Herpes simplex is an infection caused by two closely related DNA viruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), which belong to the family Herpesviridae. HSV-1 is the principal cause of oral lesions, commonly called cold sores or fever blisters, while HSV-2 is the principal cause of genital herpes. Both viruses infect the skin and mucous membranes, replicate in local cells, and then travel along sensory neurons to establish a lifelong latent infection in nerve ganglia. Because the virus is never fully cleared by the immune system, reactivation can produce recurrent symptoms, and infection is also often asymptomatic, which allows silent transmission. Herpes simplex is among the most widespread human viral infections, with global estimates in the billions for HSV-1 and hundreds of millions for HSV-2 (WHO estimates), making it a significant concern for public health.
The entry explains how the viruses are classified and built, how they replicate and enter a latent state, and why reactivation occurs. It then covers the clinical spectrum, from common mucocutaneous lesions to rarer but serious conditions such as herpes encephalitis, neonatal infection, and disease in immunocompromised people. Epidemiology, transmission, and risk groups are described next, followed by diagnosis, antiviral treatment, and the resistance problems that accompany it. The final sections address the status of vaccine development, experimental approaches aimed at a cure, the host immune response, the history of the disease, and the place of herpes simplex within the wider herpesvirus family. As of 2026, no approved treatment eliminates the virus from the body, and the entry treats this as a central unresolved issue.
Classification and Taxonomy
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two closely related members of the herpesvirus family Herpesviridae. Within that family they belong to the subfamily Alphaherpesvirinae, which also includes varicella-zoster virus, the agent of chickenpox and later herpes zoster, and several animal herpesviruses. Both viruses are placed in the genus Simplexvirus, where they are treated as two separate species, commonly designated Simplexvirus humanalpha1 and Simplexvirus humanalpha2. Under the older numbering used for human viruses, they are called human herpesvirus 1 (HHV-1) and human herpesvirus 2 (HHV-2). Among the nine human herpesvirus species, the alphaherpesviruses are distinguished by rapid replication and by their tendency to establish latency in neurons, whereas the betaherpesviruses, such as cytomegalovirus, establish latency mainly in monocytes or T lymphocytes, and the gammaherpesviruses, such as Epstein–Barr virus, establish latency in B lymphocytes.
The two types are distinct viruses, but they are genetically related and share a conserved core of genes. Their genomes are of similar length, with reported sizes of about 152 kilobase pairs for HSV-1 and about 155 kilobase pairs for HSV-2. Estimates of overall sequence similarity differ between sources and should be read with caution, since the two genomes are not identical across their length. Biological differences are also documented. HSV-1 is typically maintained in trigeminal ganglia, while HSV-2 is typically maintained in sacral ganglia, a difference that underlies the clinical pattern of each type. Phylogenetic analyses have also shown internal structure: HSV-1 is commonly divided into six clades, while HSV-2 falls into two, one of which is globally distributed and one of which is largely confined to sub-Saharan Africa. Such variation is relevant to evolutionary studies of these viruses and to their epidemiology.
The distinction between the two types was not recognized in early descriptions of herpetic disease, which treated herpes simplex as a single condition. Laboratory work in the 1960s and 1970s established that the viruses could be separated by antigenic differences, and later methods based on DNA analysis confirmed and refined the separation. The names "type 1" and "type 2" reflect this laboratory classification rather than the site of disease. Older clinical usage tied the types to anatomy, with type 1 linked to lesions above the waist, such as those of the lips and face, and type 2 linked to lesions below the waist, such as those of the genitals. This rule of thumb is unreliable. Either type can cause disease at either site, and the proportion of genital infections caused by HSV-1 has risen in some populations, while HSV-2 is also found in orofacial infections.
Typing matters for several clinical reasons. Type-specific serology, which relies on antibodies against distinct viral glycoproteins, can show whether a person has been exposed to HSV-1, HSV-2, or both. A positive result for one type shows exposure to that virus, but it does not establish that the person has symptomatic disease, and it does not reliably predict where the next lesion will appear. The type also carries practical consequences. HSV-1 is more often associated with ocular disease, such as herpes keratitis, and with herpes gladiatorum, whereas HSV-2 is more often linked to recurrent genital disease and to the most serious forms of neonatal infection. Knowledge of the type therefore informs counselling, risk assessment, and the interpretation of surveillance data, although the clinical management of either type shares the same antiviral framework described in other sections of this entry. The distinction between infection and disease, and the role of antibodies in establishing prior exposure, are discussed further under diagnosis.
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Viral Structure and Genome
Virion architecture
Herpes simplex virions are layered particles. The particle is usually described as four layers: an inner core containing the viral genome, a protein shell called the capsid, a multiprotein layer termed the tegument, and an envelope derived from cellular membranes that contains viral glycoproteins. The capsid is built from 955 copies of the major capsid protein (MCP) arranged into 150 hexons and 11 pentons that decorate icosahedral 5-fold (I5) vertices. Its geometry is icosahedral T = 16, about 125 nm in diameter. Among the twelve five-fold vertices, one is structurally distinct: it is the unique portal vertex through which the genome is translocated during assembly.
The tegument is the least ordered layer. Unlike the capsid, it lacks regular symmetry. Cryo-electron tomography shows it is about 35 nm thick on one side of extracellular virions but no more than 5 nm thick on the opposite side. In HSV-1 it contains more than 20 proteins, which are sometimes subclassified as components of an inner and outer tegument. Inner tegument components help anchor the layer to the capsid. The tegument proteins are concentrated near the capsid vertices, where the capsid-associated tegument complex, made of pUL17, pUL25, and pUL36, binds the triplexes and hexons around the 5-fold vertices of mature capsids within the nucleus. Its outer layer is enclosed by a lipid envelope that is studded with glycoproteins that mediate viral attachment and entry.
Genome organization
The genome is double-stranded DNA of about 152 kb. It is organized into two covalently linked segments: a long (L; 82% of the genome) and a short (S; 18% of the genome) fragment. Each segment contains a unique sequence, U_L and U_S, bounded by inverted repeats referred to as b and c, respectively. The genome has a high nucleotide G+C content, about 68%.
Gene counts differ between annotations, so the total is best given as a range. One review reports 74 proteins, another reports 77 annotated protein-coding sequences, and a third lists 84 genes. Many of the regulatory genes lie in the repeat regions. These include the immediate-early genes ICP0 and ICP4 and the latency-associated gene LAT, which are located within the inverted repeats. Since the repeats appear twice in the genome, these genes are present in two copies. Recombination between the repeats produces distinct molecular forms. Replication produces concatemeric molecules in which homologous recombination events occur between the inverted repeats. As a result, researchers have detected four genome isomers, designated P, IL, IS, and ILS.
The genome is packaged inside the nucleus. The viral genome is pumped into preassembled capsids by a portal motor located at a unique 5-fold symmetry axis. This step triggers a procapsid-to-capsid transition, during which the capsid shell adopts a more angular and stable structure. The same portal later serves as the exit route for DNA, and pUL25 is essential for retaining DNA within the nucleocapsid. For comparison, herpesviruses in general have genomes up to 240 kbp, so the HSV genome is mid-sized within the family.
Envelope glycoproteins
The envelope glycoproteins work as a coordinated set during entry. HSV-1 entry requires gD as the receptor-binding glycoprotein, and the trio of gH, gL, and gB is cumulatively required for fusion. gD binds either of its receptors, herpesvirus entry mediator or nectin-1. Its ectodomain is divided functionally: an N-terminal domain carries the receptor-binding sites, while a C-terminal domain carries the profusion domain, which is required for fusion but not for receptor binding.
Fusion is executed by gB and the gH/gL heterodimer. In the widely used model, receptor binding activates gH/gL, which then triggers gB to insert into the target cell and refold, causing fusion of the viral and cellular membranes. The gB and gH/gL pair is conserved across the family: gH/gL and gB are conserved among all herpesviruses. Their roles extend beyond entry, since gH/gL and gB also play important roles in primary fusion events that occur during egress of the capsid from the nucleus of infected cells. Measurements using a split-luciferase assay suggest that pairwise glycoprotein complexes form before fusion, interact at a steady level throughout fusion, and do not depend on the presence of the cellular receptor. This challenges the older view that the proteins act strictly in sequence.
Type-specific structural differences
HSV-1 and HSV-2 share the same basic architecture. Despite their shared overall morphology, herpesviruses are diverse in their host tropisms and pathologies. The two HSV types are closely related, and both infect humans, producing mucocutaneous sores that are predominantly facial in the case of HSV-1 and genital in the case of HSV-2. Their differences in sequence are real but modest. HSV-2 has a somewhat larger genome, about 155 kb, and a higher G+C content. Several glycoproteins differ in sequence between the types, and the type-specific gG glycoprotein is the basis of type-specific serology.
Envelope and tegument proteins are the main candidates for differences in clinical behavior. Envelope proteins and tegument proteins are crucial for host entry, cell tropism, immune evasion, and conditioning of the cellular environment. Divergence in these proteins may therefore help explain differences in where the viruses infect. The better-supported explanation for the distinct clinical patterns, however, is the anatomy of infection rather than capsid or genome architecture. The major clinical differences, such as the tendency of HSV-1 to infect the face and of HSV-2 to infect the genitals, can be explained by where each virus establishes latency and how it spreads.
