Herpes simplex virus 1

Herpes simplex virus 1, abbreviated HSV-1 and also called human herpesvirus 1, is the alphaherpesvirus most people carry: an estimated two-thirds of the world under 50 are infected, the great majority acquiring it silently in childhood. Its classic disease is oral herpes, from the painful gingivostomatitis of a first infection to the recurrent cold sores at the lip margin that follow for life, but the same biology underlies a far wider clinical range.

After replicating in the surface epithelium, the virus travels up sensory nerves to the trigeminal ganglion, where it establishes lifelong latency and from which it reactivates. That neurotropism makes HSV-1 the commonest cause of sporadic fatal viral encephalitis and, in the eye, the leading infectious cause of corneal blindness. The historical rule that placed HSV-1 “above the waist” and HSV-2 below it has broken down: as childhood oral acquisition declines in wealthier populations, HSV-1 now causes more than half of new genital herpes in many of them.

Most infection is mild or unnoticed, but the virus is dangerous at the edges of immune competence: in the newborn, in people with atopic skin disease, and above all in the immunocompromised. In a high-HIV-prevalence setting the last group is large, and severe, chronic and drug-resistant HSV-1 disease is correspondingly more common.

Discovery and historical significance

The word herpes is ancient, from the Greek herpein, to creep, used by Hippocrates for spreading skin lesions; genital herpetic disease was described in antiquity and later linked to sexual contact by the eighteenth-century physician Jean Astruc. The infectious nature of the lesions was suspected long before a virus could be defined. In 1893 Émile Vidal demonstrated person-to-person transmission, settling a long debate by showing that herpes was transmissible rather than arising spontaneously from within the body.

The two herpes simplex viruses were separated antigenically in the early 1960s, formalising the long-noted clinical distinction between oral and genital disease, though it was already understood that either virus could infect either site. The decisive therapeutic advance came with aciclovir, developed in the laboratory of Gertrude Elion and recognised in the 1988 Nobel Prize, the first truly selective antiviral drug: it is activated only inside infected cells and so spares uninfected tissue, a design principle that reshaped antiviral medicine. A further chapter has opened in oncology, where an HSV-1 engineered to delete its neurovirulence gene and to express an immune-stimulating cytokine is licensed as an oncolytic therapy for advanced melanoma, turning the virus’s lytic capacity to therapeutic use.

Classification, structure, and genome

Classification

HSV-1 is the species Simplexvirus humanalpha1 in the genus Simplexvirus, subfamily Alphaherpesvirinae, within the family Orthoherpesviridae (until recently named Herpesviridae) and the order Herpesvirales. Its closest relative is HSV-2, with which it shares about 83% of its genome and is colinear; the two can form recombinants in the laboratory. The type-specific glycoprotein G distinguishes the two viruses serologically, the basis on which past HSV-1 and HSV-2 infection are told apart in the blood.

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, 150 hexons, 11 pentons, and a single unique portal vertex through which the genome is packaged. The tegument, around two dozen proteins, delivers regulatory cargo into the cell at entry, including the transactivator VP16 and the host-shutoff RNase vhs. The envelope carries up to twelve glycoproteins. Four constitute the core entry machinery: the fusogen glycoprotein B, the activating glycoprotein H and L pair, and glycoprotein D, the receptor-binding protein that is the defining feature of herpes simplex virus entry and the one its sister alphaherpesvirus VZV lacks.

Genome organisation

The genome is a single linear molecule of double-stranded DNA of about 152 kilobases with a high guanine-and-cytosine content of around 68%. 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 as many as 29 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.

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 present 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. Depending on the cell type, fusion occurs at the plasma membrane or after uptake into an endosome.

The released capsid, too large to diffuse through the crowded cytoplasm, 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 in turn 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 the nucleus 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 neuron the cascade often does not start at all. VP16 fails to reach the nucleus in sufficient quantity, the incoming genome is assembled into silencing chromatin, and the virus settles into latency rather than lytic growth, the fork in the road that defines its natural history.

