang YD, Song YG, Shen ZZ, Yang H, et al. Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129. Molecular Neurodegeneration. 2017;12(1):38. https://doi.org/10.1186/s13024-017-0179-7 .

Yang H, Xiong F, Song YG, Jiang HF, Qin HB, Zhou J, et al. HSV-1 H129-Derived Anterograde Neural Circuit Tracers: Improvements, Production, and Applications. Neurosci Bull. 2021;37(5):701–19. https://doi.org/10.1007/s12264-020-00614-3 .

Su P, Ying M, Han ZP, Xia JJ, Jin S, Li YL, et al. High-brightness anterograde transneuronal HSV1 H129 tracer modified using a Trojan horse-like strategy. Mol Brain. 2020;13(1):5. https://doi.org/10.1186/s13041-020-0544-2 .

Odegard JM, Flynn PA, Campbell DJ, Robbins SH, Dong LC, Wang KN, et al. A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and guinea pigs. Vaccine. 2016;34(1):101–9. https://doi.org/10.1016/j.vaccine.2015.10.137 .

Looker KJ, Johnston C, Welton NJ, James C, Vickerman P, Turner KME, et al. The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study. Bmj Global Health. 2020;5(3): e001875. https://doi.org/10.1136/bmjgh-2019-001875 .

Article   PubMed   PubMed Central   Google Scholar  

Connolly SA, Jardetzky TS, Longnecker R. The structural basis of herpesvirus entry. Nature Reviews Microbiology. 2021;19(2):110–21. https://doi.org/10.1038/s41579-020-00448-w .

Yang H, Xiong F, Qin HB, Yu QT, Sun JY, Zhao HW, et al. A novel H129-based anterograde monosynaptic tracer exhibits features of strong labeling intensity, high tracing efficiency, and reduced retrograde labeling. Molecular Neurodegeneration. 2022;17(1):6. https://doi.org/10.1186/s13024-021-00508-6 .

Krishnan R, Stuart PM. Developments in Vaccination for Herpes Simplex Virus. Frontiers in Microbiology. 2021;12: 798927. https://doi.org/10.3389/fmicb.2021.798927 .

Reeves DB, Magaret AS, Greninger AL, Johnston C, Schiffer JT. Model-based estimation of superinfection prevalence from limited datasets. Journal of the Royal Society Interface. 2018;15(139):20170968. https://doi.org/10.1098/rsif.2017.0968 .

Rouse BT, Schmid DS. Fraternal Twins: The Enigmatic Role of the Immune System in Alphaherpesvirus Pathogenesis and Latency and Its Impacts on Vaccine Efficacy. Viruses-Basel. 2022;14(5):862. https://doi.org/10.3390/v14050862 .

Article   CAS   Google Scholar  

Farooq AV, Shukla D. Herpes Simplex Epithelial and Stromal Keratitis: An Epidemiologic Update. Survey of Ophthalmology. 2012;57(5):448–62. https://doi.org/10.1016/j.survophthal.2012.01.005 .

Kim HC, Lee HK. Vaccines against Genital Herpes: Where Are We? Vaccines. 2020;8(3):420. https://doi.org/10.3390/vaccines8030420 .

Schiffer JT, Gottlieb SL. Biologic interactions between HSV-2 and HIV-1 and possible implications for HSV vaccine development. Vaccine. 2019;37(50):7363–71. https://doi.org/10.1016/j.vaccine.2017.09.044 .

Edwards RG, Longnecker R. Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye. Journal of Virology. 2017;91(13):e00115–17. https://doi.org/10.1128/JVI.00115-17 .

Campadelli-Fiume G, Cocchi F, Menotti L, Lopez M. The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells. Rev Med Virol. 2000;10(5):305–19. https://doi.org/10.1002/1099-1654(200009/10)10:5%3c305::Aid-Rmv286%3e3.0.Co;2-T .

Warner MS, Geraghty RJ, Martinez WM, Montgomery RI, Whitbeck JC, Xu RL, et al. A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology. 1998;246(1):179–89. https://doi.org/10.1006/viro.1998.9218 .

Madavaraju K, Koganti R, Volety I, Yadavalli T, Shukla D. Herpes Simplex Virus Cell Entry Mechanisms: An Update. Frontiers in Cellular and Infection Microbiology. 2021;10: 617578. https://doi.org/10.3389/fcimb.2020.617578 .

Woelfle T, Linkohr B, Waterboer T, Thorand B, Seissler J, Chadeau-Hyam M, et al. Health impact of seven herpesviruses on(pre)diabetes incidence and HbA: results from the KORA cohort. Diabetologia. 2022;65(8):1328–38. https://doi.org/10.1007/s00125-022-05704-7 .

Liu YL, Luo SK, He SY, Zhang MD, Wang P, Li C, et al. Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins. Virology. 2015;475:96–109. https://doi.org/10.1016/j.virol.2014.11.005 .

de Souza Carneiro VC, Leon LAA, de Paula VS. miRNAs: Targets to Investigate Herpesvirus Infection Associated with Neurological Disorders. Int J Mol Sci. 2023;24(21):15876. https://doi.org/10.3390/ijms242115876 .

Guidry JT, Scott RS. The interaction between human papillomavirus and other viruses. Virus Research. 2017;231:139–47. https://doi.org/10.1016/j.virusres.2016.11.002 .

Smith JS, Herrero R, Bosetti C, Muñoz N, Bosch FX, Eluf-Neto J, et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. Jnci-J Natl Cancer I. 2002;94(21):1604–13. https://doi.org/10.1093/jnci/94.21.1604 .

Zhang H, Cai SL, Xia Y, Lin YX, Zhou GZ, Yu YH, et al. Association between human herpesvirus infection and cervical carcinoma: a systematic review and meta-analysis. Virol J. 2023;20(1):288. https://doi.org/10.1186/s12985-023-02234-5 .

Dus-Ilnicka I, Halon A, Perra A, Radwan-Oczko M. HPV related p16 INK4A and HSV in benign and potentially malignant oral mucosa pathologies. BMC Oral Health. 2024;24(1):347. https://doi.org/10.1186/s12903-024-04105-z .

Arii J, Uema M, Morimoto T, Sagara H, Akashi H, Ono E, et al. Entry of Herpes Simplex Virus 1 and Other Alphaherpesviruses via the Paired Immunoglobulin-Like Type 2 Receptor α. Journal of Virology. 2009;83(9):4520–7. https://doi.org/10.1128/jvi.02601-08 .

Omarova S, Cannon A, Weiss W, Bruccoleri A, Puccio J. Genital Herpes Simplex Virus-An Updated Review. Adv Pediatr. 2022;69(1):149–62. https://doi.org/10.1016/j.yapd.2022.03.010 .

Lince KC, DeMario VK, Yang GRT, Tran RT, Nguyen DT, Sanderson JN, et al. A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV. Cureus J Med Science. 2023;15(3): e35958. https://doi.org/10.7759/cureus.35958 .

Article   Google Scholar  

Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections-An evidence-based review. Arch Intern Med. 2008;168(11):1137–44. https://doi.org/10.1001/archinte.168.11.1137 .

Awasthi S, Hook LM, Shaw CE, Pahar B, Stagray JA, Liu D, et al. An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs. Plos Pathogens. 2017;13(1): e1006141. https://doi.org/10.1371/journal.ppat.1006141 .

Awasthi S, Huang JL, Shaw C, Friedman HM. Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes. Journal of Virology. 2014;88(15):8421–32. https://doi.org/10.1128/Jvi.01130-14 .

Rathbun MM, Szpara ML. A holistic perspective on herpes simplex virus (HSV) ecology and evolution. Advances in Virus Research. 2021;110(110):27–57. https://doi.org/10.1016/bs.aivir.2021.05.001 .

Li S, Li QB, Ren Y, Yi J, Guo JH, Kong XB. HSV: The scout and assault for digestive system tumors. Front Mol Biosci. 2023;10:1142498. https://doi.org/10.3389/fmolb.2023.1142498 .

Nasar RT, Uche IK, Kousoulas KG. Targeting Cancers with oHSV-Based Oncolytic Viral Immunotherapy. Curr Issues Mol Biol. 2024;46(6):5582–94. https://doi.org/10.3390/cimb46060334 .

Zhong YY, Le HY, Zhang X, Dai Y, Guo F, Ran XJ, et al. Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening. J Hematol Oncol. 2024;17(1):36. https://doi.org/10.1186/s13045-024-01554-5 .

Paller AS, Guide SV, Ayala D, Gonzalez ME, Lucky AW, Bagci IS, et al. Practical considerations relevant to treatment with the gene therapy beremagene geperpavec-svdt for dystrophic epidermolysis bullosa. Journal of Dermatological Treatment. 2024;35(1):2350232. https://doi.org/10.1080/09546634.2024.2350232 .

Xiong F, Yang H, Song YG, Qin HB, Zhang QY, Huang X, et al. An HSV-1-H129 amplicon tracer system for rapid and efficient monosynaptic anterograde neural circuit tracing. Nature Communications. 2022;13(1):7645. https://doi.org/10.1038/s41467-022-35355-6 .

Kakooza-Mwesige A, Tshala-Katumbay D, Juliano SL. Viral infections of the central nervous system in Africa. Brain Res Bull. 2019;145:2–17. https://doi.org/10.1016/j.brainresbull.2018.12.019 .

Cao X, Huang X, Li X, Yang L, Wang P, Yan J, et al. Construction and Optimization of Herpes Simplex Virus Vectors for Central Nervous System Gene Delivery based on CRISPR/Cas9-mediated Genome Editing. Curr Gene Ther. 2021;22(1):66–77. https://doi.org/10.2174/1566523219666210618154326 .

Arii J, Hirohata Y, Kato A, Kawaguchi Y. Nonmuscle Myosin Heavy Chain IIB Mediates Herpes Simplex Virus 1 Entry. Journal of Virology. 2015;89(3):1879–88. https://doi.org/10.1128/Jvi.03079-14 .

Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, et al. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. Journal for Immunotherapy of Cancer. 2019;7(1):214. https://doi.org/10.1186/s40425-019-0682-1 .

Rajčáni J, Andrea V, Ingeborg R. Peculiarities of Herpes Simplex Virus(HSV)Transcription: An overview. Virus Genes. 2004;28(3):293–310. https://doi.org/10.1023/b:Viru.0000025777.62826.92 .

Koelle DM, Norberg P, Fitzgibbon MP, Russell RM, Greninger AL, Huang ML, et al. Worldwide circulation of HSV-2 x HSV-1 recombinant strains. Sci Rep. 2017;7:44084. https://doi.org/10.1038/srep44084 .