Replication Cycle
Attachment and entry
The virus begins a lytic cycle when its envelope glycoproteins meet host receptors. The glycoprotein gD binds one of several entry receptors, including nectin-1, HVEM, and 3-O-sulfated heparan sulfate. The gB glycoprotein and the gH/gL complex then drive fusion of the viral envelope with the host membrane. Experimental work suggests that at least some entry proceeds through a pH-dependent endocytic route. After fusion, the tegument layer is released into the cytoplasm, and the capsid travels to the nuclear envelope, where it docks at nuclear pores and releases its DNA genome into the nucleus.
Ordered gene expression
Viral genes are expressed in three temporal classes, immediate-early (IE), early (E), and late (L), with each class depending on the one before. Tegument protein VP16 helps activate transcription of IE genes together with host factors. The IE products ICP0, ICP4, ICP22, and ICP27 regulate the expression of E and L genes. ICP4 is the principal transcriptional regulator of the virus and is essential for viral growth, and it is also present in the virion tegument. ICP0 is an E3 ubiquitin ligase, and it is thought to promote lytic infection by destabilizing host proteins that restrain the virus. Significant ICP0 levels are reached about one hour after infection, and progeny virions begin to be produced at around six hours.
Genome replication in the nucleus
After entry, the genome decondenses in the nucleus, and early proteins convert the sites of incoming genomes into replication compartments. Each incoming genome may form its own compartment, and these later fuse into larger compartments as the nucleus enlarges. Viral DNA replication depends on the viral DNA polymerase and the ICP8 DNA-binding protein, which is needed for the polymerase to localize correctly within the nucleus. Replication also reorganizes host chromatin, with heterochromatin accumulating at the nuclear periphery.
Capsid assembly, packaging, and egress
Capsids are assembled in the nucleus. The shell is an icosahedral T=16 structure roughly 125 nm across. A tripartite terminase enzyme cuts the concatemeric DNA produced during replication into unit-length genomes and pushes them through a portal into the capsid. Newly packaged capsids leave the nucleus through a process called nuclear egress, which begins with primary envelopment by budding through the inner nuclear membrane. The membrane proteins pUL34 and pUL31 form the nuclear egress complex, and loss of either one strongly impairs primary envelopment. The primary envelope then fuses with the outer nuclear membrane, releasing the capsid into the cytoplasm, where tegumentation and final envelopment occur before the virions are exported. Cells that support this lytic cycle are damaged and die, and this cell death is the basis of the epithelial lesions that characterize the infection.
Host shutoff
The virion host shutoff protein, encoded by the UL41 gene, is packaged in the tegument and enters the cell upon fusion. It is an endoribonuclease that associates with the translation initiation machinery through the eIF4F cap-binding complex and cleaves mRNA molecules. This results in the collapse of polysomes and the degradation of host transcripts, and the rapid decline in host mRNA is thought to free viral mRNAs for translation. The same protein also degrades double-stranded RNA, which dampens the protein kinase R response to infection. ICP27 contributes further by inhibiting host pre-mRNA splicing and 3′ processing. Host RNA polymerase II is progressively recruited to replicating viral genomes and removed from host chromatin beginning around two to three hours after infection. The shutoff machinery also affects innate immune signaling: vhs suppresses cytokine release from conventional dendritic cells, whereas plasmacytoid dendritic cells are unaffected.
Latency and Reactivation
Axonal transport to sensory ganglia
After replicating in the epithelium of the lips, oral mucosa, or genital skin, HSV enters the nerve endings that supply that tissue. Unenveloped capsids attach to dynein motors at the axon tip and are carried back toward the cell body, a process that requires the viral inner tegument proteins UL36 and UL37. The virus then reaches the neuron's nucleus, and the location of the infected ganglion depends on the type. For craniofacial infections, the trigeminal ganglia are a primary site for viral latency. Genital infections establish latency in the sacral dorsal root ganglia. Early studies had already found that HSV-1 established latency in the trigeminal ganglion and HSV-2 in the sacral ganglion. Later work reported that both types can also be found across spinal ganglia, from the cervical to the sacral levels, without a clear site preference.
Where the virus first enters a neuron appears to influence whether it becomes latent. In a study of trigeminal neurons, selective entry of HSV-1 into distal axons strongly favored a nonproductive, latent infection, whereas nonselective infection still allowed lytic gene expression.
The latent genome
Once inside the nucleus, the viral DNA forms a circular episome and becomes associated with nucleosomes, which promotes the latent transcriptional program. The episome is organized with histones in a chromatin structure, and active transcription occurs from only one region of this episome: the region encoding the latency-associated transcript (LAT). The LAT is a non-protein-coding RNA. Its locus produces a 2 kb intron, which is regarded as a hallmark of HSV-1 latency.
Most lytic genes are silenced during latency, and LAT expression varies between neurons. Latency can be established without it, which indicates the transcripts are not required for latency itself, but they contribute to neuronal survival and modulate the efficiency of reactivation. In mouse models, the LAT RNA represses HSV-1 gene expression in small populations of neurons, and reactivation occurred at a greater frequency from cultures of single latently infected neurons carrying LAT-negative HSV-1. The LAT region also influences the viral immediate-early regulator ICP0: ICP0 stimulates LAT expression during latency and alters the chromatin composition of the latent genome. Latency is maintained by the host cell as well. Continuous neuronal signaling appears necessary to sustain the repressive chromatin state of the viral episome and the expression of latency-associated RNAs.
Reactivation triggers and mechanism
Reactivation is inconsistent even within an infected ganglion. Only a fraction of infected neurons will reactivate, even in response to a strong stimulus. The triggers most often linked to recurrences include physical or emotional stress, illness, fever, UV light exposure, or hormonal changes. These events are thought to weaken local immune control, and they compromise the immune system and cause recurrent outbreaks.
At the molecular level, one proposed sequence involves the LAT promoter region. Changes in chromatin structure at the LAT enhancer and decreased LAT transcription appear to allow increased acetylation at the ICP0 promoter, which may facilitate productive reactivation in some neurons. This model is based largely on animal and cultured-neuron experiments, and the detailed triggering pathways remain incompletely understood.
Anterograde spread and shedding
Reactivated virus leaves the ganglion along the axon in the opposite direction. During reactivation, HSV-1 travels by anterograde axonal transport toward the peripheral epidermis, where it causes recurrent herpes or is shed without symptoms. This movement underlies the cycle of recurrent ulceration and viral shedding seen in both oral and genital disease. Some researchers also argue that latency in neurons alone does not explain all recurrences, and that secondary, non-neuronal virus reservoirs may contribute to recurrent outbreaks and persistent infections.
Clinical Presentation of Oral and Genital Disease
Oral herpes (herpes labialis)
Cold sores are the most frequent visible sign of HSV reactivation, and Herpes labialis is the most frequent clinical sign of reactivation of HSV infection. Herpes labialis, also called orofacial herpes, or cold sores, is most often caused by Herpes Simplex Virus Type 1 (HSV-1). Many people notice a warning phase first. In recurrent cases, tingling, pain, itching, or burning precede the lesions in 60 percent of persons. This phase is usually brief: it may last from a few hours to a few days and is generally accompanied by a tingling or burning sensation around the lips or nose.
The eruption typically begins on the lip and nearby skin. The lesions are clustered vesicles (often coalescing) on the lip vermilion and often on the perioral skin. Small blisters first appear around days 2 to 3, and they can also arise on the nose, chin, or cheeks. The blisters then rupture into shallow ulcers, which the most painful and contagious stage of the outbreak. A crust forms around days 5 to 8, and the healing stage can take from day 9 to day 14 but is variable. Pain is usually worst at onset and diminishes after 4-5 days. Recurrences tend to recur at the same site. Most people have few episodes: fewer than two recurrences manifest each year, but some individuals experience monthly recurrences.
Genital herpes
In women, vesicles appear on the labia majora, labia minora, or perineum. In men, recurrent lesions appear as 1 or more patches of grouped vesicles on the shaft of the penis, prepuce, or glans. Clinicians often see ulcers rather than intact blisters, because the vesicles rupture easily due to their frailty and thin walls. Healing typically takes 8-10 days in women and 7-10 days in men.
The first episode is usually the most severe. It typically covers a wider and more symmetric area, and HSV-2 causes substantially more severe primary disease than HSV-1 and is followed by more frequent relapse. Recurrences are generally milder: they are usually shorter and less severe than the primary episode, with fewer vesicles. Antibodies that develop after the first episode are part of the reason, and antibodies help ensure that recurrences are milder than the first episode. A prolonged first episode is a risk marker: in one cohort, patients with a first episode lasting at least 35 days had recurrences nearly twice as often as those with shorter first episodes.