Pathogenesis

Primary infection starts where the virus is deposited on oral or genital mucosa or on abraded skin, and the virus replicates productively in the surface epithelium, producing the vesicles and 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 that mark a herpesvirus-infected cell. From the mucosa the virus enters sensory nerve endings and is carried by retrograde axonal transport to the sensory ganglion, the trigeminal ganglion for orofacial infection and the sacral ganglia for genital infection, 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. Reactivation follows neuronal stress, ultraviolet light, fever, trauma to the nerve, or a fall in immune control; the virus resumes lytic replication and travels back down the axon to the surface, producing a recurrent lesion or shedding without symptoms.

Control of the virus rests on cell-mediated rather than humoral immunity. People who cannot make antibody do not suffer worse or more frequent herpes, whereas any failure of T-cell immunity predisposes to severe and persistent disease. Type I interferon, natural killer (NK) cells and plasmacytoid dendritic cells mount the innate response, while herpes-specific CD8 T cells clear lesions, sit as tissue-resident memory cells at the dermal-epidermal junction next to the nerve endings, and surround the latent neurons in the ganglion to suppress reactivation through interferon-gamma without killing the cell.

The virus fights back at many points. ICP47 blocks the transporter associated with antigen processing (TAP), so infected cells cannot display viral peptides to cytotoxic T cells; ICP0 dismantles the cell’s antiviral nuclear bodies and blocks interferon induction; the host-shutoff protein degrades cellular messenger RNA; and ICP34.5, the major neurovirulence determinant, reverses the host’s shutdown of protein synthesis.

A particular vulnerability of the central nervous system explains the most feared HSV-1 disease. Rare inborn errors of the Toll-like receptor 3 (TLR3) interferon pathway, including defects in TLR3 itself, its adaptor TRIF, UNC93B1, TBK1 and others, leave certain people unable to control HSV-1 in the brain and predispose to herpes simplex encephalitis, confirming that this interferon axis is what normally protects the central nervous system.

Epidemiology

HSV-1 is the most widespread of the human herpesviruses. An estimated 3.7 billion people under the age of 50 are infected, about 67% of that age group, with roughly 118 million new infections in a single recent year. Most acquisition is in childhood through ordinary oral contact, so prevalence climbs with age from around a quarter of young children to nearly four in five adults, and humans are the only reservoir.

The burden is uneven. Seroprevalence is highest in Africa, where it approaches 87% across both sexes, and lower in the Americas; within high-income countries it has been falling, with United States seroprevalence dropping to around 48% in recent surveys and the steepest declines among adolescents. This very decline in childhood oral acquisition has a downstream effect: a growing pool of young adults reaches sexual debut without HSV-1 antibody and acquires the virus genitally instead. As a result HSV-1 now accounts for more than half of new genital herpes in many of those settings, with an estimated 140 million genital HSV-1 infections worldwide among people aged 15 to 49, even though genital HSV-1 recurs and sheds far less than genital HSV-2.

Transmission turns less on visible lesions than on silent shedding. The virus is shed intermittently from the mouth or genitals of infected people in the absence of any symptoms, and this asymptomatic shedding accounts for the majority of transmission, which is why the infection spreads so efficiently through a population despite the brevity of overt disease.

Natural history

After an incubation of about two to twelve days, primary oral infection in a previously uninfected person may be silent or may present as gingivostomatitis. The terminology matters clinically: a first infection in someone with no prior herpes antibody is a primary infection, a first infection with one type in someone already carrying the other is a milder nonprimary first episode, and any later outbreak is a recurrence. Pre-existing HSV-1 antibody does not prevent HSV-2 but does soften it.

Once acquired, the virus is never cleared. It persists in the sensory ganglion for life, periodically reactivating to cause recurrent lesions or asymptomatic shedding. HSV-1 reactivates more readily from the trigeminal ganglion than from sacral ganglia, which is why oral HSV-1 recurs more often than genital HSV-1, and why the recurrent cold sore is the virus’s signature. Recurrences tend to be most frequent in the first years after infection and to become less frequent and less severe with time, as the size and severity of the original episode set the pace of what follows.

Clinical presentations and complications

Orolabial herpes

Primary oral HSV-1 in a young child classically causes gingivostomatitis: fever, painful vesicles and ulcers across the gums, tongue and buccal mucosa, tender cervical lymph nodes, and difficulty eating, lasting two to three weeks. In adolescents and adults a first infection more often presents as a pharyngitis with a mononucleosis-like illness. Far more common is recurrent herpes labialis, the cold sore: a brief prodrome of tingling or pain, then a crop of vesicles at the vermilion border of the lip that crust and heal in about eight to ten days, often triggered by fever, sunlight, stress or menstruation.

