Herpes simplex virus 2

Herpes simplex virus 2, abbreviated HSV-2 and also called human herpesvirus 2, is the alphaherpesvirus of genital herpes: the principal cause of recurrent genital ulceration worldwide and a lifelong infection acquired almost entirely through sexual contact. An estimated 417 million people aged 15 to 49 carry it, and although many never recognise a symptom, the virus sheds intermittently from the genital tract throughout life and spreads efficiently from people who feel perfectly well.

After replicating in genital or anal epithelium, the virus travels up sensory nerves to the sacral ganglia, where it establishes lifelong latency and from which it reactivates far more readily than HSV-1 does from the same site. That difference is the central clinical fact about the two viruses: a first genital episode may look the same whichever type causes it, but HSV-2 recurs and sheds many times more often, so it carries almost all the long-term burden of symptomatic recurrence and onward transmission.

HSV-2 matters well beyond the discomfort of recurrence. It is the major cause of neonatal herpes, a rare but devastating infection of the newborn; it causes aseptic and recurrent meningitis; and, by producing genital ulcers that recruit the immune cells HIV infects, it roughly triples the risk of acquiring HIV. In a high-HIV-prevalence setting, that last interaction makes HSV-2 a public-health problem out of proportion to the illness it causes directly.

Discovery and historical significance

The word herpes is ancient, from the Greek herpein, to creep, used by Hippocrates for spreading skin lesions, and herpetic genital disease was described in antiquity and linked to sexual contact by the eighteenth-century physician Jean Astruc. That herpes was transmissible rather than arising from within the body was settled when Émile Vidal demonstrated person-to-person transmission in 1893, though at that time the oral and genital diseases were not known to be caused by distinct agents.

The separation of the two viruses came in the early 1960s. Antigenic studies distinguished a second herpes simplex virus, HSV-2, as the agent of genital herpes, formalising the long-noted clinical division between oral and genital disease and opening the way to type-specific diagnosis. Recognition that genital herpes was common, lifelong and frequently transmitted without symptoms followed over the next decades, as did the discovery that HSV-2 ulceration facilitates the transmission of HIV, an interaction that has shaped how the virus is regarded in high-prevalence regions. The arrival of aciclovir in the late 1970s, the first selective antiviral, transformed the management of severe disease and made daily suppressive therapy possible.

Classification, structure, and genome

Classification

HSV-2 is the species Simplexvirus humanalpha2 in the genus Simplexvirus, subfamily Alphaherpesvirinae, within the family Orthoherpesviridae (until recently named Herpesviridae) and the order Herpesvirales. Its closest relative is HSV-1, with which it is colinear and shares about 83% of its genome, and the two can recombine in the laboratory. The type-specific glycoprotein G, in its HSV-2 form gG2, is what distinguishes the two viruses serologically, the basis on which past HSV-2 infection is identified in the blood. Genomic studies show HSV-2 to be the less diverse of the two viruses, consistent with a more recent origin from a chimpanzee herpesvirus ancestor.

Virion structure

The virion has the three-layered architecture common to all herpesviruses: an icosahedral capsid, a protein tegument, and a lipid envelope, measuring roughly 155 to 225 nanometres overall. The capsid is built on a triangulation number of 16 from 162 capsomeres, with a single portal vertex through which the genome is threaded during assembly. The tegument, around two dozen proteins, delivers regulatory cargo into the cell at entry, including the transactivator VP16 and the host-shutoff RNase that degrades cellular messenger RNA. The envelope carries up to twelve glycoproteins, four of which form the core entry machinery: the fusogen glycoprotein B, the activating glycoprotein H and L pair, and glycoprotein D, the receptor-binding protein that defines herpes simplex virus entry and that VZV, the other human alphaherpesvirus, lacks.

Genome organisation

The genome is a single linear molecule of double-stranded DNA of about 155 kilobases with a high guanine-and-cytosine content of around 70%. It is organised as a long unique region and a short unique region, each flanked by inverted repeats, so that the two segments invert relative to one another to give four equimolar genome isomers in any virus population. It encodes around 84 proteins together with non-coding RNAs and many microRNAs, expressed in the ordered kinetic classes that structure the replication cycle. Replication starts at three origins, two copies in the short-region repeats and one in the long region, and the terminal a sequence carries the signals for packaging and for circularisation of the genome on entry. The chief sequence difference from HSV-1 lies in the glycoprotein G gene, and an altered gG2 in some African isolates can reduce the sensitivity of gG2-based serology in those populations.