Recurrence frequency depends strongly on the virus type. Approximately 80% of people who have a first episode caused by HSV-2 will have at least one recurrence. Genital herpes caused by HSV-2 recurs on average 4–6 times per year, and this will reduce with time. Estimates for HSV-1 differ between sources: one review gives around 10-20%, while another gives approximately 50%. Early data from 1981 found that only 14 per cent of HSV-1 infections recurred, as compared with 60 per cent of HSV-2 infections. Men appear to have more recurrences: in one study, men with genital HSV-2 infection have about 20% more recurrences than do women. Recurrence rates are highest in the early years after infection, and most participants had fewer clinical episodes 5 years after their first genital HSV-2 episode; however, nearly 25% of the participants experienced an increase in recurrence rates.
Asymptomatic shedding
Herpes simplex virus can be released from genital skin or mucosa without any visible lesion. In a PCR-based study of 498 HSV-2 seropositive adults who collected daily swabs, persons with asymptomatic HSV-2 infection had a shedding rate of 10.2% compared with a rate of 20.1% among persons with symptomatic genital herpes. Much of this shedding is subclinical: the subclinical shedding rate was higher in persons with symptomatic disease (13.1% of days, versus 8.8% of days in those with asymptomatic infection). Shedding also tends to be heaviest early. In one cohort, total shedding occurred on 33.6% of days in participants <1 year, 20.6% in those 1–9 years, and 16.7% in those ≥10 years from first episode. Shedding is more common around symptomatic episodes, occurring more frequently in the 7 days prior to or following a symptomatic episode. Genital HSV-1 shedding appears much less frequent, at a mean of 0.5% of days, although this was studied in a small number of women using the less sensitive viral culturing detection method.
Asymptomatic shedding is central to transmission. "Most HSV-2 infections are acquired from persons without a clinical history of genital herpes," so the risk of sexual transmission does not correlate with the recognition of clinical signs and symptoms of HSV-2, but most likely correlates with viral shedding. One analysis of discordant couples suggested that up to 70% of transmissions may occur during asymptomatic shedding, although such figures are estimates.
Factors affecting recurrence and healing
Outbreaks are commonly linked to stress, sunlight, fatigue, fever, illness, poor diet, food allergy, and hormonal changes. The shedding pattern itself is related to how the infection behaves: shedding rate was associated with infection severity and number of recurrences. Immune status also matters, since patients with primary immunodeficiencies, AIDS, malignancy, malnutrition, or burns and transplant recipients receiving immunosuppressive therapy can have unusually severe HSV infections.
Early treatment can shorten an episode. It may be shorter with aborted recurrent episodes or with early treatment at the prodrome or early lesion stage. Antiviral drugs do not remove the virus from nerve cells: these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. In people with a primary HSV-2 infection, the probability of recurrence was directly related to the presence and titer of neutralizing antibody to HSV-2 in convalescent-phase serum.
Serious and Atypical Manifestations
Herpes simplex encephalitis
Most HSV infections stay in the skin and mucous membranes, but in a small number of cases the virus reaches the brain. Herpes simplex encephalitis (HSE) is an inflammation of brain tissue, typically in the medial temporal lobe, and can be caused by either HSV-1 or HSV-2. HSV-1 accounts for most cases in adults, while HSV-2 causes encephalitis that is less common in adults. The central nervous system damage reflects the virus's preference for the frontal and temporal regions, which the tropism of the virus for these areas helps explain on imaging. In the United States, HSV is the most common cause of non-epidemic, sporadic, acute focal encephalitis.
Patients usually present with a prodrome of headaches and fever, followed by sudden focal neurological deficits, altered mental status, and possible seizures. Diagnosis rests on suspicion from clinical features and temporal lesions on MRI or CT, a lumbar puncture that often reveals lymphocytic pleocytosis, and polymerase chain reaction (PCR) testing of cerebrospinal fluid, which is the usual confirmatory test (see Diagnosis). Without treatment, mortality is high; estimated at around 70%. The standard therapy is intravenous acyclovir for 14-21 days, and treatment should begin empirically before the PCR result is available. Even with treatment, the course can be prolonged: in one case series the virus remained detectable in CSF after 21 days of therapy, and repeat PCR testing is used to decide when to stop. Survivors may have lasting deficits, and in one series patients were left with neuropsychiatric disabilities after acyclovir therapy. Antiviral treatment also carries a rare risk: a massive hemorrhage, though rare, can present in a delayed fashion after initiation of acyclovir.
Herpes simplex keratitis and ocular disease
HSV infection of the eye, most often of the cornea, is a leading cause of visual impairment. Herpes simplex keratitis is an infection of the cornea caused by the herpes simplex virus, and it is the most common infectious cause of corneal blindness in the developed world. The primary eye infection is usually mild. After it resolves, the virus persists in the trigeminal ganglion via the first branch of the trigeminal nerve (V1), and reactivation sends virions back along the nerve to the ocular surface.
Recurrence is the main cause of damage. Recurrent corneal disease typically stromal keratitis in its most common form, and 40% of patients experience 2 to 5 recurrences, while 11% experience 6 to 15 recurrences. Repeated episodes can leave corneal hypoesthesia, ulceration, permanent scarring, opacification, thinning of the corneal stroma, and decreased vision. Common triggers listed in clinical references include UV light exposure, fever, menstruation, significant systemic physical stress, immunosuppression, or use of glucocorticoids, although a prospective multicenter trial failed to find an association between anecdotal environment triggers and recurrence. Long-term oral acyclovir reduces recurrence: in one trial of 703 immunocompetent patients, the 12-month probability of recurrence was 19% with acyclovir compared with 32% with placebo. Ocular herpes can also involve the iris, lens, vitreous and retina, though the cornea is the usual site.
Eczema herpeticum and disseminated disease
Eczema herpeticum is a disseminated skin infection that occurs on areas of pre-existing dermatitis. It is a disseminated cutaneous infection with herpes simplex virus (HSV) that develops in a patient with atopic dermatitis. The condition predominantly results from HSV-1 superinfection in the setting of compromised skin barriers seen in atopic dermatitis. The damaged barrier impairs the skin's ability to contain the virus, so lesions spread across the affected area. Clinically, the rash is made up of monomorphic vesicles and "punched-out" erosions with hemorrhagic crusts over eczematous areas, often accompanied by fever, lymphadenopathy and malaise. Severity varies: presentation ranges from mild and self-limiting in healthy adults to life-threatening in children, infants, and immunocompromised patients. Eczema herpeticum affects a minority of people with atopic dermatitis; one review estimates that EH and EV affect around 7%-10% of AD patients. Recurrence is also uneven, since most individuals have only a single episode, but a small subgroup of patients with AD is susceptible to multiple recurrent episodes. Because of the risk of systemic spread, the condition calls for immediate antiviral therapy.
Disseminated HSV disease is also seen in people with immune deficiency, including those with advanced HIV or transplant immunosuppression (see Immunodeficiency). Immunosuppressive drugs have been linked to severe encephalitis as well; in one review, patients receiving azathioprine, infliximab or adalimumab developed HSE with lasting neurological problems in some cases.
Neonatal herpes
Neonatal herpes is rare but severe, and it usually follows infection of the mother near the time of delivery, most often from genital secretions during birth. Infants are at particular risk when the mother has a first episode of genital infection late in pregnancy, because she has not yet developed protective antibodies to pass on. The disease is usually classified into three forms: skin, eye and mouth disease, central nervous system disease, and disseminated disease involving several organs, including the liver, lungs and blood. Disseminated disease carries the highest risk of death, and CNS disease often leaves lasting neurological damage. Untreated infants have high mortality and morbidity, so intravenous acyclovir is started promptly when neonatal infection is suspected. Infants with CNS or disseminated disease generally receive a prolonged course of intravenous antiviral therapy, and PCR testing of blood, CSF and lesions helps establish the diagnosis (see Pregnancy).
Transmission and Mechanisms of Spread
Routes of contact
Herpes simplex virus depends on close physical contact for its spread. The virus is highly unstable outside the human body, and it rapidly loses infectivity once exposed to air. Because of this, transmission through inanimate objects such as towels or toilet seats is generally considered extremely unlikely. Acquisition instead requires that virus reach the body through its surfaces. Entry points include the moist linings of the mouth, genitals, rectum and urethra, as well as small cuts in the skin's surface. Infection can follow contact with skin that appears unbroken. The greatest risk of transmission is when there are active sores.
Different patterns for HSV-1 and HSV-2
The two types differ mainly in where and how they are acquired. HSV-1 is mainly transmitted via contact with the virus in sores, saliva or skin surfaces in or around the mouth. In many populations, most oral infections are acquired early in life, from non-sexual contact with saliva, which is the setting in which the virus spreads through shared household contact. By contrast, HSV-2 is mainly transmitted during sex through contact with genital or anal surfaces, skin, sores or fluids of someone infected with the virus. A prior HSV-1 infection does not protect against HSV-2: people who already have HSV-1 are not at risk of reinfection with HSV-1, but they are still at risk of acquiring HSV-2.
Per exposure, HSV-1 is generally the less transmissible type. One summary of the transmission data attributes this to reduced shedding frequency for HSV-1, compared with frequent asymptomatic shedding for HSV-2. A patient information leaflet estimates the annual risk of genital herpes transmission for both types at 5-10% each year.