Genital herpes

HSV-1 causes genital herpes through oral-genital contact, and a first episode can be clinically indistinguishable from genital HSV-2, with painful ulcers, dysuria and inguinal adenopathy. The crucial difference lies downstream: genital HSV-1 recurs and sheds far less often than genital HSV-2, so its long-term burden of symptomatic recurrence and onward transmission is much lower. This distinction shapes counselling once the infecting type is known.

Skin and ocular disease

Inoculation of the virus into other skin sites produces characteristic syndromes. Herpetic whitlow is a painful vesicular infection of a finger, an occupational hazard of dental and medical staff before universal gloving and a risk in thumb-sucking children with oral herpes. Herpes gladiatorum spreads among wrestlers through skin contact. In people with atopic dermatitis or other broken skin, HSV-1 can spread widely as eczema herpeticum, a potentially severe disseminated cutaneous infection also called Kaposi varicelliform eruption. The virus is also the usual trigger of recurrent erythema multiforme, with HSV DNA found in up to 80% of such lesions.

In the eye HSV-1 is a major cause of disease. The hallmark is herpetic keratitis with its branching dendritic corneal ulcer, which can progress to geographic ulceration, stromal disease and scarring; recurrent keratitis is, after trauma, the leading infectious cause of corneal blindness. The virus also causes acute retinal necrosis, a rapidly progressive sight-threatening retinitis.

Herpes simplex encephalitis

HSV-1 is the cause of the most important sporadic encephalitis. Herpes simplex encephalitis is the commonest sporadic fatal viral encephalitis, with an untreated mortality above 70% and survival with normal function in only a small minority, and it characteristically attacks the temporal lobes, producing fever, altered consciousness, personality change, dysphasia and focal seizures. The cerebrospinal fluid shows a lymphocytic pleocytosis often with red cells, reflecting the haemorrhagic necrosis of the affected lobe.

A distinct late syndrome is now recognised. Weeks after treated encephalitis a patient may relapse not with viral recurrence but with anti-N-methyl-D-aspartate (anti-NMDA) receptor autoimmune encephalitis, an immune sequela that requires immunotherapy rather than more aciclovir.

Disease in the immunocompromised

Where cell-mediated immunity fails, HSV-1 disease becomes severe, chronic and atypical, its severity tracking the depth of the immune deficit, whether a falling CD4 count in HIV or iatrogenic immunosuppression after transplantation. Reactivation produces large, persistent, slowly enlarging ulcers of the mouth, perianal skin or genitals, which in advanced HIV can take a heaped, hypertrophic, pseudotumour-like form that mimics malignancy. The virus also spreads beyond the surface to cause herpetic oesophagitis, to be distinguished from cytomegalovirus and candidal oesophagitis, and, less often, hepatitis and pneumonitis from visceral dissemination.

Two practical problems follow from this prolonged, high-level replication. Under weak immune pressure the virus readily selects for aciclovir resistance through thymidine-kinase mutation, the setting in which foscarnet becomes necessary, so a herpetic ulcer that fails to heal on adequate aciclovir should prompt resistance testing rather than simple dose escalation. Reactivation is frequent enough after transplantation that aciclovir or valaciclovir prophylaxis is given through the early post-transplant period, and a transient flare of herpetic lesions can accompany the start of antiretroviral therapy as part of the immune reconstitution inflammatory syndrome.

Neonatal herpes

A newborn has little of the immune protection that limits herpes in older children, so neonatal infection is correspondingly severe. Although most neonatal herpes is due to HSV-2, HSV-1 causes a substantial and rising share, and it has a route of its own: besides acquisition from the maternal genital tract during delivery, an infant can be infected after birth from a carer’s orolabial herpes, for example a cold sore transferred by a kiss. The danger is greatest when the mother acquires a first genital infection late in pregnancy, when transmission to the baby reaches 30 to 50%, against around 3% with recurrent maternal disease, because a primary infection sheds more virus and the infant lacks transferred maternal antibody.