Replication cycle

Infection begins when glycoprotein C and glycoprotein B tether the virion to heparan sulfate proteoglycans on the cell surface. Glycoprotein D then engages one of three entry receptors, principally nectin-1, an adhesion molecule on epithelial cells and neurons, or the herpesvirus entry mediator and a modified 3-O-sulfated heparan sulfate. Receptor binding springs a conformational change in glycoprotein D that activates the glycoprotein H and L pair, which in turn triggers glycoprotein B, the fusion protein that merges the envelope with the cell membrane, either at the plasma membrane or after uptake into an endosome.

The released capsid is carried along microtubules by the motor protein dynein to the nuclear pore, where it docks and injects the genome into the nucleus. The genome circularises, and gene expression follows the herpesvirus cascade. The tegument protein VP16, with the host factors HCF-1 and Oct-1, switches on the immediate-early genes, whose products, among them ICP0, ICP4 and ICP27, redirect the cell and disable its defences. These drive the early genes that supply the replication enzymes, including the DNA polymerase that is the principal drug target, the helicase-primase complex, and the thymidine kinase. Genome replication proceeds by a rolling-circle mechanism that generates long head-to-tail concatemers, and the late genes supply the structural proteins.

Progeny capsids assemble in the nucleus, and a terminase complex threads single genome lengths through the portal vertex into each capsid. Because the assembled capsid cannot pass through the nuclear pore, it leaves by a distinctive route: it buds through the inner nuclear membrane, sheds that first envelope at the outer membrane, and acquires its final envelope at the trans-Golgi network before release. In a sacral sensory neuron the cascade often does not start: VP16 fails to reach the nucleus in quantity, the incoming genome is packaged into silencing chromatin, and the virus enters latency rather than lytic growth, the fork that defines its natural history.

Pathogenesis

Primary infection starts where the virus is deposited on genital, anal or perigenital mucosa or on abraded skin, and it replicates productively in the surface epithelium to produce the ulcers of the first episode. The vesicle shows the histological signature of the alphaherpesviruses: ballooning degeneration of keratinocytes, multinucleated giant cells, and the dense intranuclear Cowdry type A inclusion bodies of a herpesvirus-infected cell. From the mucosa the virus enters sensory nerve endings and is carried by retrograde axonal transport to the sacral ganglia, where it persists for life.

Latency is the central fact of the virus’s biology. The latent genome sits in the neuron as a circular episome wrapped in repressive chromatin, with lytic genes silenced and only the latency-associated transcript and its microRNAs expressed, an arrangement that keeps the neuron alive and the virus hidden. The defining feature of HSV-2 is the ease of its return: it reactivates from the sacral ganglia far more frequently than HSV-1 does from the same site, which is why genital HSV-2 recurs and sheds so much more than genital HSV-1, and why the bulk of recurrent genital herpes is HSV-2.

Control of the virus rests on cell-mediated rather than humoral immunity, with herpes-specific CD8 T cells clearing lesions, sitting as tissue-resident memory cells at the dermal-epidermal junction next to the nerve endings, and surrounding the latent neurons to suppress reactivation through interferon-gamma. The virus counters at many points: ICP47 blocks the transporter associated with antigen processing so infected cells cannot display viral peptides to cytotoxic T cells, ICP0 dismantles the cell’s antiviral nuclear bodies, and the host-shutoff protein degrades cellular messenger RNA.

A consequence of genital ulceration links HSV-2 to HIV. A herpetic ulcer breaches the mucosal barrier and draws activated CD4 T cells bearing the CCR5 co-receptor into the genital mucosa, the very cells HIV infects, and these persist for weeks after the ulcer has healed. This is the mechanism behind the roughly threefold increase in HIV acquisition seen in people with HSV-2, and behind the higher genital HIV shedding, and therefore greater infectiousness, of those co-infected with both viruses.

Epidemiology

HSV-2 is a sexually transmitted infection of global reach. An estimated 417 million people aged 15 to 49 are infected, about 11% of that age group, with around 19 million new infections in a single recent year. Prevalence rises through adult life with cumulative sexual exposure, is roughly twice as high in women as in men because male-to-female transmission is more efficient, and is heavily concentrated in sub-Saharan Africa, which carries the largest share of the global burden. HSV-2 is essentially absent before sexual debut, and humans are its only reservoir.