Oral-genital transmission and changing genital epidemiology
The WHO describes genital HSV-1 as a less common outcome of oral-genital contact. HSV-1 can be transmitted to the genital area through oral-genital contact to cause genital herpes. Clinically, this pathway matters more than the word "less common" suggests. Oral sex can produce infection at both sites: a person who has never had herpes may acquire the infection at both sites after oral and genital sex with an infected partner.
The proportion of genital infections caused by HSV-1 has grown in several settings. HSV-1 has overtaken HSV-2 as the primary cause of first-episode genital herpes in certain regions and populations worldwide, and this change is most visible among younger people. In one US university cohort, HSV-1 accounted for 31 percent of genital herpes cases in 1993 and grew to 78 percent in 2001. Genital-to-genital spread of HSV-1 is less common than oral-genital spread, partly because genital HSV-1 infections have fewer recurrences and are associated with less asymptomatic shedding. The broader epidemiological context is covered in the epidemiology section.
Asymptomatic shedding
Most HSV infections produce no recognised symptoms. Most HSV infections are asymptomatic or unrecognized, so many people transmit the virus without knowing they carry it. In a cohort of people with first-episode genital HSV-1, genital shedding of HSV-1 was detected on 12% of days at 2 months and declined significantly to 7% of days at 11 months. Most genital shedding was asymptomatic; genital and oral lesions and oral shedding were rare. For HSV-2, most sexual transmissions occur during periods of asymptomatic shedding. Condoms reduce the risk but do not eliminate it: correct and consistent use of condoms reduces risks of herpes transmission, while people with active symptoms should avoid sexual contact with other people, since herpes is most contagious when sores are present.
Mother-to-infant transmission
Transmission to the newborn is uncommon overall but clinically serious. In rare circumstances, herpes can be transmitted from mother to child during delivery, causing neonatal herpes. Most infections occur at birth, as about 85% of perinatal transmission occurs during the intrapartum period. The risk depends strongly on when the mother acquired the virus. The risk of neonatal infection varies from 30% to 50% for HSV infections that onset in late pregnancy, whereas early pregnancy infection carries a risk of about 1%. The type of maternal infection is decisive: neonatal herpes is much more frequent (50%) in babies from mothers with a primary HSV infection with respect to babies from mothers with recurrent HSV infection (<3%). Asymptomatic shedding also contributes. Most neonatal HSV infections (about 70%) result from exposure to asymptomatic genital HSV infection in the mother near delivery. In one study, among the 56 women who shed virus asymptomatically on admission to the labor unit, 7 transmitted HSV to their infants (12.5 percent).
Delivery practice reflects these findings. The current standard of care is that any woman with an active HSV lesion is delivered by cesarean section. However, cesarean section alone does not completely remove the risk of transmission, and rupture of membranes for more than four to six hours before delivery increases the risk of transmission of HSV to the infant. HSV-1 also carries a higher risk to the newborn than HSV-2 in some analyses, and the mechanisms of this difference are still being studied.
Epidemiology and Global Burden
The most widely cited global figures come from the World Health Organization (WHO), whose 2020 estimates are the latest full set. In 2020, 3.8 billion people under the age of 50, or 64% of the global population, had HSV-1 infection (oral or genital). Genital herpes caused by HSV-2 affects an estimated 520 million (13%) people aged 15–49 years worldwide. The earlier WHO estimates for 2016 were of the same order: 491.5 million people were living with HSV-2 infection, equivalent to 13.2% of the world's population aged 15 to 49 years. Because the 2020 model revised the 2016 methods and used different inputs, the two sets of figures are not directly comparable. WHO reported that genital HSV-2 prevalence was virtually unchanged from 2016, while estimated genital HSV-1 infections were higher.
Age and sex patterns
Most HSV-1 infections are acquired during childhood to cause oral herpes. Overall prevalence rises with age, but new infections are concentrated in younger people: prevalence increases with age, though the highest number of new infections are in adolescents and young adults. In 2020, an estimated 25.6 million people aged 15–49 acquired HSV-2, of whom 15.6 million were women. HSV-2 prevalence is markedly sex-dependent: it was 17.0% among females compared with 9.7% among males in the same age group. WHO links this gap to biology, noting that sexual transmission is more efficient from men to women. By contrast, the modelled genital HSV-1 prevalence in 15–49-year-olds was similar for women (10.5%) and men (9.9%).
Regional variation
Burden is uneven across the WHO regions. In the 2012 estimates, the highest HSV-2 burden was in Africa; despite lower prevalence, South-East Asia and Western Pacific regions also contributed large numbers because of their large populations. The 2016 estimates likewise found HSV-2 prevalence was highest among women and in the WHO African Region. Patterns for HSV-1 differ. In Asia, HSV-1 seroprevalence shows considerable variation but is generally high, increasing with age, with about 50% of children and 76.5% of adults. Modelling of HSV-1 data identified the highest prevalence in Africa, South-East Asia and the Western Pacific.
The differences are commonly attributed to socioeconomic conditions. Where children grow up in crowded households with poorer hygiene, early oral exposure to HSV-1 is more common; WHO notes that reduced oral spread during childhood may be linked to less crowded living conditions and improved hygiene, which then increases susceptibility to the virus at older ages.
Shifting HSV-1 transmission
In several high-income countries, the route of HSV-1 acquisition is changing. In the United States, a 2024 meta-analysis estimated HSV-1 seroprevalence at 38.0% among children and 63.5% among adults in the general population, and found that seroprevalence is decreasing at a rate of 1% per year. Over the same period, the proportion of genital herpes cases caused by HSV-1 increased by about 2% per year. The authors describe the shift as a decline in oral acquisition during childhood and an increase in genital acquisition during adulthood. Earlier data point the same way: a college-student study in the US found that the proportion of genital herpes infections caused by HSV-1 increased from 31% to 78% between 1993 and 2001. Europe shows a similar trend, with one analysis estimating that HSV-1 prevalence there is falling by 1% per year.
The consequence is that more adolescents enter sexual life without antibodies to HSV-1. Researchers have linked this to decreases in childhood infection combined with increases in the frequency of oral sex. Because a first genital HSV-1 infection in an adolescent without prior exposure can be a primary episode, this change matters for public health even though HSV-1 recurs less often in the genital tract. Recurrent genital herpes had a lower proportion of HSV-1 detection compared with first-episode cases.
Limits of the estimates
Global figures rest on pooled seroprevalence surveys, which are uneven in quality. The WHO models adjusted for the sensitivity and specificity of HSV tests and applied a constant incidence model to pooled prevalence by age and sex for each WHO region. Data are thinner in some regions: for HSV-1, the 2020 analysis used surveys from 1995 onward for the African and South-East Asia regions because of poor data availability. Estimates of genital HSV-1 are the most sensitive to assumptions; in the 2016 model, between 122 million and 192 million people were estimated to have genital HSV-1 infection, depending on the assumptions used.
Risk Groups and Associated Conditions
Newborns are the group in which herpes simplex infection is most dangerous. Most affected infants show signs during their first month of life. Disseminated infection, which accounts for roughly a quarter of cases, carries a case-fatality of about 85% when untreated, while CNS infection, which makes up about 30%, is fatal in roughly half of untreated cases. Antiviral treatment with parenteral acyclovir lowers mortality in CNS and disseminated disease by about half, but survival does not guarantee normal development. Even among treated infants, neurological or developmental sequelae appear in 13% of those with disseminated disease and in 40 to 70% of those with CNS disease.
Infection confined to the skin, eyes, or mouth is rarely fatal by itself, but it is not benign. Without treatment, many of these neonates progress to disseminated disease or CNS disease that may be unrecognized. Maternal infection status also matters: the risk for transmission to the newborn is much higher in women with primary HSV infections, meaning a first episode in the mother carries more risk than a recurrence. Neonatal disease is uncommon overall, but incidence in the United States is as high as approximately 1 in 2000 live births, and HSV type 2 causes more cases than HSV type 1.
HSV-2 is also closely linked to HIV, in both directions. Pooled prospective data from 2017 show that the risk of HIV acquisition was almost tripled in the presence of established (prevalent) HSV-2 infection and quintupled in the presence of recently acquired (incident) HSV-2 infection. In a Looker and colleagues meta-analysis, the adjusted relative risk was 2.7 in general populations with prevalent infection and roughly doubled among higher-risk populations. The proposed mechanism is physical: ulcerative first episodes and recurrences of HSV-2 infection result in disruption to the epithelial barrier, which facilitates the entry of HIV. The effect also runs the other way. Data from Rakai, Uganda, suggest that HSV-2 can increase HIV infectiousness, with a 5-fold increased risk on a per-contact basis among HIV-infected individuals who have genital herpes lesions. Because of this, the authors argued that interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV.
Immunocompromised people experience herpes simplex that is more frequent, more severe, or harder to treat. In advanced HIV, refractory and/or resistant HSV infections have prevalence rates of 3%–7%, although they are much less common in patients receiving effective antiretroviral treatment. Low CD4 T-cell counts correlate with an increased risk of symptomatic HSV infections. In such patients, atypical presentations of HSV-2 can be associated with more severe disseminated clinical presentations such as meningoencephalitis, hepatitis, and pneumonitis. Anogenital lesions in severely immunosuppressed patients are typically painful, well-demarcated anogenital ulcers, often with associated necrosis or ulcerative erosions.