Wu WM, Newcomb WW, Cheng NQ, Aksyuk A, Winkler DC, Steven AC. Internal Proteins of the Procapsid and Mature Capsids of Herpes Simplex Virus 1 Mapped by Bubblegram Imaging. Journal of Virology. 2016;90(10):5176–86. https://doi.org/10.1128/Jvi.03224-15 .

Kukhanova MK, Korovina AN, Kochetkov SN. Human Herpes Simplex Virus: Life Cycle and Development of Inhibitors. Biochemistry-Moscow. 2014;79(13):1635–52. https://doi.org/10.1134/S0006297914130124 .

Suazo PA, Ibañez FJ, Retamal-Díaz AR, Paz-Fiblas MV, Bueno SM, Kalergis AM, et al. Evasion of Early Antiviral Responses by Herpes Simplex Viruses. Mediators of Inflammation. 2015;2015: 593757. https://doi.org/10.1155/2015/593757 .

Whisnant AW, Jürges CS, Hennig T, Wyler E, Prusty B, Rutkowski AJ, et al. Integrative functional genomics decodes herpes simplex virus 1. Nature Communications. 2020;11(1):2038. https://doi.org/10.1038/s41467-020-15992-5 .

Zhu SY, Viejo-Borbolla A. Pathogenesis and virulence of herpes simplex virus. Virulence. 2021;12(1):2670–702. https://doi.org/10.1080/21505594.2021.1982373 .

Brandariz-Nuñez A, Liu T, Du T, Evilevitch A. Pressure-driven release of viral genome into a host nucleus is a mechanism leading to herpes infection. Elife. 2019;8: e47212. https://doi.org/10.7554/eLife.47212.001 .

Zhu H, Zheng C. Correction for Zhu and Zheng, “The Race between Host Antiviral Innate Immunity and the Immune Evasion Strategies of Herpes Simplex Virus 1.” Microbiol Mol Biol Rev. 2023;87(4): e0010323. https://doi.org/10.1128/mmbr.00103-23 .

Zhang N, Yan JH, Lu GW, Guo ZF, Fan Z, Wang JW, et al. Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion. Nature Communications. 2011;2(1):577. https://doi.org/10.1038/ncomms1571 .

Sasivimolrattana T, Bhattarakosol P. Impact of actin polymerization and filopodia formation on herpes simplex virus entry in epithelial, neuronal, and T lymphocyte cells. Frontiers in Cellular and Infection Microbiology. 2023;13:1301859. https://doi.org/10.3389/fcimb.2023.1301859 .

Oh MJ, Akhtar J, Desai P, Shukla D. A role for heparan sulfate in viral surfing. Biochem Biophys Res Commun. 2010;391(1):176–81. https://doi.org/10.1016/j.bbrc.2009.11.027 .

Agelidis AM, Shukla D. Cell entry mechanisms of HSV: what we have learned in recent years. Future Virol. 2015;10(10):1145–54. https://doi.org/10.2217/fvl.15.85 .

Atanasiu D, Saw WT, Cohen GH, Eisenberg RJ. Cascade of Events Governing Cell-Cell Fusion Induced by Herpes Simplex Virus Glycoproteins gD, gH/gL, and gB. Journal of Virology. 2010;84(23):12292–9. https://doi.org/10.1128/Jvi.01700-10 .

Cooper RS, Heldwein EE. Herpesvirus gB: A Finely Tuned Fusion Machine. Viruses-Basel. 2015;7(12):6552–69. https://doi.org/10.3390/v7122957 .

Fontana J, Atanasiu D, Saw WT, Gallagher JR, Cox RG, Whitbeck JC, et al. The Fusion Loops of the Initial Prefusion Conformation of Herpes Simplex Virus 1 Fusion Protein Point Toward the Membrane. Mbio. 2017;8(4):e01268–17. https://doi.org/10.1128/mBio.01268-17 .

Clement C, Tiwari V, Scanlan PM, Valyi-Nagy T, Yue BYJT, Shukla D. A novel role for phagocytosis-like uptake in herpes simplex virus entry. J Cell Biol. 2006;174(7):1009–21. https://doi.org/10.1083/jcb.200509155 .

Aggarwal A, Miranda-Saksena M, Boadle RA, Kelly BJ, Diefenbach RJ, Alam W, et al. Ultrastructural Visualization of Individual Tegument Protein Dissociation during Entry of Herpes Simplex Virus 1 into Human and Rat Dorsal Root Ganglion Neurons. Journal of Virology. 2012;86(11):6123–37. https://doi.org/10.1128/Jvi.07016-11 .

Sodeik B, Ebersold MW, Helenius A. Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus. J Cell Biol. 1997;136(5):1007–21. https://doi.org/10.1083/jcb.136.5.1007 .

Döhner K, Wolfstein A, Prank U, Echeverri C, Dujardin D, Vallee R, et al. Function of Dynein and Dynactin in Herpes Simplex Virus Capsid Transport. Mol Biol Cell. 2002;13(8):2795–809. https://doi.org/10.1091/mbc.01-07-0348 .

Radtke K, Kieneke D, Wolfstein A, Michael K, Steffen W, Scholz T, et al. Plus- and Minus-End Directed Microtubule Motors Bind Simultaneously to Herpes Simplex Virus Capsids Using Different Inner Tegument Structures. Plos Pathogens. 2010;6(7): e1000991. https://doi.org/10.1371/journal.ppat.1000991 .

Wolfstein A, Nagel CH, Radtke K, Döhner K, Allan VJ, Sodeik B. The Inner Tegument Promotes Herpes Simplex Virus Capsid Motility Along Microtubules in vitro. Traffic. 2005;7(2):227–37. https://doi.org/10.1111/j.1600-0854.2005.00379.x .

Musarrat F, Chouljenko V, Kousoulas KG. Cellular and Viral Determinants of Herpes Simplex Virus 1 Entry and Intracellular Transport toward the Nuclei of Infected Cells. Journal of Virology. 2021;95(7):e02434–20. https://doi.org/10.1128/JVI.02434-20 .

Roizman B. The Checkpoints of Viral Gene Expression in Productive and Latent Infection: the Role of the HDAC/CoREST/LSD1/REST Repressor Complex. Journal of Virology. 2011;85(15):7474–82. https://doi.org/10.1128/Jvi.00180-11 .

Roizman B, Whitley RJ. An Inquiry into the Molecular Basis of HSV Latency and Reactivation. Annual Review of Microbiology. 2013;67(67):355–74. https://doi.org/10.1146/annurev-micro-092412-155654 .

Kalamvoki M, Roizman B. The Histone Acetyltransferase CLOCK Is an Essential Component of the Herpes Simplex Virus 1 Transcriptome That Includes TFIID, ICP4, ICP27, and ICP22. Journal of Virology. 2011;85(18):9472–7. https://doi.org/10.1128/Jvi.00876-11 .

Kalamvoki M, Roizman B. Interwoven Roles of Cyclin D3 and cdk4 Recruited by ICP0 and ICP4 in the Expression of Herpes Simplex Virus Genes. Journal of Virology. 2010;84(19):9709–17. https://doi.org/10.1128/Jvi.01050-10 .

Chee AV, Lopez P, Pandolfi PP, Roizman B. Promyelocytic leukemia protein mediates interferon-based anti-herpes simplex virus 1 effects. Journal of Virology. 2003;77(12):7101–5. https://doi.org/10.1128/Jvi.77.12.7101-7105.2003 .

Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu JM et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Science Translational Medicine. 2020;12(559):eaaz1863. https://doi.org/10.1126/scitranslmed.aaz1863 .

Thomas ECM, Finnen RL, Mewburn JD, Archer SL, Banfield BW. The Herpes Simplex Virus pUL16 and pUL21 Proteins Prevent Capsids from Docking at Nuclear Pore Complexes. Plos Pathogens. 2023;19(12): e1011832. https://doi.org/10.1371/journal.ppat.1011832 .

Cifuentes-Munoz N, El Najjar F, Dutch RE. Viral cell-to-cell spread: Conventional and non-conventional ways. Virus Assembly and Exit Pathways. 2020;108:85–125. https://doi.org/10.1016/bs.aivir.2020.09.002 .

Zhong P, Agosto LM, Munro JB, Mothes W. Cell-to-cell transmission of viruses. Curr Opin Virol. 2013;3(1):44–50. https://doi.org/10.1016/j.coviro.2012.11.004 .

Sattentau Q. Avoiding the void: cell-to-cell spread of human viruses. Nature Reviews Microbiology. 2008;6(11):815–26. https://doi.org/10.1038/nrmicro1972 .

Johnson DC, Baines JD. Herpesviruses remodel host membranes for virus egress. Nature Reviews Microbiology. 2011;9(5):382–94. https://doi.org/10.1038/nrmicro2559 .

Sanjuán R. Collective Infectious Units in Viruses. Trends Microbiol. 2017;25(5):402–12. https://doi.org/10.1016/j.tim.2017.02.003 .

Rice SA. Release of HSV-1 Cell-Free Virions: Mechanisms, Regulation, and Likely Role in Human-Human Transmission. Viruses-Basel. 2021;13(12):2395. https://doi.org/10.3390/v13122395 .

Feutz E, McLeland-Wieser H, Ma JL, Roller RJ. Functional interactions between herpes simplex virus pUL51, pUL7 and gE reveal cell-specific mechanisms for epithelial cell-to-cell spread. Virology. 2019;537:84–96. https://doi.org/10.1016/j.virol.2019.08.014 .

Murphy EA, Carmichael JC, Yokota H, Craven RC, Schmitt A, Wills JW. The HSV-1 mechanisms of cell-to-cell spread and fusion are critically dependent on host PTP1B. PLOS Pathogens. 2018;14(5): e1007054. https://doi.org/10.1371/journal.ppat.1007054 .

Dingwell KS, Johnson DC. The herpes simplex virus gE-gI complex facilitates cell-to-cell spread and binds to components of cell junctions. Journal of Virology. 1998;72(11):8933–42. https://doi.org/10.1128/Jvi.72.11.8933-8942.1998 .

Frost TC, Salnikov M, Rice SA. Enhancement of HSV-1 cell-free virion release by the envelope protein gC. Virology. 2024;596: 110120. https://doi.org/10.1016/j.virol.2024.110120 .

Park D, Lalli J, Sedlackova-Slavikova L, Rice SA. Functional Comparison of Herpes Simplex Virus 1 (HSV-1) and HSV-2 ICP27 Homologs Reveals a Role for ICP27 in Virion Release. Journal of Virology. 2015;89(5):2892–905. https://doi.org/10.1128/Jvi.02994-14 .