The seroprevalence figures conceal how little of the infection is recognised. The large majority of HSV-2-seropositive people have never received a diagnosis, because most infection is asymptomatic or its symptoms are mild and unrecognised, yet these unaware carriers shed virus and transmit it. Transmission occurs predominantly during asymptomatic shedding, in more than 70% of cases, which is why suppressive therapy and condoms reduce but cannot abolish the risk. By sensitive polymerase chain reaction the virus is detectable in the genital tract on around a fifth of days in people with symptomatic HSV-2 and on roughly a tenth of days even in those who are asymptomatic, with most shedding episodes lasting only hours.

The interaction with HIV gives HSV-2 an epidemiological weight beyond its direct morbidity. Where both infections are common, the population-attributable contribution of HSV-2 to new HIV infections is substantial, greatest in sub-Saharan Africa and among women, making HSV-2 control a recurring theme in HIV-prevention research even though antiviral suppression of HSV-2 has not, in trials, reduced HIV acquisition.

Natural history

After an incubation of about two to twelve days (the same as HSV-1), a first genital infection in a previously uninfected person may be silent or may cause a severe primary illness. The terminology matters: a first infection in someone with no prior herpes antibody is a primary infection, a first genital HSV-2 infection in someone already carrying HSV-1 is a milder nonprimary first episode, and any later outbreak is a recurrence. Pre-existing HSV-1 antibody does not prevent HSV-2 acquisition but tends to soften the first episode.

Once acquired, the virus is never cleared, and HSV-2 is distinguished by how often it returns. About 90% of people with symptomatic genital HSV-2 have at least one recurrence in the first year, and a substantial minority have more than six, a far higher rate than for genital HSV-1. Recurrences are most frequent in the first year or two and tend to become less frequent and milder over time. Throughout, whether or not there are symptoms, the virus is shed intermittently from the genital tract, so the natural history is one of lifelong, mostly silent infectiousness punctuated by recurrent lesions.

Clinical presentations and complications

Genital herpes

The defining illness of HSV-2 is genital herpes. A primary episode is the most severe, with crops of painful vesicles and ulcers on the genitals, perineum or anus that evolve over about three weeks, usually accompanied by systemic symptoms of fever, malaise and tender inguinal lymph nodes; women tend to have more extensive disease than men, often with cervical involvement. Painful urination and, in up to 10 to 15% of women, urinary retention may occur, and a sacral radiculopathy can disturb bladder and bowel function. Recurrent episodes are far milder and briefer: a localised cluster of lesions, often with a prodrome of tingling or pain, healing within about a week. Anorectal HSV-2, with proctitis and perianal ulceration, is common in men who have sex with men.

The clinical importance of distinguishing the type lies almost entirely in prognosis. A first genital episode caused by HSV-2 cannot be told from one caused by HSV-1 at the bedside, but HSV-2 recurs and sheds many times more often, so confirming the type guides counselling about the likely frequency of recurrence, the value of suppressive therapy, and the risk of transmission to a partner. The reverse situation is uncommon but real: HSV-2 can cause oral herpes through oral-genital contact, though, mirroring genital HSV-1, it reactivates poorly at this non-preferred site and so recurs there only rarely.

Neurological disease

HSV-2 is an important cause of viral meningitis. Aseptic meningitis complicates up to a quarter of primary genital infections, especially in women, presenting with headache, photophobia and neck stiffness alongside the genital lesions and resolving without specific sequelae. The virus is also the usual cause of Mollaret meningitis, a benign recurrent lymphocytic meningitis in which episodes of self-limiting aseptic meningitis recur over years, diagnosed by detecting HSV-2 DNA in the cerebrospinal fluid during an attack. Unlike HSV-1, HSV-2 rarely causes encephalitis in adults, although it can cause severe meningoencephalitis in the newborn.