In transplant recipients, the pattern follows the intensity of immunosuppression. Solid organ recipients shed virus frequently and also have more frequent and severe clinical manifestations of HSV, and most symptomatic HSV disease occurs early after transplantation and in the setting of antirejection therapy. After hematopoietic cell transplantation, the presence and severity of graft-versus-host disease (GVHD; grade ≥2) is the strongest predictor of ACV-resistant HSV infections. Other common risk factors include hematological malignancy (particularly relapsed disease), HIV infection, hypogammaglobulinemia, and corticosteroid use.
Persistent ulcers in these patients can have more than one cause. Cytomegalovirus coinfection has also rarely been documented in individuals with advanced HIV infection or in solid organ transplant recipients undergoing immunosuppressive therapy. Clinicians therefore consider a second virus when ulcers persist despite adequate HSV-directed therapy. Because herpes simplex shares sexual transmission routes with other sexually transmitted infections, its management is generally integrated into broader sexual health services, including testing for co-occurring infections.
Diagnosis
Diagnosis usually begins with the history and examination. Physicians often recognize the typical grouped vesicles, but clinical diagnosis of HSV is insensitive and nonspecific, so laboratory confirmation is needed. Atypical or mild presentations, such as erosions without visible vesicles, are where this limitation matters most.
Detecting the virus directly
Viral culture was long the reference method, but it misses many cases. One summary puts its sensitivity at about 50%, especially for recurrent lesions or lesions that have begun to heal. Culture material should come from the base of a vesicle or a freshly ulcerated lesion, and test sensitivity declines if the vesicular lesion has been present for more than 24 hours. PCR is now preferred: it is more sensitive than culture, allowing rapid laboratory diagnosis, and HSV DNA PCR from lesions is reported to be 98–100% sensitive. Some commercial assays target a type-specific sequence within the glycoprotein B gene, which allows typing from the same swab. Antigen-detection methods, such as immunoperoxidase staining, are faster but less sensitive, with a sensitivity of about 80% in one comparison table, and they depend on fresh specimens.
Type-specific serology
Serology measures IgG against the virus. Because most high-throughput assays detect type-specific IgG responses to glycoprotein G, gG1 for HSV-1 and gG2 for HSV-2, which share only about 40% amino acid identity, these tests distinguish the types far better than older assays. Earlier tests were hampered by extensive cross-reactivity of HSV-2 antibodies to HSV-1, and the CDC recommends type-specific glycoprotein G based assays when serology is performed.
The main limitation concerns timing. Type-specific IgG to HSV-1 and HSV-2 glycoproteins takes an average of 2–3 weeks, and up to 6 months, to develop, and some patients never develop type-specific antibodies. Consequently, if suspicion is high but results are negative, testing should be repeated 6–12 months later. Serology also cannot establish active disease: one reference laboratory states that this test should not be used to diagnose active or recent infection.
A positive result shows that a person has been exposed to a given type, but it does not mean that the person has symptomatic disease. A positive result may indicate a current or past infection, and a positive IgG result cannot determine the exact time of exposure or the site of infection. Serology is therefore most useful for identifying people with subclinical or unrecognized infection, and because of high rates of asymptomatic shedding, symptoms alone cannot guide testing to prevent transmission.
Encephalitis
No pathognomonic clinical findings are associated with herpes simplex encephalitis (HSE), and focal neurologic deficits, CSF pleocytosis, and CT abnormalities may be absent initially. Diagnosis therefore rests on the combination of cerebrospinal fluid (CSF) testing and neuroimaging. CSF PCR is the principal test: one review reports sensitivity of 94–98% and specificity of 98–100%, and it is as accurate as brain biopsy in confirming the diagnosis, which has largely given way to PCR. CSF culture is far less useful, since culture of HSV from the CSF of adults with HSE has a sensitivity of less than 10 percent.
False negatives occur. They are more likely early in the course of the disease, when viral DNA levels are low (within 72 hours of the onset of symptoms), or when blood contaminates the sample. In one reported case, two early CSF PCR tests were negative before a third sample was positive, and current guidelines suggest repeating CSF HSV-1 PCR within 3 to 7 days in suspicious cases while continuing empiric therapy.
MRI is the main imaging tool. Lesions are typically most common in the inferomedial portion of the temporal lobe, sometimes with abnormalities of the cingulate gyrus. Diffusion-weighted imaging is more sensitive than T2 imaging in acute infection, but MRI may be normal early in the course of illness, so a normal early scan does not exclude the diagnosis. The basal ganglia and thalami are nearly always spared, which helps distinguish HSE from some other patterns of encephalitis.
Neonatal infection
In newborns, PCR is typically performed on several specimens. Blood PCR is valuable: one laboratory directs that blood testing is for neonates less than 2 months of age and for immunocompromised patients. In a review of 1,028 infants, of the 21 who had positive CSF PCR, 76% also had positive HSV PCR in their blood. Testing of mucosal and skin sites is usually added to these tests. Because many cases of neonatal HSV infection can be prevented by cesarean section, identifying maternal infection before delivery is considered important.
Antiviral Treatment
Nucleoside analogues
Acyclovir is the prototype drug for HSV. Valacyclovir (a prodrug converted to acyclovir after oral absorption) and famciclovir (converted to penciclovir) belong to the same general class of nucleoside analogues. Acyclovir suppresses replication of both HSV types and varicella-zoster virus (acyclovir is a nucleoside analog that selectively inhibits the replication of herpes simplex virus types 1 and 2 and varicella-zoster virus). Its selectivity depends on the viral thymidine kinase, which performs the first phosphorylation step, a reaction that uninfected cells carry out only weakly (after intracellular uptake, the drug is converted to acyclovir monophosphate by the virally encoded thymidine kinase, a step that does not occur to any significant degree in uninfected cells). Host kinases then produce the triphosphate, which accumulates in infected cells at roughly 40 to 100 times the concentration found in uninfected cells (cellular enzymes convert the monophosphate to acyclovir triphosphate, which is present in 40-fold to 100-fold higher concentrations in HSV-infected than in uninfected cells). The triphosphate inhibits viral DNA polymerase, and its incorporation into viral DNA stops chain elongation (incorporation into viral DNA, leading to chain termination and inhibition of viral replication).
Episodic and suppressive therapy
Episodic treatment shortens an outbreak, but its benefit depends on timing. Starting within about one day of lesion onset, or during the prodrome, is required for effective treatment (effective treatment requires therapy initiation within 1 day of lesion onset or during the prodrome preceding an episode or recurrence). Daily suppressive therapy, usually with valacyclovir or acyclovir, is used in people with frequent recurrences and in those who wish to lower the risk of passing the virus to a partner.
Severe and central nervous system disease
Herpes simplex encephalitis is treated with intravenous acyclovir at 10 mg/kg every 8 hours, which is the standard regimen (intravenous acyclovir 10 mg/kg every 8 h is the standard treatment for HSE). The introduction of acyclovir in place of vidarabine reduced mortality from about half of patients to under one fifth (intravenous acyclovir replaced vidarabine by decreasing mortality in HSE from approximately 50% to less than 20%). Treatment delay also affects outcome: in one cohort, a mean delay of six days from symptom onset was associated with an adverse result (mean delay from onset of symptoms to treatment was 6 days; this was associated with adverse outcome).
Recommended duration has lengthened. A fatal relapse reported in 1988 in an adult treated for 10 days led to a shift toward 14 to 21 days of therapy (the report of a fatal relapse in an adult with confirmed HSE resulted in the change of initial treatment from 10 days of intravenous acyclovir to the current 14–21 day recommendation). Guidance varies: the CDC recommends 21 days, while the manufacturer's labeling lists 10 days (manufacturer 10 days; CDC 21 days).
For severe mucocutaneous disease, intravenous acyclovir for 10 to 14 days is preferred, with a switch to oral therapy once lesions begin to regress, and treatment continues until lesions have fully healed (severe mucocutaneous lesions respond best to initial treatment with intravenous acyclovir for 10 to 14 days; once the lesions begin to regress, patients can be switched to oral therapy; therapy should be continued until lesions have completely healed). Visceral or disseminated infection is handled with intravenous acyclovir for at least 10 to 14 days (people with visceral or disseminated HSV disease should be treated with acyclovir 10 mg/kg IV every 8 hours for at least 10 to 14 days). In practice, courses can be prolonged by diagnostic delay: in one Texas cohort, patients with a positive panel result received a median of about 115 hours of intravenous acyclovir afterward, compared with about 18 hours for those who tested negative (the median intravenous acyclovir duration after the BioFire result was 115.2 hours for HSV-positive patients versus 18.1 hours for HSV-negative patients).