Bello-Morales R, Praena B, de la Nuez C, Rejas MT, Guerra M, Galán-Ganga M, et al. Role of Microvesicles in the Spread of Herpes Simplex Virus 1 in Oligodendrocytic Cells. Journal of Virology. 2018;92(10):e00088–18. https://doi.org/10.1128/JVI.00088-18 .

Bello-Morales R, López-Guerrero JA. Extracellular Vesicles in Herpes Viral Spread and Immune Evasion. Frontiers in Microbiology. 2018;9:2572. https://doi.org/10.3389/fmicb.2018.02572 .

Kalamvoki M, Du T, Roizman B. Cells infected with herpes simplex virus 1 export to uninfected cells exosomes containing STING, viral mRNAs, and microRNAs. Proc Natl Acad Sci U S A. 2014;111(46):E4991–6. https://doi.org/10.1073/pnas.1419338111 .

Dogrammatzis C, Deschamps T, Kalamvoki M. Biogenesis of Extracellular Vesicles during Herpes Simplex Virus 1 Infection: Role of the CD63 Tetraspanin. Journal of Virology. 2019;93(2):e01850–18. https://doi.org/10.1128/JVI.01850-18 .

Sun BQ, Yang XW, Hou FJ, Yu XF, Wang QY, Oh HS, et al. Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency. Nature Microbiology. 2021;6(5):682–96. https://doi.org/10.1038/s41564-020-00860-1 .

Ma YL, Deng XM, Zhou LY, Dong HC, Xu P. HSV-1 selectively packs the transcription factor Oct-1 into EVs to facilitate its infection. Frontiers in Microbiology. 2023;14:1205906. https://doi.org/10.3389/fmicb.2023.1205906 .

Antinone SE, Smith GA. Retrograde Axon Transport of Herpes Simplex Virus and Pseudorabies Virus: a Live-Cell Comparative Analysis. Journal of Virology. 2010;84(3):1504–12. https://doi.org/10.1128/Jvi.02029-09 .

Miranda-Saksena M, Denes CE, Diefenbach RJ, Cunningham AL. Infection and Transport of Herpes Simplex Virus Type 1 in Neurons: Role of the Cytoskeleton. Viruses-Basel. 2018;10(2):92. https://doi.org/10.3390/v10020092 .

Simpson SA, Manchak MD, Hager EJ, Krummenacher C, Whitbeck JC, Levin MJ, et al. Nectin-1/HveC mediates herpes simplex virus type 1 entry into primary human sensory neurons and fibroblasts. Journal of Neurovirology. 2005;11(2):208–18. https://doi.org/10.1080/13550280590924214 .

Sayers CL, Elliott G. Herpes Simplex Virus 1 Enters Human Keratinocytes by a Nectin-1-Dependent, Rapid Plasma Membrane Fusion Pathway That Functions at Low Temperature. Journal of Virology. 2016;90(22):10379–89. https://doi.org/10.1128/Jvi.01582-16 .

Pegg CE, Zaichick SV, Bomba-Warczak E, Jovasevic V, Kim D, Kharkwal H, et al. Herpesviruses assimilate kinesin to produce motorized viral particles. Nature. 2021;599(7886):662–6. https://doi.org/10.1038/s41586-021-04106-w .

Bernstein DI, Cardin RD, Smith GA, Pickard GE, Sollars PJ, Dixon DA, et al. The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model. Npj Vaccines. 2020;5(1):104. https://doi.org/10.1038/s41541-020-00254-8 .

Roizman B, Sears AE. An Inquiry into the Mechanisms of Herpes-Simplex Virus Latency. Annual Review of Microbiology. 1987;41:543–71. https://doi.org/10.1146/annurev.mi.41.100187.002551 .

Cliffe AR, Garber DA, Knipe DM. Transcription of the Herpes Simplex Virus Latency-Associated Transcript Promotes the Formation of Facultative Heterochromatin on Lytic Promoters. Journal of Virology. 2009;83(16):8182–90. https://doi.org/10.1128/Jvi.00712-09 .

Kubat NJ, Tran RK, McAnany P, Bloom DC. Specific Histone Tail Modification and Not DNA Methylation Is a Determinant of Herpes Simplex Virus Type 1 Latent Gene Expression. Journal of Virology. 2004;78(3):1139–49. https://doi.org/10.1128/jvi.78.3.1139-1149.2004 .

Kwiatkowski DL, Thompson HW, Bloom DC. The Polycomb Group Protein Bmi1 Binds to the Herpes Simplex Virus 1 Latent Genome and Maintains Repressive Histone Marks during Latency. Journal of Virology. 2009;83(16):8173–81. https://doi.org/10.1128/Jvi.00686-09 .

Sodroski CN, Knipe DM. Nuclear interferon-stimulated gene product maintains heterochromatin on the herpes simplex viral genome to limit lytic infection. Proc Natl Acad Sci U S A. 2023;120(45): e2310996120. https://doi.org/10.1073/pnas.2310996120 .

Li L, Acioglu C, Heary RF, Elkabes S. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behavior and Immunity. 2021;91:740–55. https://doi.org/10.1016/j.bbi.2020.10.007 .

van Lint AL, Kleinert L, Clarke SRM, Stock A, Heath WR, Carbone FR. Latent Infection with Herpes Simplex Virus Is Associated with Ongoing CD8+ T-Cell Stimulation by Parenchymal Cells within Sensory Ganglia. Journal of Virology. 2005;79(23):14843–51. https://doi.org/10.1128/jvi.79.23.14843-14851.2005 .

Leib DA, Bogard CL, Koszvnenchak M, Hicks KA, Coen DM, Knipe DM, et al. A Deletion Mutant of the Latency-Associated Transcript of Herpes-Simplex Virus Type-1 Reactivates from the Latent State with Reduced Frequency. Journal of Virology. 1989;63(7):2893–900. https://doi.org/10.1128/Jvi.63.7.2893-2900.1989 .

Anderson SG, Hamilton J. The Epidemiology of Primary Herpes Simplex Infection. Med J Aust. 1949;1(10):308–11. https://doi.org/10.5694/j.1326-5377.1949.tb70544.x .

Skalsky RL, Cullen BR. Viruses, microRNAs, and Host Interactions. Annual Review of Microbiology, Vol 64, 2010. 2010;64(1):123-41. https://doi.org/10.1146/annurev.micro.112408.134243 .

Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature. 2008;454(7205):780–3. https://doi.org/10.1038/nature07103 .

Tang S, Bertke AS, Patel A, Wang K, Cohen JI, Krause PR. An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor. Proc Natl Acad Sci U S A. 2008;105(31):10931-6. https://doi.org/10.1073/pnas.0801845105 .

Deng Y, Lin YQ, Chen SY, Xiang YH, Chen HJ, Qi SY, et al. Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes. Nature Communications. 2024;15(1):1991. https://doi.org/10.1038/s41467-024-46057-6 .

Tormanen K, Wang SH, Matundan HH, Yu J, Jaggi U, Ghiasi H. Herpes Simplex Virus 1 Small Noncoding RNAs 1 and 2 Activate the Herpesvirus Entry Mediator Promoter. Journal of Virology. 2022;96(3): e0198521. https://doi.org/10.1128/jvi.01985-21 .

Allen SJ, Rhode-Kurnow A, Mott KR, Jiang XZ, Carpenter D, Rodriguez-Barbosa JI, et al. Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency. Journal of Virology. 2014;88(4):1961–71. https://doi.org/10.1128/Jvi.02467-13 .

Tormanen K, Wang SH, Jaggi U, Ghiasi H. Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D. Journal of Virology. 2020;94(16):e00700–20. https://doi.org/10.1128/JVI.00700-20 .

Thompson RL, Sawtell NM. The herpes simplex virus type 1 latency associated transcript locus is required for the maintenance of reactivation competent latent infections. Journal of Neurovirology. 2011;17(6):552–8. https://doi.org/10.1007/s13365-011-0071-0 .

Bloom DC. HSV LAT and neuronal survival. Int Rev Immunol. 2004;23(1–2):187–98. https://doi.org/10.1080/08830180490265592 .

Thompson RL, Sawtell NM. Herpes simplex virus type 1 latency-associated transcript gene promotes neuronal survival. Journal of Virology. 2001;75(14):6660–75. https://doi.org/10.1128/Jvi.75.14.6660-6675.2001 .

Raja P, Lee JS, Pan DL, Pesola JM, Coen DM, Knipe DM. A Herpesviral Lytic Protein Regulates the Structure of Latent Viral Chromatin. Mbio. 2016;7(3):e00633–16. https://doi.org/10.1128/mBio.00633-16 .

Knipe DM, Raja P, Lee JS. Clues to mechanisms of herpesviral latent infection and potential cures. Proc Natl Acad Sci U S A. 2015;112(39):11993–4. https://doi.org/10.1073/pnas.1516224112 .

Gnann JW, Whitley RJ. Herpes Simplex Encephalitis: an Update. Curr Infect Dis Rep. 2017;19(3):13. https://doi.org/10.1007/s11908-017-0568-7 .

Chen SH, Yao HW, Huang WY, Hsu KS, Lei HY, Shiau AL, et al. Efficient reactivation of latent herpes simplex virus from mouse central nervous system tissues. Journal of Virology. 2006;80(24):12387–92. https://doi.org/10.1128/Jvi.01232-06 .

Salazar S, Luong KTY, Koyuncu OO. Cell Intrinsic Determinants of Alpha Herpesvirus Latency and Pathogenesis in the Nervous System. Viruses-Basel. 2023;15(12):2284. https://doi.org/10.3390/v15122284 .

Gopinath D, Koe KH, Maharajan MK, Panda S. A Comprehensive Overview of Epidemiology, Pathogenesis and the Management of Herpes Labialis. Viruses-Basel. 2023;15(1):225. https://doi.org/10.3390/v15010225 .

Jones C. Intimate Relationship Between Stress and Human Alpha-Herpes Virus 1 (HSV-1) Reactivation from Latency. Current Clinical Microbiology Reports. 2023;10(4):236–45. https://doi.org/10.1007/s40588-023-00202-9 .

Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–New mechanisms for old drugs. New England Journal of Medicine. 2005;353(16):1711–23. https://doi.org/10.1056/NEJMra050541 .

Busillo JM, Cidlowski JA. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol Metab. 2013;24(3):109–19. https://doi.org/10.1016/j.tem.2012.11.005 .