Neonatal herpes

HSV-2 is the major cause of neonatal herpes, a rare but grave infection acquired chiefly from the maternal genital tract during delivery. The risk is greatest when the mother acquires a first genital infection late in pregnancy, when transmission reaches 30 to 50%, against around 3% with recurrent maternal disease, because primary infection sheds more virus and the infant lacks transferred maternal antibody; prolonged rupture of membranes and the use of fetal scalp electrodes add further risk. Most affected infants are born to women who were asymptomatic and unaware of their infection at delivery. The disease takes three overlapping forms of increasing danger: skin, eye and mouth disease confined to the surface, with the best outlook; central-nervous-system disease, often without skin lesions, presenting in the second week with seizures and lethargy; and disseminated disease with hepatitis, pneumonitis and coagulopathy, which carries the highest mortality. Because around a third of babies with central-nervous-system or disseminated disease never develop the diagnostic rash, neonatal herpes must be suspected in any septic-looking neonate even when the skin is clear, and treated with high-dose intravenous aciclovir followed by six months of oral suppression.

Disease in the immunocompromised

Where cell-mediated immunity fails, HSV-2 disease becomes severe, chronic and atypical, its severity tracking the depth of the immune deficit. Reactivation produces large, persistent, slowly enlarging anogenital ulcers, which in advanced HIV can take a heaped, hypertrophic, pseudotumour-like form, recur frequently, and shed for prolonged periods. That prolonged high-level replication favours the emergence of aciclovir resistance through thymidine-kinase mutation, the setting in which foscarnet becomes necessary, so an anogenital herpetic ulcer that fails to heal on adequate aciclovir should prompt resistance testing. Genital recurrences may flare transiently when antiretroviral therapy is started, as part of the immune reconstitution inflammatory syndrome.

The two herpes simplex viruses are biologically almost identical yet differ in the patterns of disease they cause.

Herpes simplex virus type 1 and type 2 compared

Feature	HSV-1	HSV-2
Classic site of disease	Oral, and increasingly genital	Genital and anal
Main transmission route	Oral contact in childhood; oral-genital contact	Sexual contact
Latency ganglion	Trigeminal (and sacral when genital)	Sacral
Global seroprevalence	~67% of those under 50 (~3.7 billion)	~11% of those aged 15 to 49 (~417 million)
Genital recurrence and shedding	Low; recurs minimally	High; the usual cause of recurrent genital herpes
Signature central-nervous-system disease	Temporal-lobe encephalitis	Aseptic and recurrent (Mollaret) meningitis
Role in neonatal herpes	Rising minority	Majority of cases
Link to HIV acquisition	Not established	Raises HIV acquisition ~3-fold

Diagnosis

Polymerase chain reaction (PCR) for viral DNA is the diagnostic standard, sensitive and rapid on a swab of a genital lesion base, on cerebrospinal fluid, blood or tissue, and able to report the infecting type, which is what makes it more useful than older methods for genital disease. In suspected HSV-2 meningitis, including the recurrent Mollaret form, detection of viral DNA in the cerebrospinal fluid during an attack is the diagnostic test. Viral culture is now reserved mainly for situations where a live isolate is needed for antiviral resistance testing, since the virus is labile and culture is slow.

Older lesion-side methods, the Tzanck smear and direct immunofluorescence, are largely superseded by PCR; the multinucleated giant cells of a Tzanck preparation are suggestive but cannot distinguish HSV from VZV. Serology has a defined and limited role. Type-specific assays based on glycoprotein G2 identify past HSV-2 infection and are useful for counselling, for example in a couple of discordant serostatus, but immunoglobulin M results are unreliable, and routine serological screening of people without symptoms is not recommended because a positive result carries psychological harm without changing management.

Management

Three antiviral drugs are the mainstay: aciclovir, its valine ester prodrug valaciclovir, which is far better absorbed by mouth, and famciclovir, the prodrug of penciclovir. All depend on the viral thymidine kinase for their first activating step before they inhibit the viral DNA polymerase, so they act only in infected cells. Genital herpes is treated in two distinct ways: episodic therapy, a short course started at the first sign of a recurrence to shorten it, and suppressive therapy, a daily dose taken continuously to prevent recurrences and, importantly, to reduce the asymptomatic shedding that transmits the virus to others.

Daily suppressive therapy both lowers the frequency of recurrence and reduces transmission to a susceptible partner by around half, which makes it a tool of prevention as much as of symptom control, particularly in serodiscordant couples. Intravenous aciclovir is reserved for severe disease: HSV-2 meningitis where treatment is warranted, disseminated infection, and neonatal herpes, where high-dose intravenous therapy followed by six months of oral suppression has transformed survival and improved neurological outcome.