Resistance
Resistance is a major concern in immunocompromised patients (herpes simplex virus resistant to acyclovir is a major concern among immunocompromised patients). Most resistance arises from changes in the thymidine kinase gene, which accounts for about 95% of cases, while mutations in the DNA polymerase gene are the other route (resistance might be due to mutations in the thymidine kinase gene, involved in 95% of the cases, and the DNA polymerase gene). A laboratory study of a resistant mutant with an altered thymidine kinase showed that it kept much of its neurovirulence in mice (this virus retains pathogenicity for mice with only a slight attenuation of neurovirulence). Older alternatives for refractory infection, such as intravenous foscarnet, cidofovir, and topical imiquimod, are often limited by toxicity, resistance, and the need for prolonged intravenous administration (current options for refractory HSV, such as intravenous foscarnet, cidofovir, or topical imiquimod, are often limited by toxicity, resistance, and the need for prolonged intravenous administration).
Pritelivir and helicase-primase inhibitors
Pritelivir is a helicase-primase inhibitor that targets the helicase-primase complex of HSV rather than the polymerase step used by nucleoside analogues (a novel small molecule antiviral targeting the helicase-primase complex of HSV). Because of this different mechanism, it remains active against strains resistant to nucleoside analogues (pritelivir is active against viral strains that are resistant to nucleoside analogs). Its long half-life, about 60 hours, permits once-daily oral dosing (pritelivir is bioavailable with a long half-life of 60 hours, enabling once-daily oral dosing). In an early series of 23 immunocompromised patients with acyclovir-resistant disease, 19 showed complete resolution of lesions during the 28-day course (19 patients showed full resolution of their HSV-related lesions during the 28 day treatment period).
The phase 3 PRIOH-1 trial randomized 101 people with refractory or resistant infection to pritelivir or investigator-chosen standard therapy (the open-label PRIOH-1 study randomised 101 people with refractory or drug-resistant HSV-1/2 to either daily oral pritelivir or investigator-chosen standard of care). Lesion healing occurred in 62.7% of pritelivir recipients versus 34.0% in the comparator group (62.7% lesion healing compared to 34.0% for ICT). Resistance data at treatment failure were available for only 2 of 9 pritelivir failures, and one of these showed a new mutation that emerged on treatment (drug resistance results at failure were only available for 2/9, one of whom showed pritelivir-associated new mutation detected at day 36). Reported adverse effects were mild, including headache and nausea (some headache and nausea). The drug has received FDA breakthrough therapy designation (the drug has received breakthrough therapy designation from the FDA), and the sponsor planned a New Drug Application submission in the first quarter of 2026 (Aicuris is on track to submit a New Drug Application to the U.S. FDA in Q1 of 2026). In the most recent reports reviewed, it was still described as investigational (pritelivir, an investigational antiviral drug for herpes simplex virus).
Vaccine Development
Why no vaccine has been licensed
An HSV-2 vaccine is not available, according to a US trial registry entry from 2026, and testing of HSV vaccines is ongoing, but so far none have achieved FDA approval. The goal of an ideal vaccine is to induce immune responses adequate to prevent infection. A less complete result, such as mitigating primary clinical episodes or limiting colonization of the nervous system, may still be judged a partial success. The difficulty lies partly in the virus itself. Because HSV establishes neuronal latency that antibodies in the blood cannot reach, a vaccine must block infection at the mucosa before the virus reaches sensory ganglia. Reviews also point to the virus's sophisticated pathogenic and immune evasion mechanisms, which have led most candidates to fail in preclinical or early clinical work.
Subunit vaccines and the Herpevac trial
Subunit vaccines based on glycoprotein D (gD) have been the most tested approach. Earlier efficacy trials in serodiscordant couples reported 73% and 74% efficacy against genital disease in women who lacked antibodies to both HSV-1 and HSV-2, but efficacy was not observed in men or HSV-1 seropositive women. The larger Herpevac trial enrolled 8,323 women aged 18 to 30 who were seronegative for both viruses and used gD2 with an alum and MPL adjuvant. The result was that vaccine efficacy against HSV-1 infection (with or without disease) was 35%, but efficacy against HSV-2 infection was not observed. Reviews cite a different figure of 58% against genital HSV-1 disease, which reflects a different analysis. Antibody levels correlated with protection against HSV-1, whereas protection was associated with antibody titer but not CD4 or CD8 T cells. Rodent models had suggested broader benefit, but these outcomes did not translate into protection in the clinical trial. One analysis found that immunized women produced antibodies against fewer critical gD2 epitopes than guinea pigs did, which may explain part of the gap.
Live-attenuated and DNA candidates
Live-attenuated vaccines are considered potentially powerful. The success of the live-attenuated chickenpox vaccine demonstrates that an appropriately live-attenuated α-herpesvirus may be used to safely control human disease. The main concern is that their ability to replicate can result in vaccine-related illness particularly in immunocompromised individuals. The preclinical VC2 candidate, which carries small deletions in UL20 and UL53, prevents HSV infection of neuronal axons and establishment of latency in animal models. A replication-defective HSV-2 vaccine, HSV529, which is deleted for two essential viral proteins, has been studied in a randomized, placebo-controlled trial, with three groups of 20 subjects each planned. A DNA candidate, COR-1, gave a different profile: in a phase I study, vaccine-induced antibody responses were not detectable, while cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study.
mRNA prophylactic candidates
The most advanced prophylactic program is BNT163, developed by BioNTech with the University of Pennsylvania. The phase 1 trial enrolled 318 participants beginning in December 2022, and the study is ongoing and expected to be completed in October 2026. Early results reported that BNT163 is well-tolerated with an acceptable safety profile and it induces binding antibody and neutralizing titers to HSV-2 antigens. A 2026 mouse study found that a bivalent gD2-gE1 mRNA produced the most potent antigen-specific T-cell responses among the candidates tested, and that all tested candidates protected mice against intravaginal challenge with HSV-1 and HSV-2.
Therapeutic vaccines
Therapeutic candidates target people who already carry the virus, with the aim of reducing reactivation and recurrence. The best-documented example is mRNA-1608, which encodes modified versions of 3 HSV-2 glycoprotein antigens (gB, gC, and gD) and 2 immediate early proteins (ICP0 and ICP4). Its phase 1/2 trial randomized 302 participants, and no safety concerns were identified. Antibody responses rose in all dose groups, and dosing showed a trend for delay in time to first genital herpes recurrence. Even so, Moderna has decided not to advance the program into phase 3 testing. GSK's recombinant protein therapeutic, GSK3943104, failed to hit the primary efficacy endpoint of reducing episodes of recurrent genital herpes in the phase 2 portion of the study. Across the field, a limited number of candidates have reached phase III, yet none have achieved their primary efficacy goals.
Research Toward a Cure
The main obstacle to a cure is latency. Existing HSV drugs lack the means to clear the dormant genome from sensory neurons, so they control flare-ups without removing the reservoir that causes them. Nucleoside analogues such as acyclovir are the commonly used clinical drugs, but they cannot eliminate the latent virus or stop reactivation. Because the viral genome persists in neurons for the life of the host, a cure must reach the nucleus of cells that are otherwise out of reach of drugs that act during active replication.
Gene editing
Most cure research on herpes simplex has focused on CRISPR-Cas9 systems that cut viral DNA. In a three-dimensional human brain organoid model, researchers established latency, then delivered CRISPR-Cas9 vectors aimed at the viral regulatory genes ICP0 or ICP27, which significantly reduced viral rebound in the organoids that were latently infected with HSV-1. In animal work, CRISPR–Cas9 targeting of the virus has been reported to cure herpetic stromal keratitis in mice. These results are encouraging, but a scoping review of CRISPR approaches to human herpesviruses noted that only a small editing efficiency of HSV-1 latent viral genomes was observed, with no reduction in the number of latent genomes.
The first human study
The only in vivo CRISPR study in patients for HSV-1 targeted corneal disease rather than neuronal latency. A single dose of an HSV-1-targeting CRISPR formulation was injected into the cornea of three patients, in an investigator-initiated, open-label, single-arm trial at one centre (NCT04560790). Clinical follow-up reached 21 months at the longest and 18 months on average, with no virus relapse, no herpetic stromal keratitis recurrence and no treatment-associated side effects. No CRISPR-induced off-target cleavage was detected, and no systemic adverse events occurred. A sample of three patients cannot establish efficacy against ganglionic latency, and the study does not address that reservoir.
Latency reversal and clearance
Latency-reversal strategies are drawn largely from HIV research. In the so-called shock-and-kill concept, reactivating agents expose the dormant virus, and immune effectors or viral cytopathic effects then destroy the exposed cells. HIV trials of such agents showed the limits of this approach: several small non-randomised clinical trials increased viral production but did not reduce the number of latently infected cells or delay viral rebound after therapy stopped. For herpes simplex, reactivation without reliable clearance would risk new lesions and shedding, which is why researchers favour approaches that act on the latent genome itself. Among the proposed CRISPR mechanisms, targeting genes required to maintain latency is considered the most promising, since it could in principle remove viral genomes permanently, something existing drugs cannot do.
Even so, complete removal has not been demonstrated in related viruses. Despite efficient reductions in latent genome numbers, no study has achieved complete eradication of latent EBV or KSHV episomes. The authors attribute this to several factors, including multiple viral genome copies per cell, incomplete delivery of CRISPR components, chromatin-associated protection of episomes, and a possible survival advantage for cells that keep episomes.