Harrison KS, Wijesekera N, Robinson AGJ, Santos VC, Oakley RH, Cidlowski JA, et al. Impaired glucocorticoid receptor function attenuates herpes simplex virus 1 production during explant-induced reactivation from latency in female mice. Journal of Virology. 2023;97(10): e0130523. https://doi.org/10.1128/jvi.01305-23 .

Deleon M, Covenas R, Chadi G, Narvaez JA, Fuxe K, Cintra A. Subpopulations of Primary Sensory Neurons Show Coexistence of Neuropeptides and Glucocorticoid Receptors in the Rat Spinal and Trigeminal Ganglia. Brain Res. 1994;636(2):338–42. https://doi.org/10.1016/0006-8993(94)91034-0 .

Rodríguez MC, Dybas JM, Hughes J, Weitzman MD, Boutell C. The HSV-1 ubiquitin ligase ICP0: Modifying the cellular proteome to promote infection. Virus Research. 2020;285: 198015. https://doi.org/10.1016/j.virusres.2020.198015 .

Maul GG, Everett RD. The Nuclear Location of Pml, a Cellular Member of the C3hc4 Zinc-Binding Domain Protein Family, Is Rearranged during Herpes-Simplex Virus-Infection by the C3hc4 Viral Protein Icp0. Journal of General Virology. 1994;75:1223–33. https://doi.org/10.1099/0022-1317-75-6-1223 .

Gu HD, Liang Y, Mandel G, Roizman B. Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells. Proc Natl Acad Sci U S A. 2005;102(21):7571–6. https://doi.org/10.1073/pnas.0502658102 .

Fan DJ, Wang MS, Cheng AC, Jia RY, Yang Q, Wu Y, et al. The Role of VP16 in the Life Cycle of Alphaherpesviruses. Frontiers in Microbiology. 2020;11:1910. https://doi.org/10.3389/fmicb.2020.01910 .

Chao MV. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nature Reviews Neuroscience. 2003;4(4):299–309. https://doi.org/10.1038/nrn1078 .

Camarena V, Kobayashi M, Kim JY, Roehm P, Perez R, Gardner J, et al. Nature and Duration of Growth Factor Signaling through Receptor Tyrosine Kinases Regulates HSV-1 Latency in Neurons. Cell Host & Microbe. 2010;8(4):320–30. https://doi.org/10.1016/j.chom.2010.09.007 .

Sun GR, Kropp KA, Kirchner M, Plückebaum N, Selich A, Serrero M, et al. Herpes simplex virus type 1 modifies the protein composition of extracellular vesicles to promote neurite outgrowth and neuroinfection. Mbio. 2024;15(2): e0330823. https://doi.org/10.1128/mbio.03308-23 .

Cabrera JR, Viejo-Borbolla A, Martinez-Martín N, Blanco S, Wandosell F, Alcamí A. Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection. Plos Pathogens. 2015;11(1): e1004571. https://doi.org/10.1371/journal.ppat.1004571 .

Kropp KA, López-Muñoz AD, Ritter B, Martín R, Rastrojo A, Srivaratharajan S, et al. Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner. Journal of Virology. 2020;94(20):e01370–20. https://doi.org/10.1128/JVI.01370-20 .

Hill JM, Garza HH, Helmy MF, Cook SD, Osborne PA, Johnson EM, et al. Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits. Journal of Neurovirology. 1997;3(3):206–11. https://doi.org/10.3109/13550289709018295 .

Jaggi U, Matundan HH, Oh JJ, Ghiasi H, Frappier L. Absence of CD80 reduces HSV-1 replication in the eye and delays reactivation but not latency levels. Journal of Virology. 2024;98(3): e0201023. https://doi.org/10.1128/jvi.02010-23 .

Dochnal SA, Whitford AL, Francois AK, Krakowiak PA, Cuddy S, Cliffe AR. c-Jun signaling during initial HSV-1 infection modulates latency to enhance later reactivation in addition to directly promoting the progression to full reactivation. J Virol. 2024;98(2): e0176423. https://doi.org/10.1128/jvi.01764-23 .

Hu HL, Srinivas KP, Wang S, Chao MV, Lionnet T, Mohr I et al. Single‐cell transcriptomics identifies Gadd45b as a regulator of herpesvirus‐reactivating neurons. EMBO Rep. 2021;23(2):e53543. https://doi.org/10.15252/embr.202153543 .

Sawtell NM, Poon DK, Tansky CS, Thompson RL. The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation. Journal of Virology. 1998;72(7):5343–50. https://doi.org/10.1128/Jvi.72.7.5343-5350.1998 .

Schiffer JT, Abu-Raddad L, Mark KE, Zhu J, Selke S, Koelle DM, et al. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proceedings of the National Academy of Sciences. 2010;107(44):18973–8. https://doi.org/10.1073/pnas.1006614107 .

Schiffer JT, Swan DA, Prlic M, Lund JM. Herpes simplex virus-2 dynamics as a probe to measure the extremely rapid and spatially localized tissue-resident T-cell response. Immunol Rev. 2018;285(1):113–33. https://doi.org/10.1111/imr.12672 .

Roychoudhury P, Swan DA, Duke ER, Corey L, Zhu J, Davé VA, et al. Tissue-resident T cell derived cytokines eliminate herpes simplex virus-2-infected cells. Journal of Clinical Investigation. 2020;130(6):2903–19. https://doi.org/10.1172/Jci132583 .

Schenkel JM, Masopust D. Tissue-Resident Memory T Cells. Immunity. 2014;41(6):886–97. https://doi.org/10.1016/j.immuni.2014.12.007 .

Schiffer JT, Swan DA, Roychoudhury P, Lund JM, Prlic M, Zhu J, et al. A Fixed Spatial Structure of CD8 T Cells in Tissue during Chronic HSV-2 Infection. J Immunol. 2018;201(5):1522–35. https://doi.org/10.4049/jimmunol.1800471 .

Chen NH, Xia PP, Li SJ, Zhang TJ, Wang TT, Zhu JZ. RNA Sensors of the Innate Immune System and Their Detection of Pathogens. Iubmb Life. 2017;69(5):297–304. https://doi.org/10.1002/iub.1625 .

Verzosa AL, McGeever LA, Bhark SJ, Delgado T, Salazar N, Sanchez EL. Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms. Frontiers in Immunology. 2021;12: 644664. https://doi.org/10.3389/fimmu.2021.644664 .

Chew T, Taylor KE, Mossman KL. Innate and Adaptive Immune Responses to Herpes Simplex Virus. Viruses-Basel. 2009;1(3):979–1002. https://doi.org/10.3390/v1030979 .

Zhang JJ, Zhao J, Xu SM, Li JH, He SP, Zeng Y, et al. Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host & Microbe. 2018;24(2):234–48. https://doi.org/10.1016/j.chom.2018.07.004 .

Su CH, Zheng CF. Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41. Journal of Virology. 2017;91(6):e02414–16. https://doi.org/10.1128/JVI.02414-16 .

Xu H, Su C, Pearson A, Mody CH, Zheng C, Sandri-Goldin RM. Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-κB Activation. Journal of Virology. 2017;91(7):e00025–17. https://doi.org/10.1128/jvi.00025-17 .

Wang S, Wang KZ, Li J, Zheng CF. Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3. Journal of Virology. 2013;87(21):11851–60. https://doi.org/10.1128/Jvi.01211-13 .

Zhang DD, Su CH, Zheng CF. Herpes Simplex Virus 1 Serine Protease VP24 Blocks the DNA-Sensing Signal Pathway by Abrogating Activation of Interferon Regulatory Factor 3. Journal of Virology. 2016;90(12):5824–9. https://doi.org/10.1128/Jvi.00186-16 .

Tognarelli EI, Palomino TF, Corrales N, Bueno SM, Kalergis AM, González PA. Herpes Simplex Virus Evasion of Early Host Antiviral Responses. Frontiers in Cellular and Infection Microbiology. 2019;9:127. https://doi.org/10.3389/fcimb.2019.00127 .

van Gent M, Chiang JJ, Muppala S, Chiang C, Azab W, Kattenhorn L, et al. The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity. Journal of Virology. 2022;96(4): e0151021. https://doi.org/10.1128/jvi.01510-21 .

Zhao J, Zeng Y, Xu SM, Chen J, Shen GB, Yu CQ, et al. A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation. Cell Host & Microbe. 2016;20(6):770–84. https://doi.org/10.1016/j.chom.2016.10.011 .

Lanfranca MP, Mostafa HH, Davido DJ. HSV-1 ICP0: An E3 Ubiquitin Ligase That Counteracts Host Intrinsic and Innate Immunity. Cells-Basel. 2014;3(2):438–54. https://doi.org/10.3390/cells3020438 .

van Lint AL, Murawski MR, Goodbody RE, Severa M, Fitzgerald KA, Finberg RW, et al. Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling. Journal of Virology. 2010;84(20):10802–11. https://doi.org/10.1128/jvi.00063-10 .

Johnson KE, Song B, Knipe DM. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling. Virology. 2008;374(2):487–94. https://doi.org/10.1016/j.virol.2008.01.001 .

Pasquero S, Gugliesi F, Biolatti M, Dell’Oste V, Albano C, Bajetto G, et al. Citrullination profile analysis reveals peptidylarginine deaminase 3 as an HSV-1 target to dampen the activity of candidate antiviral restriction factors. Plos Pathogens. 2023;19(12): e1011849. https://doi.org/10.1371/journal.ppat.1011849 .

Orvedahl A, Alexander D, Tallóczy Z, Sun Q, Wei Y, Zhang W et al. HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein. Cell Host & Microbe. 2007;1(1):23-35. https://doi.org/10.1016/j.chom.2006.12.001 .

Farahani E, Reiner LS, Narita R, Serrero MC, Skouboe MK, van der Horst D, et al. The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation. Cell Rep. 2024;43(2): 113792. https://doi.org/10.1016/j.celrep.2024.113792 .

Iijima N, Linehan MM, Zamora M, Butkus D, Dunn R, Kehry MR, et al. Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J Exp Med. 2008;205(13):3041–52. https://doi.org/10.1084/jem.20082039 .

Sajic D, Patrick AJ, Rosenthal KL. Mucosal delivery of CpG oligodeoxynucleotides expands functional dendritic cells and macrophages in the vagina. Immunology. 2005;114(2):213–24. https://doi.org/10.1111/j.1365-2567.2004.02081.x .

Martin ET, Krantz E, Gottlieb SL, Magaret AS, Langenberg A, Stanberry L, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233–40. https://doi.org/10.1001/archinternmed.2009.177 .