The disease takes three overlapping forms of increasing danger. Skin, eye and mouth (SEM) disease, confined to the surface, carries the best outlook; central-nervous-system disease, often without any skin lesions, presents in the second week with seizures and lethargy and leaves many survivors impaired; and disseminated disease, with hepatitis, pneumonitis and coagulopathy, 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 considered in any septic-looking neonate even when the skin is clear. Treatment is high-dose intravenous aciclovir, which has transformed survival, followed by six months of oral suppressive therapy that improves the neurological outcome of central-nervous-system disease.

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 (under 50)	~67% (~3.7 billion)	~11% in 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 lesion base, on cerebrospinal fluid, blood or tissue, and able to report the infecting type. It is especially decisive in the central nervous system: cerebrospinal-fluid PCR for HSV is the test of choice for herpes simplex encephalitis, with a sensitivity above 95% and a specificity approaching 100%, and a quantitative result can also be followed to gauge the response to treatment. Viral culture, once the reference method, 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 G distinguish past HSV-1 from 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.

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 and spare uninfected tissue. The principle of use follows the severity of disease: short oral courses for orolabial and genital recurrences, longer or suppressive courses to reduce the frequency of recurrence and the shedding that transmits the virus, and intravenous therapy for anything that threatens life or sight.

Herpes simplex encephalitis is a medical emergency treated with intravenous aciclovir, which cuts mortality from above 70% to around a quarter and must be started on clinical suspicion, before confirmation, because delay worsens the outcome. Intravenous aciclovir is likewise used for disseminated and visceral disease and for severe disease in the immunocompromised. For herpetic keratitis the cornea is treated with a topical antiviral such as trifluridine, often with an oral agent, and the management of stromal disease adds careful corticosteroid use under specialist supervision.

Resistance is uncommon and is seen chiefly in profoundly immunocompromised people after prolonged drug exposure, usually through mutation of the viral thymidine kinase, which abolishes the activation step the standard drugs depend on. 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. A newer drug class, the helicase-primase inhibitors, acts on a different viral enzyme and offers a route around thymidine-kinase resistance; its development has been slowed by toxicity concerns but it represents the most promising novel approach. 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, illustrated how hard the target is: in a large trial it failed to meet its primary endpoint and gave little protection against HSV-2, while showing partial efficacy against HSV-1 disease and acquisition. That pattern is consistent with the changing epidemiology in which HSV-1 has become a major genital pathogen. Current research has moved toward trivalent subunit, replication-defective and therapeutic vaccines aimed at reducing recurrence and shedding, 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.

Treatment as prevention

In the absence of a vaccine, reducing transmission rests on behaviour and on antiviral suppression. Daily suppressive antiviral therapy lowers both symptomatic recurrence and the asymptomatic shedding that drives most transmission, and avoiding contact with active lesions, including the avoidance of oral-genital contact during a cold sore, reduces spread to new sites and new people. Because much transmission occurs during asymptomatic shedding, none of these measures abolishes the risk, a fact central to honest counselling. Particular care surrounds the newborn and the person with atopic skin disease, in whom acquisition can be severe.

South African context

South Africa carries the epidemiological signature of a high-HIV-prevalence setting, and this shapes HSV-1 disease more than any local programmatic difference. In advanced HIV infection HSV-1 causes more severe, chronic and atypical disease: large persistent orolabial and oesophageal ulcers, slow healing, and prolonged viral shedding that favours the emergence of aciclovir-resistant virus, the situation in which foscarnet becomes necessary. Herpes simplex encephalitis and sight-threatening ocular disease occur across the population, and the interaction between herpesviruses and HIV runs in both directions, an interaction set out in the national HIV management guidelines.

There is no vaccine and no immunisation-programme dimension to HSV-1, so prevention in the South African public sector is clinical: prompt aciclovir for severe and immunocompromised disease, intravenous therapy for encephalitis and disseminated infection, and attention to the newborn of a mother with active genital herpes. The reduced childhood oral acquisition seen in wealthier countries is less marked here, so the genital-HSV-1 shift is correspondingly less pronounced, though it is likely to grow.

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 clinical syndromes, diagnosis, antiviral 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 severe and resistant HSV-1 disease is managed.