Other strategies and the clinical gap
Pharmacological work is more advanced in clinical terms, though it does not aim at a cure. ABI-5366, a long-acting HSV helicase-primase inhibitor, reduced viral shedding by 94% compared with placebo in a Phase Ib trial in people with recurrent genital HSV-2, and a Phase II programme was planned for mid-2026. Gilead has exercised its option to license the program, and development is now under its sole control. Immune-based approaches, including therapeutic vaccines and antibody-based methods, are also under study, but earlier HIV experience suggests that hopes for latency reversal alone to reduce infected cells have not been realized.
As of 2026, no herpes cure has been approved, and treatment focuses on symptom control, reducing recurrence and limiting transmission. Some overviews state that human clinical trials for a CRISPR-based herpes cure have not yet begun, while others point to the corneal study above, which shows that in vivo editing has reached patients for a narrower target. Timelines remain uncertain: one developer's team is reported to be aiming for its first human trials around 2026 or 2027, with no firm date.
Host Immune Response and Immune Evasion
Innate defenses in epithelium and neurons
Lytic replication in epithelial cells activates host defenses, mainly through the production of interferons, chemokines and cytokines. These signals recruit innate immune cells such as neutrophils, macrophages, natural killer (NK) cells and dendritic cells. Type I interferons are made by almost every virus-infected nucleated cell, whereas type III interferons come mainly from infected mucosal epithelial cells. Type I interferons also establish an antiviral state in neighbouring uninfected cells, which limits the spread of the virus to nearby tissue (they make it harder for the virus to replicate in these cells as well).
Interferon-gamma acts alongside the type I interferons. It multiplies the potency with which the innate interferons alpha and beta suppress HSV-1 replication, and this cooperative inhibition effectively prevents infected cells from producing new virions. Whether NK cells themselves are central to this early defense is less settled. In a study using lymphocyte-deficient mice, losing NK cell cytotoxicity or depleting NK cells did not change the progression of infection, whereas depleting white blood cells made viral spread and disease develop much faster. Loss of Stat1 function also strongly weakened innate resistance, which points to interferon signaling as the key pathway in that model.
Neurons are not passive targets. Mature sensory neurons respond to interferon-beta at both the cell body and the end of their long projections, and this neuronal interferon response is critical for controlling infection in vivo, whereas interferon responses in non-neuronal cells alone were insufficient to provide protection.
Adaptive responses: CD8 T cells, resident memory and antibodies
CD8 T cells are the best-characterized adaptive defense against latent infection. Virus-specific CD8+ T cells infiltrate the ganglia at the onset of latency and then contract to a stable, activated tissue-resident memory population. In human trigeminal ganglia, this persistent local response comprises activated late effector memory CD8+ T cells that appear to control latency by noncytolytic pathways, although only a limited number of the ganglionic CD8 T cells recognize latent HSV-1. In mice, a gB-specific CD8 T cell clone blocked reactivation in ex vivo ganglion cultures through a dose-dependent, MHC-restricted mechanism that depended partly on interferon-gamma. These cells can also act through interferon-gamma or cytolytic effector molecules such as perforin and granzyme B.
The protective population is vulnerable. Restraint stress raises corticosterone levels, reduces the ganglion-resident CD8 T cell population, impairs the function of the remaining cells, and induces reactivation from latency in mice. Neutralizing antibodies bind free virions and interfere with their entry into cells, but they act mainly on extracellular virus and are less effective against spread from cell to cell. Circulating memory responses therefore complement, rather than replace, the resident T cell population in the ganglia.
Immune evasion
HSV encodes several proteins that impair antigen presentation. The immediate-early protein ICP47 conceals infected cells from CD8+ T cells by inhibiting peptide presentation on MHC class I, binding to the transporter associated with antigen processing (TAP) and blocking peptide transport and loading onto MHC I molecules in the endoplasmic reticulum. Its activity is strongly species-dependent. Inhibition of murine TAP requires ICP47 concentrations 50- to 100-fold higher than those needed to inhibit human TAP. In one comparison, antigen presentation was reduced by 44% in mouse cells but by 85% in human cells. Because of this, recombinant viruses engineered to inhibit murine MHC class I replicated to higher titers in the central nervous system and induced paralysis more frequently than control virus.
A second mechanism is the virion host shutoff protein (vhs), which targets host mRNA for destruction, thereby shutting down antigen presentation at several steps in a nonspecific way. During latency, the latency-associated transcript (LAT) has been linked to dysfunction of T cells rather than to direct blocking of antigen presentation. Most HSV-1-specific ganglionic CD8 T cells in LAT-positive latency showed low cytotoxic function and reduced interferon-gamma and TNF-alpha production.
Why immunity controls but does not clear the virus
The immune system contains HSV but cannot eliminate it from the body. Latent genomes sit in neurons with minimal gene expression, and the immune response works by surveillance rather than by destroying every infected cell. Ganglion-resident memory CD8 T cells can block reactivation through interferon-gamma or lytic granules, and although they cannot clear HSV-1 from the body, they can actively suppress viral reactivation. A 2025 study also described an interferon-dependent form of epigenetic silencing of the latent genome, which produces a deeper, more silent form of latent infection that is restricted for reactivation.
Lesion formation is also shaped by the immune response. Recruited neutrophils induce apoptosis in infected cells and clear dying cells, while activated NK cells release interferon-gamma and granzymes A and B, which trigger apoptosis of infected cells. The same inflammatory processes that remove infected cells also damage surrounding tissue. Repeated recurrences in the cornea, for example, can lead to a chronic inflammatory reaction, herpetic stromal keratitis, which impairs vision and can cause blindness.
History of Discovery and Treatment
Physicians recorded herpes-like eruptions long before anyone knew a virus was involved. The earliest written accounts came from Greek and later Arabic medical authors, whose descriptions match lesions now attributed to HSV-1, HSV-2 and varicella-zoster virus Hippocrates, Celsus, Herodotus, Galen, Avicenna and others described cutaneous lesions typical of infections caused by herpes simplex viruses (HSV) 1 and 2, and varicella-zoster virus (VZV). The label itself is Greek. The word herpein, meaning "to creep" or "move slowly," characterized the latent onset of the infection and the inconspicuous, recurrent spread of lesions on the skin. Over the following centuries the term was stretched across many unrelated conditions, from lupus to zoster, until the definition of herpes, particularly for oral lesions, became more rigorous in the 17th century.
Understanding of transmission advanced slowly. Vidal's 1893 account is usually credited with recognizing that the infection passes from one person to another. A 1930s finding by Andrews and Carmichael tied the recurrence of cold sores to the presence of neutralizing antibodies in adults. The virus itself was not identified until the 1950s. Clinicians had separated orofacial from genital disease for centuries before the laboratory could confirm any division, and the naming of the two types drew on that clinical pattern. Laboratory work, however, showed that the split is not anatomical. Both viruses are capable of causing either genital or oral-pharyngeal infections that appear identical on examination. Accounts differ on the date of the typing. One review states that it was proposed that two different types of HSV caused infection in 1971, whereas a patent background section credits Schneweis and Brandis with demonstrating 2 different antigenic types of herpes simplex virus in 1961. The classification therefore rests on antigenic differences, not on the site of disease.
The therapeutic turning point came from a screening program at Burroughs Wellcome. A screening program for antiviral drugs begun at Burroughs Wellcome in the 1960s resulted in the discovery of acyclovir in 1974. Accounts differ on the date, and one review places the work in 1977 when acyclovir was discovered. The original synthesis is credited to Howard Schaeffer, after which Gertrude Elion's team studied how the drug worked, why it worked, and why it was so nontoxic. Elion had noticed much earlier, in 1948, that a related compound showed antiviral activity but she was intrigued but became discouraged by the drug's toxicity, and ultimately shelved it. Clinical trials began in 1977, and the first formulation, a topical one, reached physicians in 1982. The FDA approved the ointment on March 29, 1982, and oral capsules followed in 1985. Elion and Hitchings received the Nobel Prize in 1988 for this research approach.
Acyclovir's selectivity explains its value in practice. It becomes active only after phosphorylation in infected cells by a viral-induced thymidine kinase. Cellular enzymes then convert it into a triphosphate form that inactivates viral deoxyribonucleic acid polymerase. Acyclovir incorporation into the growing viral deoxyribonucleic acid chain causes its termination. The antiviral process has relatively little effect on normal, uninfected cells. The drug changed expectations about antiviral therapy. Before it, few scientists believed a drug could fight viruses with low side effects. Its approval also covered herpes simplex virus type 1 (HSV-1) encephalitis, a serious condition for which specific treatment became available in the early 1980s.
Acyclovir has remained a benchmark. It is considered a second generation of antiviral nucleoside analogues characterized by lower toxicity and greater selectivity compared to first generation drugs. Its oral absorption is limited: it is only moderately well absorbed upon oral administration with corresponding levels of drug in the plasma. This drove the development of more readily absorbed prodrugs, including valacyclovir and famciclovir, which reached the market in the 1990s. Resistance appeared early, and a 1982 report described resistant Herpes simplex virus after acyclovir therapy. No one of the newer antivirals has been shown to be more effective for HSV than acyclovir. Newer agents such as the helicase-primase inhibitor pritelivir act on a different viral target and have been studied mainly for infections resistant to acyclovir. Since then, research priorities have shifted toward prevention and toward the latent viral DNA that nucleoside drugs do not eliminate.