Smith JB, Herbert JJ, Truong NR, Cunningham AL. Cytokines and chemokines: The vital role they play in herpes simplex virus mucosal immunology. Front Immunol. 2022;13: 936235. https://doi.org/10.3389/fimmu.2022.936235 .

Nakanishi Y, Lu B, Gerard C, Iwasaki A. CD8 T lymphocyte mobilization to virus-infected tissue requires CD4 T-cell help. Nature. 2009;462(7272):510–3. https://doi.org/10.1038/nature08511 .

Wong SBJ, Bos R, Sherman LA. Tumor-specific CD4 T cells render the tumor environment permissive for infiltration by low-avidity CD8 T cells. J Immunol. 2008;180(5):3122–31. https://doi.org/10.4049/jimmunol.180.5.3122 .

Hoshino Y, Pesnicak L, Cohen JI, Straus SE. Rates of reactivation of latent herpes simplex virus from mouse trigeminal ganglia ex vivo correlate directly with viral load and inversely with number of infiltrating CD8 T cells. Journal of Virology. 2007;81(15):8157–64. https://doi.org/10.1128/Jvi.00474-07 .

Simmons A, Tscharke DC. Anti-Cd8 Impairs Clearance of Herpes-Simplex Virus from the Nervous-System-Implications for the Fate of Virally Infected Neurons. J Exp Med. 1992;175(5):1337–44. https://doi.org/10.1084/jem.175.5.1337 .

Khanna KM, Bonneau RH, Kinchington PR, Hendricks RL. Herpes simplex virus-specific memory CD8 T cells are selectively activated and retained in latently infected sensory ganglia. Immunity. 2003;18(5):593–603. https://doi.org/10.1016/S1074-7613(03)00112-2 .

Koelle DM, Posavad CM, Barnum GR, Johnson ML, Frank JM, Corey L. Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes. Journal of Clinical Investigation. 1998;101(7):1500–8. https://doi.org/10.1172/Jci1758 .

Zhu J, Koelle DM, Cao JH, Vazquez J, Huang ML, Hladik F, et al. Virus-specific CD8 T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med. 2007;204(3):595–603. https://doi.org/10.1084/jem.20061792 .

Schiffer JT, Abu-Raddad L, Mark KE, Zhu J, Selke S, Magaret A et al. Frequent Release of Low Amounts of Herpes Simplex Virus from Neurons: Results of a Mathematical Model. Science Translational Medicine. 2009;1(7):7ra16. https://doi.org/10.1126/scitranslmed.3000193 .

Suvas S, Azkur AK, Kim BS, Kumaraguru U, Rouse BT. CD4 CD25 regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol. 2004;172(7):4123–32. https://doi.org/10.4049/jimmunol.172.7.4123 .

Oldham ML, Grigorieff N, Chen J. Structure of the transporter associated with antigen processing trapped by herpes simplex virus. Elife. 2016;5: e21829. https://doi.org/10.7554/eLife.21829 .

Jin H, Ma Y, Prabhakar BS, Feng Z, Valyi-Nagy T, Yan Z et al. The γ134.5 Protein of Herpes Simplex Virus 1 Is Required To Interfere with Dendritic Cell Maturation during Productive Infection. Journal of Virology. 2009;83(10):4984-94. https://doi.org/10.1128/jvi.02535-08 .

Matundan H, Ghiasi H. Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells. Journal of Virology. 2019;93(3):e01803–18. https://doi.org/10.1128/JVI.01803-18 .

Budida R, Stankov MV, Döhner K, Buch A, Panayotova-Dimitrova D, Tappe KA, et al. Herpes simplex virus 1 interferes with autophagy of murine dendritic cells and impairs their ability to stimulate CD8 T lymphocytes. European Journal of Immunology. 2017;47(10):1819–34. https://doi.org/10.1002/eji.201646908 .

Prechtel AT, Turza NM, Kobelt DJ, Eisemann JI, Coffin RS, McGrath Y, et al. Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration. Journal of General Virology. 2005;86(Pt 6):1645–57. https://doi.org/10.1099/vir.0.80852-0 .

Bedoui S, Greyer M. The role of dendritic cells in immunity against primary herpes simplex virus infections. Frontiers in Microbiology. 2014;5:533. https://doi.org/10.3389/fmicb.2014.00533 .

Retamal-Díaz A, Weiss KA, Tognarelli EI, Freire M, Bueno SM, Herold BC, et al. US6 Gene Deletion in Herpes Simplex Virus Type 2 Enhances Dendritic Cell Function and T Cell Activation. Frontiers in Immunology. 2017;8:1523. https://doi.org/10.3389/fimmu.2017.01523 .

Orr MT, Edelmann KH, Vieira J, Corey L, Raulet DH, Wilson CB. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice. Plos Pathogens. 2005;1(1):62–71. https://doi.org/10.1371/journal.ppat.0010007 .

Kim M, Osborne NR, Zeng WG, Donaghy H, McKinnon K, Jackson DC, et al. Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes. J Immunol. 2012;188(9):4158–70. https://doi.org/10.4049/jimmunol.1103450 .

Friedman HM, Cohen GH, Eisenberg RJ, Seidel CA, Cines DB. Glycoprotein-C of Herpes-Simplex Virus-1 Acts as a Receptor for the C3b Complement Component on Infected-Cells. Nature. 1984;309(5969):633–5. https://doi.org/10.1038/309633a0 .

McNearney TA, Odell C, Holers VM, Spear PG, Atkinson JP. Herpes simplex virus glycoproteins gC-1 and gC-2 bind to the third component of complement and provide protection against complement-mediated neutralization of viral infectivity. The Journal of experimental medicine. 1987;166(5):1525–35. https://doi.org/10.1084/jem.166.5.1525 .

Lubinski JM, Jiang M, Hook L, Chang Y, Sarver C, Mastellos D, et al. Herpes simplex virus type 1 evades the effects of antibody and complement in vivo. Journal of Virology. 2002;76(18):9232–41. https://doi.org/10.1128/Jvi.76.18.9232-9241.2002 .

Hook LM, Lubinski JM, Jiang M, Pangburn MK, Friedman HM. Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural immunoglobulin M antibody. Journal of Virology. 2006;80(8):4038–46. https://doi.org/10.1128/Jvi.80.8.4038-4046.2006 .

Lubinski JM, Lazear HM, Awasthi S, Wang FS, Friedman HM. The Herpes Simplex Virus 1 IgG Fc Receptor Blocks Antibody-Mediated Complement Activation and Antibody-Dependent Cellular Cytotoxicity. Journal of Virology. 2011;85(7):3239–49. https://doi.org/10.1128/Jvi.02509-10 .

Awasthi S, Friedman HM. An mRNA vaccine to prevent genital herpes. Translational Research. 2022;242:56–65. https://doi.org/10.1016/j.trsl.2021.12.006 .

Egan K, Hook LM, Latourette P, Desmond A, Awasthi S, Friedman HM. Vaccines to prevent genital herpes. Translational Research. 2020;220:138–52. https://doi.org/10.1016/j.trsl.2020.03.004 .

Sharma D, Sharma S, Akojwar N, Dondulkar A, Yenorkar N, Pandita D, et al. An Insight into Current Treatment Strategies, Their Limitations, and Ongoing Developments in Vaccine Technologies against Herpes Simplex Infections. Vaccines. 2023;11(2):206. https://doi.org/10.3390/vaccines11020206 .

Egan KP, Hook LM, Naughton A, Pardi N, Awasthi S, Cohen GH, et al. An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection. Plos Pathogens. 2020;16(7): e1008795. https://doi.org/10.1371/journal.ppat.1008795 .

Spear PG, Longnecker R. Herpesvirus entry: an update. Journal of Virology. 2003;77(19):10179–85. https://doi.org/10.1128/Jvi.77.19.10179-10185.2003 .

Awasthi S, Hook LM, Shaw CE, Friedman HM. A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model. Human Vaccines & Immunotherapeutics. 2017;13(12):2785–93. https://doi.org/10.1080/21645515.2017.1323604 .

Kawamura Y, Komoto S, Fukuda S, Kugita M, Tang S, Patel A, et al. Development of recombinant rotavirus carrying herpes simplex virus 2 glycoprotein D gene based on reverse genetics technology. Microbiol Immunol. 2024;68(2):56–64. https://doi.org/10.1111/1348-0421.13107 .

Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. New England Journal of Medicine. 2002;347(21):1652–61. https://doi.org/10.1056/NEJMoa011915 .

Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, et al. Efficacy Results of a Trial of a Herpes Simplex Vaccine. New England Journal of Medicine. 2012;366(1):34–43. https://doi.org/10.1056/NEJMoa1103151 .

Corey L, Langenberg AGM, Ashley R, Sekulovich RE, Izu AE, Douglas JM, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection-Two randomized controlled trials. Jama-J Am Med Assoc. 1999;282(4):331–40. https://doi.org/10.1001/jama.282.4.331 .

Koelle DM, Corey L. Recent progress in herpes simplex virus immunobiology and vaccine research. Clinical Microbiology Reviews. 2003;16(1):96–113. https://doi.org/10.1128/Cmr.16.1.96-113.2003 .

Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment (vol 23, pg e450, 2022). Lancet Oncol. 2022;23(11):e450–8. https://doi.org/10.1016/S1470-2045(22)00372-2 .

Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med. 2018;215(6):1571–88. https://doi.org/10.1084/jem.20171450 .

Awasthi S, Hook LM, Pardi N, Wang FS, Myles A, Cancro MP et al. Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. Science Immunology. 2019;4(39):eaaw7083. https://doi.org/10.1126/sciimmunol.aaw7083 .

Awasthi S, Knox JJ, Desmond A, Alameh M-G, Gaudette BT, Lubinski JM, et al. Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models. Journal of Clinical Investigation. 2021;131(23): e152310. https://doi.org/10.1172/jci152310 .

Egan KP, Awasthi S, Tebaldi G, Hook LM, Naughton AM, Fowler BT, et al. A Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Provides Outstanding Protection in Mice against Genital and Non-Genital HSV-1 Infection, Comparable to the Same Antigens Derived from HSV-1. Viruses-Basel. 2023;15(7):1483. https://doi.org/10.3390/v15071483 .

LaTourette PC, Awasthi S, Desmond A, Pardi N, Cohen GH, Weissman D, et al. Protection against herpes simplex virus type 2 infection in a neonatal murine model using a trivalent nucleoside-modified mRNA in lipid nanoparticle vaccine. Vaccine. 2020;38(47):7409–13. https://doi.org/10.1016/j.vaccine.2020.09.079 .