Resistance is uncommon and is seen chiefly in profoundly immunocompromised people after prolonged drug exposure, usually through mutation of the viral thymidine kinase. Resistant virus remains susceptible to foscarnet and to cidofovir, which inhibit the DNA polymerase directly without needing viral activation, the salvage agents whose use is limited mainly by their toxicity to the kidney. The helicase-primase inhibitors, a newer class acting on a different viral enzyme, offer a route around thymidine-kinase resistance but are not yet in routine use. None of these drugs eradicates the latent virus, so none is curative.

Prevention and public health

Vaccination

There is no licensed vaccine against herpes simplex virus, despite a century of effort. The most advanced candidate, a glycoprotein D subunit with an adjuvant, failed against HSV-2 in a large trial while showing only partial protection against HSV-1, a disappointing result for the virus whose recurrent and transmissible genital disease makes a vaccine most desirable. Current research has moved toward trivalent subunit, replication-defective and therapeutic vaccines aimed at reducing recurrence and shedding rather than preventing infection outright, but none is yet licensed, and no validated correlate of protective immunity exists to guide development.

The formulation of an effective HSV vaccine is primarily impeded by the pathogen’s ability to establish lifelong latency within sensory neurons that are poorly visible to immune surveillance and its sophisticated molecular mechanisms for evading host defences, as well as a lack of suitable animal models.

Infection prevention and control

Because most transmission occurs from people who are shedding without symptoms, prevention rests on several partial measures rather than any single reliable one. Consistent condom use reduces HSV-2 acquisition by around 30%, more so for women, and disclosure of infection to partners, avoidance of sex during recognised outbreaks, and suppressive antiviral therapy of the infected partner each add further protection. Medical male circumcision reduces HSV-2 acquisition in men by a similar margin and forms part of the combination-prevention approach used where both HSV-2 and HIV are common.

Treatment as prevention

Suppressive antiviral therapy occupies a particular place in HSV-2 control because it reduces not only recurrence but the asymptomatic shedding that drives transmission, lowering the risk to a susceptible partner by roughly half. Its limits are equally important: it does not abolish shedding, so it cannot guarantee protection, and trials of HSV-2 suppression as a means of reducing HIV transmission did not succeed, so it is not an HIV-prevention tool despite the strong biological link between the two infections.

South African context

South Africa carries one of the heaviest HSV-2 burdens in the world, with high seroprevalence, a marked excess in women, and early acquisition in sexually active young adults, the pattern typical of the sub-Saharan region. The interaction with HIV is the dominant local concern: by roughly tripling the risk of HIV acquisition and increasing genital HIV shedding, HSV-2 contributes a substantial share of new HIV infections in a population where HIV prevalence is already high, and genital ulcer disease is approached in the public sector through syndromic management in which both HSV and other ulcerative sexually transmitted infections are treated.

In advanced HIV infection HSV-2 causes the chronic, extensive, aciclovir-resistant anogenital disease described above, and aciclovir is widely available for episodic and suppressive use and for severe disease. The management of HSV in people living with HIV sits within the national HIV programme, whose consolidated guidelines set out where antiviral suppression and treatment of co-infections fit alongside antiretroviral therapy. There is no vaccine and no immunisation-programme dimension to HSV-2, so prevention is the combination of condoms, circumcision, partner services and, around delivery, the obstetric measures that protect the newborn.

References and recommended reading

• Whitley RJ, Roizman B. Herpes Simplex Viruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The principal source for the virology, pathogenesis, clinical spectrum, diagnosis and antiviral management set out here.
• Knipe DM, Heldwein EE, Mohr I, Sodroski CN. Herpes Simplex Viruses: Mechanisms of Lytic and Latent Infection. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The current reference for virion architecture, the entry and replication machinery, and the molecular biology of latency and reactivation.
• Whitley RJ, Johnston C. Herpes Simplex Virus: Pathogenesis and Clinical Disease. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The current reference for global epidemiology, the genital and neonatal syndromes, the HIV interaction, diagnosis, therapy and the vaccine landscape.
• National Department of Health, South Africa. National Consolidated Guidelines for the Management of HIV in Adults, Adolescents, Children and Infants and Prevention of Mother-to-Child Transmission; 2026. The source for the South African HIV context within which HSV-2 co-infection and genital ulcer disease are managed.