Public Health, Stigma, and Psychosocial Impact
Herpes simplex infection is common enough that prevention is primarily a matter of population-scale education and sexual health services rather than a single intervention. The WHO's most recent modelling puts prevalence of HSV-2, the main cause of genital herpes, at roughly 520 million people aged 15–49, or about 13% of that age group, and it estimates that more than 1 in 5 adults in this age range has a genital herpes infection of either type. Genital HSV infection is therefore a large and lasting burden on public-health systems, even though most people with it experience mild or intermittent symptoms.
Stigma is among the most documented psychosocial effects. Genital herpes is often treated as a marker of sexual misconduct, and this is reinforced when clinicians or educators discuss it in moralising terms. Research on sexually transmitted infections that cannot be cured, including genital herpes and genital human papillomavirus infection, describes stigma as a barrier to psychosocial and sexual adjustment after diagnosis. A study of people with chronic genital herpes found that stigma was associated with not telling sexual partners about the diagnosis, and that disclosure usually happened within established relationships. In that sample, about a third of participants had moderate to severe anxiety. Fear of disclosure, and the secrecy it produces, can in turn make partner notification and protective behaviour harder to arrange.
The psychological burden is closely tied to the recurrent course of the disease. A review of the literature proposed a cycle in which negative affect and poor coping are associated with more frequent outbreaks, and frequent outbreaks make the stigma more salient, which reinforces a stigmatised self-image. A prospective cohort study from India, which followed 100 adults with at least two outbreaks a year against matched controls over two years, found higher rates of depression and anxiety at baseline, and stigma and sexual distress remained elevated over the following year. Frequent outbreaks, low adherence to antiviral treatment, being in a relationship in which one partner is uninfected, and a lack of social support independently predicted worse outcomes. Studies of women with genital herpes have also found that perceived stigma is strongly linked to lower quality of life, and that the way people cope and the support they receive shape how well they adjust.
Accurate information is a practical as well as an emotional need. Many people learn their diagnosis without clear explanations of how the virus behaves, how often recurrences occur, or how much transmission risk actually exists. Clinical communication that explains latency, the difference between infection and disease, and the fact that many people with HSV-2 never have obvious symptoms can reduce distress and unnecessary blame. Public discussion of genital herpes is limited in many settings, and this silence is often identified as a factor that sustains stigma and discourages testing and open conversations about sexual health.
Prevention relies on several complementary measures. Condoms have been shown to reduce HSV-2 transmission in serodiscordant couples. In a US trial of 528 monogamous couples, consistent condom use during more than a quarter of sex acts was associated with strong protection for susceptible women, though the protective association was not significant for men. A later analysis of couples in East and Southern Africa estimated that condoms reduced the per-act risk of transmission from men to women by 96% and from women to men by 65%, with the latter estimate less precise. Behavioural counselling also matters: in the US study, a decline in transmission over time coincided with fewer sex acts and with fewer acts occurring while the source partner had visible lesions. Health services contribute through testing, counselling, and the management of pregnant people, and through partner support. Because no vaccine against herpes simplex is licensed, these measures remain the main tools available to individuals and health systems.
Surveillance presents its own difficulties. Most HSV infections are asymptomatic or mild, many are never diagnosed, and genital herpes is not notifiable in many countries. Global estimates therefore rely on mathematical models built from antibody surveys, which are sparse or outdated for some regions. The most recent WHO modelling drew on data from 1995 onward for some African and South-East Asian countries because more recent data were limited, and the estimates carry wide uncertainty intervals. Type-specific testing, which is not routine in many health systems, is needed to distinguish HSV-1 and HSV-2 infections accurately, and without it counts of genital disease can be misleading. Better surveillance would clarify trends and help target prevention, but it would also require health systems to address stigma so that people are willing to be tested and reported.
Relation to Other Herpesviruses
Shared features and subfamily boundaries
HSV-1 and HSV-2 belong to a large family of viruses whose members share a common life strategy. Across the family, the double-stranded DNA genome measures roughly 124 to 295 kilobases, and all members can establish latency in host cells All members of the Herpesviridae family have the ability to establish a latent infection in the host cell. The three subfamilies differ mainly in where that latency is maintained. Members of the Alphaherpesvirinae subfamily establish latency in neurones, members of the Betaherpesvirinae subfamily establish latency in a range of nonneuronal cells while members of the Gammherpesvirinae subfamily establish latency in mainly B and T lymphocytes.
The subfamily boundaries were drawn from biological traits rather than from genetic sequence. The three subfamilies were defined initially on the basis of biological criteria: host range in cell culture, length of replication cycle, cytopathology, and characteristics of latency. The family name and the three subfamilies were introduced in 1979, and this nomenclature has persisted. Later sequence comparisons confirmed the grouping. Based on sequence homology, the members of the family of Herpesviridae have been grouped into three subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae.
HSV-1 and HSV-2 fall within the Alphaherpesvirinae. Within that subfamily, HSV-1 and HSV-2 are grouped in the genus Simplexvirus, while other genera in the subfamily include Varicellovirus. Alphaherpesviruses are marked by a variable host range, short reproductive cycles, the ability to spread rapidly in culture and efficiently destroy infected cells. Accounts of the family's human members also differ slightly in their totals: one source identifies nine herpesviruses representing all three subfamilies as clinically important in humans, whereas another describes eight.
Varicella-zoster virus
Varicella-zoster virus (VZV) is the most clinically related member of the subfamily. After the primary infection, the virus becomes latent throughout the entire neuroaxis, where it is located primarily in neurons in human ganglia, including the dorsal root ganglia, trigeminal ganglia, and autonomic ganglia. Reactivation produces a different clinical picture from HSV. After a highly variable period, which may last for several decades, the virus may reactivate from the latent state to cause herpes zoster, which is a vesicular skin eruption that occurs in one or more sensory dermatomes. VZV reactivates in about one-third of infected individuals to cause herpes zoster, and the risk rises with age because of diminished cell-mediated immunity to the virus.
Its genome is smaller than that of HSV-1. VZV has a genome of approximately 125,000 base pairs and there are 68 unique open reading frames. Its latency transcripts also show a parallel with HSV. In human trigeminal ganglia, VZV gene expression during latency is restricted to transcripts arising from the VLT and ORF63 loci, and VLT lies partially antisense to ORF61, the ICP0 homologue conserved among αHV.
Gammaherpesviruses and betaherpesviruses
Betaherpesviruses such as human cytomegalovirus differ in their growth. Alphaherpesviruses grow rapidly in culture, whereas CMV shows slow growth in cultured cells and a restricted host range. Gammaherpesviruses grow in lymphoid cells. Among them, Epstein–Barr virus and Kaposi's sarcoma-associated herpesvirus are associated with disease in this subfamily.
The shared latency strategy also has immunological parallels. In HSV-1 latency, ganglia are typically infiltrated by CD8 T cells, and granzyme B has been reported to cleave the immediate-early protein ICP4, which helps limit reactivation. The latency-associated transcript of HSV-1 is reported to block granzyme B from cleaving caspase-3, which protects the neuron and the latent virus alike.
Evolutionary history
Herpesviruses are old lineages. The evolutionary history of herpesviruses dates from the Early Devonian, around at least 400 million years ago. For a long time, herpesviruses were considered species-specific and to have evolved alongside their hosts mainly by cospeciation. Later work has shown that host switching also matters. A study of gammaherpesviruses found that cross-species transmissions have occurred much more frequently than previously estimated.
The family is not a single lineage. Three distinct groupings of herpesviruses exist, one containing viruses with mammals, birds and reptiles as natural hosts, another containing viruses of amphibians and fish, and a third consisting of a single invertebrate herpesvirus. Within the first two groups, the genomes show clear evidence of descent from a common ancestor, but relationships between the three groups are extremely remote. For HSV specifically, a selection-informed phylogenetic analysis proposed that HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. In January 2026, researchers reported ancient HHV-6 genomes from Europe, documenting the viruses' evolution traced over more than 2,500 years.
Lessons for vaccine and antiviral design
Relatives of HSV show that some targets are conserved across the subfamily. The gH/gL glycoprotein complex is one example. A structural analysis proposed that Alphaherpesvirinae and Gammaherpesvirinae glycoprotein L and Betaherpesvirinae UL130 originate from chemokines, which suggests that these entry proteins share an ancient host-derived origin. Licensed VZV vaccines, which are live-attenuated and recombinant products, demonstrate that an alphaherpesvirus can be prevented in humans, although no comparable vaccine exists for HSV. Because VZV also persists in ganglia, its latency biology offers a model for how a latent herpesvirus might be controlled rather than cleared. Antiviral drugs active against HSV, such as acyclovir, also act against VZV, reflecting the shared viral enzymes in the subfamily.
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