Cohen JI. Vaccination to Reduce Reactivation of Herpes Simplex Virus Type 2. J Infect Dis. 2017;215(6):844–6. https://doi.org/10.1093/infdis/jix006 .

Wald A, Koelle DM, Fife K, Warren T, LeClair K, Chicz RM, et al. Safety and immunogenicity of long HSV-2 peptides complexed with rhHsc70 in HSV-2 seropositive persons. Vaccine. 2011;29(47):8520–9. https://doi.org/10.1016/j.vaccine.2011.09.046 .

Chandra J, Woo WP, Dutton JL, Xu Y, Li B, Kinrade S, et al. Immune responses to a HSV-2 polynucleotide immunotherapy COR-1 in HSV-2 positive subjects: A randomized double blinded phase I/IIa trial. Plos One. 2019;14(12): e0226320. https://doi.org/10.1371/journal.pone.0226320 .

Bernstein DI, Wald A, Warren T, Fife K, Tyring S, Lee P, et al. Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial. J Infect Dis. 2017;215(6):856–64. https://doi.org/10.1093/infdis/jix004 .

Iyer AV, Pahar B, Chouljenko VN, Walker JD, Stanfield B, Kousoulas KG. Single dose of Glycoprotein K (gK)-deleted HSV-1 live-attenuated virus protects mice against lethal vaginal challenge with HSV-1 and HSV-2 and induces lasting T cell memory immune responses. Virol J. 2013;10:317. https://doi.org/10.1186/1743-422x-10-317 .

Stanfield BA, Rider PJF, Caskey J, Del Piero F, Kousoulas KG. Intramuscular vaccination of guinea pigs with the live-attenuated human herpes simplex vaccine VC2 stimulates a transcriptional profile of vaginal Th17 and regulatory Tr1 responses. Vaccine. 2018;36(20):2842–9. https://doi.org/10.1016/j.vaccine.2018.03.075 .

Bernstein DI, Pullum DA, Cardin RD, Bravo FJ, Dixon DA, Kousoulas KG. The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes. Vaccine. 2019;37(1):61–8. https://doi.org/10.1016/j.vaccine.2018.11.042 .

Malik S, Sah R, Ahsan O, Muhammad K, Waheed Y. Insights into the Novel Therapeutics and Vaccines against Herpes Simplex Virus. Vaccines. 2023;11(2):325. https://doi.org/10.3390/vaccines11020325 .

Wijesinghe VN, Farouk IA, Zabidi NZ, Puniyamurti A, Choo WS, Lal SK. Current vaccine approaches and emerging strategies against herpes simplex virus (HSV). Expert Review of Vaccines. 2021;20(9):1077–96. https://doi.org/10.1080/14760584.2021.1960162 .

Shalhout SZ, Miller DM, Emerick KS, Kaufman HL. Therapy with oncolytic viruses: progress and challenges. Nature Reviews Clinical Oncology. 2023;20(3):160–77. https://doi.org/10.1038/s41571-022-00719-w .

Ilkow CS, Swift SL, Bell JC, Diallo JS. From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer. Plos Pathogens. 2014;10(1): e1003836. https://doi.org/10.1371/journal.ppat.1003836 .

Jahan N, Ghouse SM, Martuza RL, Rabkin SD. In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV. Viruses-Basel. 2021;13(9):1740. https://doi.org/10.3390/v13091740 .

Zhao J, Wang H, Chen J, Wang C, Gong N, Zhou F, et al. An oncolytic HSV-1 armed with Visfatin enhances antitumor effects by remodeling tumor microenvironment against murine pancreatic cancer. Biochem Biophys Res Commun. 2024;718: 149931. https://doi.org/10.1016/j.bbrc.2024.149931 .

Taguchi S, Fukuhara H, Todo T. Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. Jap J Clin Oncol. 2019;49(3):201–9. https://doi.org/10.1093/jjco/hyy170 .

Frampton JE. Teserpaturev/G47Δ: First Approval. Biodrugs. 2022;36(5):667–72. https://doi.org/10.1007/s40259-022-00553-7 .

Chen LJ, Zuo MS, Zhou Q, Wang Y. Oncolytic virotherapy in cancer treatment: challenges and optimization prospects. Frontiers in Immunology. 2023;14:1308890. https://doi.org/10.3389/fimmu.2023.1308890 .

Omuro A, DeAngelis LM. Glioblastoma and Other Malignant Gliomas A Clinical Review. Jama-J Am Med Assoc. 2013;310(17):1842–50. https://doi.org/10.1001/jama.2013.280319 .

Ling AL, Solomon IH, Landivar AM, Nakashima H, Woods JK, Santos A, et al. Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature. 2023;623(7985):157–66. https://doi.org/10.1038/s41586-023-06623-2 .

Wang Y, Wang RY, Hu H, Jin J, Cai LK, Zhang SQ, et al. Preclinical safety assessment of an oncolytic herpes simplex virus type 2 expressed PD-L1/CD3 bispecific antibody. Int Immunopharmacol. 2023;124(Pt B): 110975. https://doi.org/10.1016/j.intimp.2023.110975 .

Deng XY, Shen YA, Yi M, Zhang CM, Zhao B, Zhong GS, et al. Combination of novel oncolytic herpesvirus with paclitaxel as an efficient strategy for breast cancer therapy. J Med Virol. 2023;95(5): e28768. https://doi.org/10.1002/jmv.28768 .

Cui CL, Wang X, Lian B, Ji Q, Zhou L, Chi ZH, et al. OrienX010, an oncolytic virus, in patients with unresectable stage IIIC-IV melanoma: a phase Ib study. Journal for Immunotherapy of Cancer. 2022;10(4): e004307. https://doi.org/10.1136/jitc-2021-004307 .

Zawit M, Swami U, Awada H, Arnouk J, Milhem M, Zakharia Y. Current status of intralesional agents in treatment of malignant melanoma. Annals of Translational Medicine. 2021;9(12):1038. https://doi.org/10.21037/atm-21-491 .

Frank I, Friedman HM. A Novel Function of the Herpes-Simplex Virus Type-1 Fc Receptor-Participation in Bipolar Bridging of Antiviral Immunoglobulin-G. Journal of Virology. 1989;63(11):4479–88. https://doi.org/10.1128/Jvi.63.11.4479-4488.1989 .

Ma WQ, He HB, Wang HM. Oncolytic herpes simplex virus and immunotherapy. BMC Immunol. 2018;19(1):40. https://doi.org/10.1186/s12865-018-0281-9 .

Allen L, Allen L, Carr SB, Davies G, Downey D, Egan M, et al. Future therapies for cystic fibrosis. Nature Communications. 2023;14(1):693. https://doi.org/10.1038/s41467-023-36244-2 .

Tovar Vetencourt A, Sayed-Ahmed I, Gomez J, Chen H, Agostini B, Carroll K, et al. Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa. New England Journal of Medicine. 2024;390(6):530–5. https://doi.org/10.1056/NEJMoa2301244 .

Guide SV, Gonzalez ME, Bagci IS, Agostini B, Chen HB, Feeney G, et al. Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. New England Journal of Medicine. 2022;387(24):2211–9. https://doi.org/10.1056/NEJMoa2206663 .

Ma L, Dichwalkar T, Chang JYH, Cossette B, Garafola D, Zhang AQ, et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science. 2019;365(6449):162–8. https://doi.org/10.1126/science.aav8692 .

Ottolino-Perry K, Diallo JS, Lichty BD, Bell JC, McCart JA. Intelligent Design: Combination Therapy With Oncolytic Viruses. Mol Ther. 2010;18(2):251–63. https://doi.org/10.1038/mt.2009.283 .

Sun M, Kong LX, Wang XD, Lu XG, Gao QS, Geller AI. Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson’s disease. Brain Res. 2005;1052(2):119–29. https://doi.org/10.1016/j.brainres.2005.05.072 .

Glorioso JC, Fink DJ. Herpes vector-mediated gene transfer in treatment of diseases of the nervous system. Annual Review of Microbiology. 2004;58:253–71. https://doi.org/10.1146/annurev.micro.58.030603.123709 .

Frazer ME, Hughes JE, Mastrangelo MA, Tibbens JL, Federoff HJ, Bowers WJ. Reduced Pathology and Improved Behavioral Performance in Alzheimer’s Disease Mice Vaccinated With HSV Amplicons Expressing Amyloid-β and Interleukin-4. Mol Ther. 2008;16(5):845–53. https://doi.org/10.1038/mt.2008.39 .

Wang D, Wang XW, Peng XC, Xiang Y, Song SB, Wang YY, et al. CRISPR/Cas9 genome editing technology significantly accelerated herpes simplex virus research. Cancer Gene Ther. 2018;25(5–6):93–105. https://doi.org/10.1038/s41417-018-0016-3 .

Xu XM, Holmes TC, Luo MH, Beier KT, Horwitz GD, Zhao F, et al. Viral Vectors for Neural Circuit Mapping and Recent Advances in Trans-synaptic Anterograde Tracers. Neuron. 2020;107(6):1029–47. https://doi.org/10.1016/j.neuron.2020.07.010 .

Li JM, Liu TA, Dong Y, Kondoh K, Lu ZH. Trans-synaptic Neural Circuit-Tracing with Neurotropic Viruses. Neurosci Bull. 2019;35(5):909–20. https://doi.org/10.1007/s12264-019-00374-9 .

Nassi JJ, Cepko CL, Born RT, Beier KT. Neuroanatomy goes viral! Front Neuroanat. 2015;9:80. https://doi.org/10.3389/fnana.2015.00080 .

Li D, Yang H, Xiong F, Xu XM, Zeng WB, Zhao F, et al. Anterograde Neuronal Circuit Tracers Derived from Herpes Simplex Virus 1: Development, Application, and Perspectives. Int J Mol Sci. 2020;21(16):5937. https://doi.org/10.3390/ijms21165937 .

Yu DG, Ellis HM, Lee EC, Jenkins NA, Copeland NG, Court DL. An efficient recombination system for chromosome engineering in Escherichia coli. Proc Natl Acad Sci U S A. 2000;97(11):5978–83. https://doi.org/10.1073/pnas.100127597 .

Download references

Acknowledgements

We would like to acknowledge the researchers whose relevant works are cited in this review and all co-authors for their support.

This work was supported by Chinese National Natural Science Funds (31925013, 32125016, U20A20393, T2321005, 82103115), special programs from the Ministry of Science and Technology of China (2021YFA1101000, 2022YFA1105200 and 2023YFA1800200), Suzhou Innovation and Entrepreneurship Leading Talent Program (ZXL2022505, ZXL2022442), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and "Leading Goose" R&D Program of Zhejiang Province (2024C03142).

Author information

Authors and affiliations.

International Biomed-X Research Center, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China

Lan Bai & Long Zhang

Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China

Lan Bai & Jiuzhi Xu

Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China

School of Medicine, Zhejiang University City College, Hangzhou, 310015, China

Linghui Zeng & Fangfang Zhou

MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China

Cancer Center, Zhejiang University, Hangzhou, China

Institutes of Biology and Medical Science, Soochow University, Suzhou, 215123, China

Fangfang Zhou

You can also search for this author in PubMed   Google Scholar

Contributions

Lan Bai & Jiuzhi Xu wrote the manuscript, drew figures and tables. Linghui Zeng, Long Zhang and Fangfang Zhou provided the conceptual idea and revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Linghui Zeng , Long Zhang or Fangfang Zhou .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors declare no conflicts of interest.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Bai, L., Xu, J., Zeng, L. et al. A review of HSV pathogenesis, vaccine development, and advanced applications. Mol Biomed 5 , 35 (2024). https://doi.org/10.1186/s43556-024-00199-7

Download citation

Received : 08 May 2024

Accepted : 02 August 2024

Published : 29 August 2024

DOI : https://doi.org/10.1186/s43556-024-00199-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Herpes simplex virus
• Pathogenesis
• Immune evasion
• Biological application
• Find a journal
• Publish with us
• Track your research

share this!

August 27, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Study sheds light on what enables herpes simplex virus to become impervious to drugs

by Harvard Medical School

All organisms—from fungi to mammals—have the capacity to evolve and adapt to their environments. But viruses are master shapeshifters with an ability to mutate greater than any other organism. As a result, they can evade treatments or acquire resistance to once-effective antiviral medications.

Working with herpes simplex virus (HSV), a study led by Harvard Medical School researchers sheds light on one of the ways in which the virus becomes resistant to treatment, a problem that could be particularly challenging among people with compromised immune function , including those receiving immune-suppressive treatment and those born with immune deficiencies.

Using a sophisticated imaging technique called cryogenic electron microscopy (cryo-EM), the researchers found that how parts of a protein responsible for viral replication move into different positions can alter the virus's susceptibility to medicines.

The findings, published Aug. 27 in Cell , answer long-standing questions about why certain viruses, but not others, are susceptible to antiviral medications and how viruses become impervious to drugs. The results could inform new approaches that impede viruses' capacity to outpace effective therapies.

Counterintuitive results

Researchers have long known changes that occur on the parts of a virus where antiviral drugs bind to it can render it resistant to therapy. However, the HMS researchers found that, much to their surprise, this was often not the case with HSV.

Instead, the investigators discovered that protein mutations linked to drug resistance often arise far from the drug's target location. These mutations involve alterations that change the movements of a viral protein, or enzyme, that allows the virus to replicate itself. This raises the possibility that using drugs to block or freeze the conformational changes of these viral proteins could be a successful strategy for overcoming drug resistance.

"Our findings show that we have to think beyond targeting the typical drug-binding sites," said the study's senior author, Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at HMS and infectious disease specialist at Brigham and Women's Hospital. "This really helps us see drug resistance in a new light."

The new findings propel the understanding of how alterations in the conformation of a viral protein—or changes in how the different parts within that protein move when it carries out its function—fuel drug resistance and may be relevant for understanding drug effectiveness and drug resistance in other viruses, the researchers noted.

HSV, estimated to affect billions of people worldwide, is most commonly known as the cause of cold sores and fever blisters, but it can also lead to serious eye infections, brain inflammation, and liver damage in people with compromised immunity. Additionally, HSV can be transmitted from mother to baby via the birth canal during delivery and cause life-threatening neonatal infections.

Clues on resistance rooted in structure and movement

A virus can't replicate on its own. To do so, viruses must enter a host cell, where they unleash their replication tools—proteins called polymerases—to make copies of themselves.

The current study focused on one such protein—a viral DNA polymerase—crucial for HSV's ability to reproduce and propagate itself. The ability to carry out its function is rooted in the DNA polymerase's structure, often likened to a hand with three parts: the palm, the thumb, and the fingers, each carrying out critical functions.

Given their role in enabling replication, these polymerases are critical targets of antiviral drugs, which aim to stop the virus from reproducing itself and halt the spread of infection. The HSV polymerase is the target of acyclovir, the leading antiviral drug for treating HSV infection, and of foscarnet, a second-line drug used for drug-resistant infections. Both drugs work by targeting the viral polymerase but do so in different ways.

Scientists have long struggled to fully understand how alterations in the polymerase render the virus impervious to normal doses of antiviral drugs and, more broadly, why acyclovir and foscarnet are not always effective against the altered forms of the HSV polymerase.

"Over the years, the structures of many polymerases from various organisms have been determined, but we still don't fully understand what makes some polymerases, but not others, susceptible to certain drugs," Abraham said. "Our study reveals that how the different parts of the polymerases move, known as their conformational dynamics, is a critical component of their relative susceptibility to drugs."

Proteins, including polymerases, are not rigid, motionless objects. Instead, they are flexible and dynamic. Composed of amino acids, they initially fold into a steady, three‐dimensional shape known as the native conformation—their baseline structure.

But as a result of various bonding and dispersing forces, the different parts of proteins can move when they come into contact with other cellular components as well as through external influences, such as changes in pH or temperature. For example, the fingers of a polymerase protein can open and close, as would the fingers of a hand.

Conformational dynamics—the ability of different parts of a protein to move—allows them to efficiently administer many essential functions with a limited number of ingredients. A better understanding of polymerase conformational dynamics is the missing link between structures and functions, including whether a protein responds to a drug and whether it could become resistant to it down the road.

Unraveling the mystery

Many structural studies have captured DNA polymerases in various distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. To solve the puzzle, the researchers carried out a series of experiments, focusing on two common polymerase conformations—an open one and a closed one—to determine how each affects drug susceptibility.

First, using cryo-EM, they conducted structural analysis to get high-resolution visualizations of the atomic structures of HSV polymerase in multiple conformations, as well as when bound to the antiviral drugs acyclovir and foscarnet. The drug-bound structures revealed how the two drugs selectively bind polymerases that more readily adopt one conformation versus another.

One of the drugs, foscarnet, works by trapping the fingers of the DNA polymerase so that they are stuck in a so-called closed configuration.

Further, structural analysis paired with computational simulations suggested that several mutations that are distant from the sites of drug binding confer antiviral resistance by altering the position of the polymerase fingers responsible for closing onto the drug to halt DNA replication.

The finding was an unexpected twist. Up until now, scientists have believed that polymerases closed partially only when they attached to DNA and closed fully only when they added a DNA building block, a deoxynucleotide. It turns out, however, that HSV polymerase can fully close just by being near DNA. This makes it easier for acyclovir and foscarnet to latch on and stop the polymerase from working, thus halting viral replication.

"I've worked on HSV polymerase and acyclovir resistance for 45 years. Back then I thought that resistance mutations would help us understand how the polymerase recognizes features of the natural molecules that the drugs mimic," said study co-author Donald Coen, professor of biological chemistry and molecular pharmacology at HMS.

"I'm delighted that this work shows that I was wrong and finally gives us at least one clear reason why HSV polymerase is selectively inhibited by the drug."

Journal information: Cell

Provided by Harvard Medical School

Explore further

Feedback to editors

Saturday Citations: Corn sweat! Nanoplastics! Plus: Massive objects in your area are dragging spacetime

How fruit flies use internal representations of head direction to support goal-directed navigation

2 hours ago

Study finds RNA molecule controls butterfly wing coloration

6 hours ago

Doughnut-shaped region found inside Earth's core deepens understanding of planet's magnetic field

19 hours ago

Study combines data and molecular simulations to accelerate drug discovery

Biodiversity loss: Many students of environment-related subjects are partly unaware of the causes

20 hours ago

How stressed are you? Nanoparticles pave the way for home stress testing

21 hours ago

Researchers identify genes for low glycemic index and high protein in rice

22 hours ago

New discoveries about how mosquitoes mate may help the fight against malaria

New study highlights expansion of drylands amidst impact of climate change

23 hours ago

Relevant PhysicsForums posts

The predictive brain (stimulus-specific error prediction neurons).

5 hours ago

Will cryosleep ever be a reality?

Any suggestions to dampen the sounds of a colostomy bag.

Aug 28, 2024

Any stereo audio learning resources for other languages?

Aug 25, 2024

Cannot find a comfortable side-sleeping position

Therapeutic interfering particle.

Aug 24, 2024

More from Biology and Medical

Related Stories

New insights on how bird flu crosses the species barrier

Aug 19, 2024

Gaining structural insight into the influenza virus

Nov 4, 2022

Your immune system makes its own antiviral drug—and it's likely one of the most ancient

Oct 11, 2023

Targeting a human protein may stop Ebola virus in its tracks

Mar 22, 2022

How the influenza virus achieves efficient viral RNA replication

Oct 3, 2019

Understanding interactions between drugs and viruses is key to readiness for variants, next pandemic

Jan 13, 2022

Recommended for you

Scientists discover molecular mechanism that plays key role in gene transcription and macrophage functional activation

Aug 30, 2024

Enhancing microbe memory to better upcycle excess CO₂

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Phys.org in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Affiliation.

• 1 Department of Medicine, University of Washington, Seattle, Washington, USA.
• PMID: 22214845
• PMCID: PMC3266794
• DOI: 10.1172/JCI60556
• J Clin Invest. 2012 Aug 1;122(8):3024

Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens.

PubMed Disclaimer

Figure 1. Use of CD137 to detect…

Figure 1. Use of CD137 to detect and enrich HSV-1–specific CD8 + T cells from…

Figure 2. Representative data from participant 1…

Figure 2. Representative data from participant 1 (Table 1) for CD8 + T cell reactivity…

Figure 3. Representative data from participant 1…

Figure 3. Representative data from participant 1 (Figure 2 and Table 1) for CD8 +…

Figure 4. Representative data from participant 1…

Figure 4. Representative data from participant 1 (Figures 2 and 3 and Table 1) for…

Figure 5. Representative analyses of polyclonal HSV-1–reactive…

Figure 5. Representative analyses of polyclonal HSV-1–reactive CD8 + cells from the same individual represented…

Figure 6. HLA allele– and HSV-1 ORF-level…

Figure 6. HLA allele– and HSV-1 ORF-level IFN-γ immune signature of CD8 + cells in…

Figure 7. Graphical summary of direct PBMC…

Figure 7. Graphical summary of direct PBMC IFN-γ ELISPOT.

HSV-1 peptides from Table 4 (…

Figure 8. Use of CD137 expression to…

Figure 8. Use of CD137 expression to enrich HSV-1–specific CD4 + T cells, and representative…

Figure 9. Graphical representation of CD4 and…

Figure 9. Graphical representation of CD4 and CD8 reactivity to HSV-1 ORFs in PBMCs from…

Figure 10. Detection and enrichment of vaccinia-specific…

Figure 10. Detection and enrichment of vaccinia-specific CD8 + and CD4 + T cells.

Figure 11. Schematic overview of the high-throughput…

Figure 11. Schematic overview of the high-throughput T cell antigen discovery pathway.

See text for…

Similar articles

• Local CD4 and CD8 T-cell reactivity to HSV-1 antigens documents broad viral protein expression and immune competence in latently infected human trigeminal ganglia. van Velzen M, Jing L, Osterhaus AD, Sette A, Koelle DM, Verjans GM. van Velzen M, et al. PLoS Pathog. 2013 Aug;9(8):e1003547. doi: 10.1371/journal.ppat.1003547. Epub 2013 Aug 15. PLoS Pathog. 2013. PMID: 23966859 Free PMC article.
• Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4 + T EM Cells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in "Humanized" HLA-DR Transgenic Mice. Srivastava R, Coulon PA, Prakash S, Dhanushkodi NR, Roy S, Nguyen AM, Alomari NI, Mai UT, Amezquita C, Ye C, Maillère B, BenMohamed L. Srivastava R, et al. J Virol. 2020 Mar 17;94(7):e01991-19. doi: 10.1128/JVI.01991-19. Print 2020 Mar 17. J Virol. 2020. PMID: 31915285 Free PMC article.
• Noncognate Signals Drive Enhanced Effector CD8 + T Cell Responses through an IFNAR1-Dependent Pathway after Infection with the Prototypic Vaccine, 0ΔNLS, against Herpes Simplex Virus 1. Gmyrek GB, Predki P, Gershburg E, Carr DJJ. Gmyrek GB, et al. J Virol. 2022 Mar 23;96(6):e0172421. doi: 10.1128/JVI.01724-21. Epub 2022 Jan 19. J Virol. 2022. PMID: 35045268 Free PMC article.
• Immune response of T cells during herpes simplex virus type 1 (HSV-1) infection. Zhang J, Liu H, Wei B. Zhang J, et al. J Zhejiang Univ Sci B. 2017 Apr.;18(4):277-288. doi: 10.1631/jzus.B1600460. J Zhejiang Univ Sci B. 2017. PMID: 28378566 Free PMC article. Review.
• Immunology in the Clinic Review Series; focus on host responses: T cell responses to herpes simplex viruses. Laing KJ, Dong L, Sidney J, Sette A, Koelle DM. Laing KJ, et al. Clin Exp Immunol. 2012 Jan;167(1):47-58. doi: 10.1111/j.1365-2249.2011.04502.x. Clin Exp Immunol. 2012. PMID: 22132884 Free PMC article. Review.
• Treponema pallidum Periplasmic and Membrane Proteins Are Recognized by Circulating and Skin CD4+ T Cells. Reid TB, Godornes C, Campbell VL, Laing KJ, Tantalo LC, Gomez A, Pholsena TN, Lieberman NAP, Krause TM, Cegielski VI, Culver LA, Nguyen N, Tong DQ, Hawley KL, Greninger AL, Giacani L, Cameron CE, Dombrowski JC, Wald A, Koelle DM. Reid TB, et al. J Infect Dis. 2024 Aug 16;230(2):281-292. doi: 10.1093/infdis/jiae245. J Infect Dis. 2024. PMID: 38932740
• Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma. Pulliam T, Jani S, Jing L, Ryu H, Jojic A, Shasha C, Zhang J, Kulikauskas R, Church C, Garnett-Benson C, Gooley T, Chapuis A, Paulson K, Smith KN, Pardoll DM, Newell EW, Koelle DM, Topalian SL, Nghiem P. Pulliam T, et al. Cell Rep Med. 2024 Feb 20;5(2):101412. doi: 10.1016/j.xcrm.2024.101412. Epub 2024 Feb 10. Cell Rep Med. 2024. PMID: 38340723 Free PMC article.
• Cellular Processes Induced by HSV-1 Infections in Vestibular Neuritis. Zhao Z, Liu X, Zong Y, Shi X, Sun Y. Zhao Z, et al. Viruses. 2023 Dec 20;16(1):12. doi: 10.3390/v16010012. Viruses. 2023. PMID: 38275947 Free PMC article. Review.
• Repeated mRNA vaccination sequentially boosts SARS-CoV-2-specific CD8 + T cells in persons with previous COVID-19. Ford ES, Mayer-Blackwell K, Jing L, Laing KJ, Sholukh AM, St Germain R, Bossard EL, Xie H, Pulliam TH, Jani S, Selke S, Burrow CJ, McClurkan CL, Wald A, Greninger AL, Holbrook MR, Eaton B, Eudy E, Murphy M, Postnikova E, Robins HS, Elyanow R, Gittelman RM, Ecsedi M, Wilcox E, Chapuis AG, Fiore-Gartland A, Koelle DM. Ford ES, et al. Nat Immunol. 2024 Jan;25(1):166-177. doi: 10.1038/s41590-023-01692-x. Epub 2023 Dec 6. Nat Immunol. 2024. PMID: 38057617 Free PMC article.
• ICP8-vhs- HSV-2 Vaccine Expressing B7 Costimulation Molecules Optimizes Safety and Efficacy against HSV-2 Infection in Mice. Korom M, Wang H, Bernier KM, Geiss BJ, Morrison LA. Korom M, et al. Viruses. 2023 Jul 18;15(7):1570. doi: 10.3390/v15071570. Viruses. 2023. PMID: 37515256 Free PMC article.
• Roizman B, Knipe DM, Whitley RJ. Herpes simplex viruses. In: Knipe DM, Howley PM, eds.Fields Virology . Philadelphia, Pennsylvania, USA: Lippincott, Williams, and Wilkins; 2007:2501–2602.
• Stanberry LR, et al. Prophylactic vaccination against genital herpes with adjuvanted recombinant glycoprotein D vaccine: two randomized contolled trials. N Engl J Med. 2002;347(21):1652–1661. doi: 10.1056/NEJMoa011915. - DOI - PubMed
• Verjans GMGM, et al. Selective retention of herpes simplex virus specific T cells in latently infected human trigeminal ganglia. Proc Natl Acad Sci U S A. 2007;104(9):3496–3501. doi: 10.1073/pnas.0610847104. - DOI - PMC - PubMed
• Lichen J, et al. Tegument- and glycoprotein-reactive HSV-1-specific CD4 and CD8 T cells localize to human trigeminal ganglia [abstract]. J Immunol. 2009;182:128.24.
• Prabhakaran K, et al. Sensory neurons regulate the effector functions of CD8+ T cells in controlling HSV-1 latency ex vivo. Immunity. 2005;23(5):515–525. doi: 10.1016/j.immuni.2005.09.017. - DOI - PubMed

Publication types

• Search in MeSH

Related information

Grants and funding.

• R37 AI042528/AI/NIAID NIH HHS/United States
• G0501453/MRC_/Medical Research Council/United Kingdom
• P30 CA015704/CA/NCI NIH HHS/United States
• AI081060/AI/NIAID NIH HHS/United States
• AI094019/AI/NIAID NIH HHS/United States
• R01 AI094019/AI/NIAID NIH HHS/United States
• P01 AI030731/AI/NIAID NIH HHS/United States
• AI30731/AI/NIAID NIH HHS/United States
• R21 AI081060/AI/NIAID NIH HHS/United States
• P30 AI027757/AI/NIAID NIH HHS/United States
• AI042528/AI/NIAID NIH HHS/United States
• R01 AI042528/AI/NIAID NIH HHS/United States

LinkOut - more resources

Full text sources.

• American Society for Clinical Investigation
• Europe PubMed Central
• Ovid Technologies, Inc.
• PubMed Central

Other Literature Sources

• The Lens - Patent Citations

Research Materials

• NCI CPTC Antibody Characterization Program

Miscellaneous

• NCI CPTAC Assay Portal

• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Log in using your username and password

• Search More Search for this keyword Advanced search
• Latest content
• Global health
• BMJ Journals

You are here

• Volume 17, Issue 8
• Acute generalised exanthematous pustulosis and herpes simplex virus: a case of possible overlap
• Article Text
• Article info
• Citation Tools
• Rapid Responses
• Article metrics

• http://orcid.org/0009-0002-4502-7517 Rachel Leigh Zachian 1 , 2 ,
• Bernita V Sidhu 1 ,
• Phillip Liu 1 and
• Rina Weimann 3 , 4
• 1 Internal Medicine , Lankenau Medical Center , Wynnewood , Pennsylvania , USA
• 2 Dermatology , University of Maryland , Baltimore , Maryland , USA
• 3 Main Line Health System , King of Prussia , Pennsylvania , USA
• 4 Schweiger Dermatology Group , King of Prussia , Pennsylvania , USA
• Correspondence to Dr Rachel Leigh Zachian; rzachian{at}gmail.com

Acute generalised exanthematous pustulosis (AGEP) is a rare cutaneous disorder that presents with numerous non-follicular, pinpoint sterile pustules on a background of oedematous erythema that can coalesce, leading to desquamation. 90% of cases are triggered by medications, most often with antibiotics as the culprit. However, other triggers including viral infection have also been reported. Herpes simplex virus (HSV) as a viral trigger has not been previously explored. Here, we present a case of AGEP caused by bupropion, followed by a second presentation of assumed acute limited exanthematous pustulosis in the setting of disseminated HSV. This case may represent the first report of AGEP and HSV overlap. It also presents the interesting dilemma of differentiating AGEP and disseminated HSV (which can present similarly) as well as determining appropriate treatment and the utility versus risk of systemic steroid administration.

• Dermatology
• Infectious diseases

https://doi.org/10.1136/bcr-2024-260873

Statistics from Altmetric.com

Request permissions.

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Contributors The following authors were responsible for drafting the text, sourcing and editing clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: RLZ, BVS, PL and RW. The following authors gave final approval of the manuscript: RLZ, BVS, PL and RW.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Read the full text or download the PDF: