Varicella-zoster virus

Varicella-zoster virus, abbreviated VZV and also known as human herpesvirus 3, is the alphaherpesvirus that causes two distinct illnesses: chickenpox (varicella) on first infection, and shingles (herpes zoster) when the virus reactivates years or decades later. A single primary infection in childhood is followed by lifelong latency in sensory neurons, from which the virus can re-emerge along one nerve to produce the dermatomal rash and pain of zoster.

It is biologically the most economical of the human herpesviruses, carrying the smallest genome of the group at around 125 kilobases, and it is the only one against which licensed vaccines exist. It is also the only human herpesvirus that spreads efficiently through the air, which makes chickenpox one of the most contagious of all human infections.

Most disease is mild, but the virus is dangerous at the edges of immune competence: in the fetus and newborn, in pregnancy, in older adults whose cell-mediated immunity has waned, and above all in the immunocompromised. In a high-HIV-prevalence setting this last group is large, and severe varicella, recurrent zoster in young adults, and sight-threatening retinal disease are correspondingly more common.

Discovery and historical significance

Chickenpox was distinguished from smallpox as a separate, milder disease in the eighteenth century. The link between chickenpox and shingles was suspected long before the virus could be grown: in 1888 János Bókay observed that susceptible children often developed chickenpox a few weeks after contact with an adult who had shingles, suggesting a single shared agent.

Proof came in the laboratory. In 1952 Thomas Weller and Margaret Stoddard achieved the first reliable culture of the virus in human cells and showed that isolates from chickenpox and from shingles were immunologically identical. In 1965 the epidemiologist Robert Edgar Hope-Simpson proposed that zoster results from the gradual waning of immunity acquired at the original infection, the model of declining cell-mediated immunity that still underpins how the disease is understood. Later molecular work sealed the argument by showing that the virus recovered from an episode of zoster matches the strain of the person’s original chickenpox, confirming that zoster is reactivation of latent virus rather than fresh infection from outside. The decisive therapeutic advance followed in 1974, when Michiaki Takahashi attenuated the Oka strain to create the first vaccine licensed against any human herpesvirus.

Classification, structure, and genome

Classification

VZV is the species Varicellovirus humanalpha3 in the genus Varicellovirus, subfamily Alphaherpesvirinae, within the family Orthoherpesviridae (until recently named Herpesviridae). Its closest relative is simian varicella virus, which causes a comparable disease in non-human primates and serves as an animal model. The virus has a single serotype, so immunity raised against any strain is broadly cross-protective, although whole-genome sequencing resolves circulating strains into a small number of geographic clades and has shown that recombination occurs between them.

Virion structure

The virion has the three-layered architecture common to all herpesviruses: an icosahedral capsid, a protein tegument, and a lipid envelope, measuring 180 to 200 nanometres overall. The capsid is built on a triangulation number of 16 from 162 capsomeres. The tegument delivers regulatory proteins, including the major transactivator IE62, into the cell at entry. The envelope carries the conserved fusion machinery, glycoprotein B together with the glycoprotein H and L pair, and the most abundant surface protein, glycoprotein E, which partners glycoprotein I. VZV lacks an ortholog of glycoprotein D, the entry receptor-binding protein central to herpes simplex virus, and instead relies on glycoprotein E for its defining mode of cell-to-cell spread.

Genome organisation

The genome is a single linear molecule of double-stranded DNA of about 125 kilobases, the smallest of the human herpesviruses and the first herpesvirus genome to be fully sequenced. A long unique region and a short unique region, each flanked by inverted repeats, encode roughly 71 open reading frames, of which about 40 are core genes shared across the herpesvirus family. Several gene products recur throughout the virus biology: IE62 from open reading frame 62 is the master transcriptional activator, ORF61 is a regulator that disperses the cell’s antiviral nuclear bodies, ORF63 dominates the latent phase, the thymidine kinase of ORF36 activates the antiviral drugs, and the DNA polymerase of ORF28 is their target.

Replication cycle

Infection begins when a cell-free virion attaches to heparan sulfate proteoglycans on the cell surface and then engages its entry receptors, the cation-independent mannose-6-phosphate receptor and insulin-degrading enzyme. Fusion, driven by glycoprotein B with the glycoprotein H and L pair, follows cholesterol-dependent uptake and delivers the nucleocapsid to the cytoplasm, which carries it to the nuclear pore to release the genome.

Inside the nucleus, gene expression follows the ordered herpesvirus cascade. The immediate-early phase, led by IE62 carried in with the incoming virion, switches on the next stages and disables host defences; early genes supply the replication enzymes, above all the DNA polymerase that is the principal drug target; and late genes supply the structural proteins. Progeny capsids assemble in the nucleus, bud through the nuclear membrane, and acquire their tegument and final envelope at the trans-Golgi network.

A peculiarity of this last step shapes the whole natural history of the virus. Because the VZV glycoproteins are tagged with mannose-6-phosphate, newly enveloped virions are recognised by the mannose-6-phosphate receptor and diverted into lysosomes, where they are degraded. In most tissues, therefore, almost no infectious cell-free virus is released, and the virus propagates instead by direct cell-to-cell spread mediated by glycoprotein E and its partners, fusing infected cells with their neighbours. The exception is the superficial epidermis: as keratinocytes mature toward the skin surface they lose the mannose-6-phosphate receptor, so infectious cell-free virus is released into the vesicle fluid. This is the source of the airborne virus that transmits chickenpox and of the virus that seeds the sensory nerve endings to establish latency.

Pathogenesis

Primary infection starts at the respiratory mucosa and tonsillar lymphoid tissue, where the virus infects T cells. These infected T cells, a tiny fraction of the circulating pool, carry the virus to the skin as a cell-associated viraemia, the route by which a respiratory exposure becomes a generalised rash. The unusually long incubation period reflects the time the virus needs to overcome a powerful innate barrier in the skin, where constitutive interferon signalling restrains it until the infected T cells, reprogrammed by the virus into a skin-homing phenotype, finally deliver enough virus to erupt as successive crops of vesicles. The skin lesion shows the histological signature of the alphaherpesviruses: multinucleated giant cells with intranuclear inclusions and ballooning degeneration.

During this primary infection the virus enters sensory nerve endings in the skin and travels to the neurons of the dorsal-root and cranial-nerve ganglia, where it establishes lifelong latency. Latency is confined to neurons, and extends beyond the sensory ganglia to autonomic and enteric neurons, the last detectable in the gut wall of most people who have had chickenpox. In the latent state the virus shuts down almost all gene expression, restricting itself largely to a non-coding latency-associated transcript that suppresses ORF61 and so blocks the cascade that would otherwise drive replication.

Reactivation occurs when this restraint fails. The virus resumes lytic replication in the neuron and travels back down the sensory nerve to the skin, producing the unilateral, single-dermatome rash of zoster, while inflammation, haemorrhagic necrosis and demyelination in the affected ganglion account for the accompanying pain. A feature peculiar to VZV, fusion between neurons and their surrounding satellite cells, helps the virus spread within the ganglion and contributes to its greater neurological reach.

Throughout, cell-mediated immunity rather than antibody is the decisive control: children who cannot make antibody are not unusually susceptible to severe chickenpox, whereas any failure of T-cell immunity, whether from age, drugs or HIV, predisposes to severe primary disease and to reactivation. The virus actively undermines this arm of immunity, downregulating major histocompatibility complex (MHC) class I to hide infected cells from cytotoxic T cells, blocking the interferon-gamma induction of MHC class II, and disabling natural killer (NK) cells, including the antibody-dependent cellular cytotoxicity (ADCC) by which they would otherwise kill infected targets.

Epidemiology

VZV is found in every population, but the age at infection depends on climate. In temperate regions chickenpox is a disease of early childhood, with most people infected before the age of ten. In tropical regions the virus transmits less efficiently, so a far larger proportion of adolescents and adults remain susceptible, a pattern relevant across much of Africa and one that leaves more adults exposed to the more severe adult form of the disease.

Chickenpox is extraordinarily contagious. The secondary attack rate in susceptible household contacts approaches 90%, and the virus is genuinely airborne, requiring no direct contact. Cases peak in late winter and spring in temperate climates, whereas zoster occurs at a steady rate throughout the year. A person with shingles can transmit the virus to a susceptible contact and cause chickenpox in them, though zoster is roughly half as contagious as chickenpox because the virus is largely confined to the rash.

Shingles is a disease of waning immunity. The lifetime risk is about one in three, and incidence climbs steeply after the age of 50 as cell-mediated immunity declines, reaching its highest rates in the very old. Immune compromise multiplies this risk many times over: it is raised roughly 15 to 25-fold in advanced HIV infection, occurs in a quarter or more of stem-cell transplant recipients and around a sixth of renal transplant recipients, and is common in leukaemia and lymphoma. Zoster in a young adult should therefore prompt the question of underlying immunosuppression. Where universal childhood varicella vaccination has been introduced, chickenpox has become far less common, shifting the epidemiology of the virus toward the vaccinated cohort.

Natural history

After an incubation of 10 to 21 days, averaging about two weeks, chickenpox presents as fever and a generalised, intensely itchy rash that appears in successive crops over a day or two and evolves through macule, papule, vesicle and crust. A person is infectious from about two days before the rash until the last lesion has crusted over. The illness is self-limited in healthy children but tends to be more severe in adults, who often have a prodrome and more extensive disease, and is dangerous in the immunocompromised, in whom it can progress relentlessly.

The virus is never cleared. It persists in the sensory ganglia for life, held in check by cell-mediated immunity that is periodically boosted by silent reactivations. Decades later, as that immunity wanes, the virus reactivates as zoster: a band of pain, often preceding the rash by a few days, followed by vesicles confined to one or a few dermatomes that crust over about two weeks. In older people the acute episode is frequently followed by postherpetic neuralgia, pain that persists long after the rash has healed.

Clinical presentations and complications

Chickenpox and its complications

Uncomplicated chickenpox is a benign childhood illness, but complications are not rare and rise sharply in adults, neonates and the immunocompromised. The commonest complication is secondary bacterial infection of the skin lesions by Streptococcus pyogenes or Staphylococcus aureus, ranging from local sepsis to necrotising fasciitis. Varicella pneumonia, mainly a disease of adults, pregnant women and the immunocompromised, is the leading cause of varicella-related death and may appear a few days after the rash with cough and breathlessness. Neurological complications include a benign, self-limiting cerebellar ataxia and a more serious encephalitis, and the virus can also cause a haemorrhagic eruption, thrombocytopenia, and hepatitis. The use of aspirin during chickenpox can precipitate Reye syndrome, the reason salicylates are avoided in children.

Congenital and neonatal varicella

Maternal chickenpox in the first half of pregnancy can damage the fetus. The congenital varicella syndrome, whose signature is cicatricial (scarring) skin lesions in a dermatomal pattern, also brings limb hypoplasia, eye defects such as chorioretinitis and cataract, and neurological injury. The risk is low, of the order of ~1% in the first 12 weeks and ~2% between 13 and 20 weeks, and reflects intrauterine reactivation of virus from a primary infection rather than the rash itself. A separate and acute danger arises when a mother develops chickenpox around the time of delivery: if her rash appears from about five days before to two days after birth, the infant is exposed to virus without the protection of maternal antibody, and untreated neonatal varicella carries a mortality of up to ~30%.

Herpes zoster

Shingles presents as pain and a vesicular rash confined to one or a few dermatomes on one side of the body, most often in the thoracic region or the ophthalmic division of the trigeminal nerve. Postherpetic neuralgia, the persistence of dermatomal pain after the rash heals, is the commonest complication and is strongly age-dependent, uncommon in the young but affecting up to a third of patients in the oldest age groups. Involvement of the ophthalmic division of the trigeminal nerve causes herpes zoster ophthalmicus, with keratitis, uveitis and a threat to sight. Reactivation in the geniculate ganglion produces Ramsay Hunt syndrome, a facial palsy with painful vesicles in the ear and altered taste. Less often, reactivation produces segmental motor weakness in the muscles served by the affected nerve root, or, in sacral zoster, a neurogenic bladder and bowel. Pain and even visceral reactivation can occur without any rash, the state known as zoster sine herpete.

Neurological and ocular disease

Beyond the dermatome, VZV is an important cause of central nervous system disease. Its cerebral vasculopathy, an inflammation of the arteries that follows reactivation, causes ischaemic and haemorrhagic stroke, and the risk of stroke is raised for months after an episode of zoster, particularly after herpes zoster ophthalmicus, where it rises around 4.5-fold. The virus also causes myelitis and meningoencephalitis. In the eye, in addition to zoster ophthalmicus, it causes acute retinal necrosis in immunocompetent people and the aggressive progressive outer retinal necrosis seen in advanced HIV, both sight-threatening.

Disease in the immunocompromised

Where cell-mediated immunity fails, both forms of the disease become severe. Primary varicella can progress over weeks with continuing crops of lesions, visceral dissemination to lung, liver and brain, and coagulopathy that can prove fatal. Zoster is more likely to disseminate beyond its dermatome into a generalised eruption resembling chickenpox, to recur, and to take a chronic or atypical course, and the neurological and retinal complications are concentrated in this group. Both presentations are indications for prompt intravenous antiviral therapy rather than the watchful approach reasonable in a healthy child.

Diagnosis

Polymerase chain reaction (PCR) for viral DNA is the diagnostic standard, sensitive and rapid on vesicle fluid, a swab of a lesion base, cerebrospinal fluid, blood or tissue, and able to distinguish wild-type from vaccine strains. Direct immunofluorescence using a labelled antibody against glycoprotein E gives a rapid answer at the bedside from a lesion scraping and is more sensitive than culture, which is slow and often unrewarding because the virus is labile and largely cell-associated. Unlike herpes simplex virus, VZV is not shed asymptomatically from mucosa between episodes, so detection of the virus by any method indicates active infection rather than incidental carriage.

Serology has a defined rather than a frontline role. It is used mainly to determine whether a person is immune, for which the fluorescent-antibody-to-membrane-antigen assay is the most sensitive method; widely used commercial immunoassays are less reliable and may misclassify vaccinated people as susceptible. Immunoglobulin M results are too unreliable to confirm acute infection on their own. One diagnostic situation deserves emphasis: in suspected VZV vasculopathy the cerebrospinal fluid PCR is positive in only about 30% of cases, so demonstrating intrathecal synthesis of anti-VZV immunoglobulin G is the more sensitive test, and the same applies to other rash-free neurological presentations.

Management

Three antiviral drugs are the mainstay: aciclovir, its valine ester prodrug valaciclovir, which is far better absorbed by mouth, and famciclovir. All three are guanosine analogues that must first be activated by the viral thymidine kinase before they inhibit the viral DNA polymerase, so they act only in infected cells. The principle of use is straightforward: oral therapy for uncomplicated zoster and for varicella where treatment is warranted, and intravenous aciclovir for severe, disseminated or immunocompromised disease, for varicella pneumonia, and for central nervous system involvement including vasculopathy. Benefit depends on starting early, within the first two to three days of the rash, and timeliness matters more than the choice of agent. For shingles, brivudine, a thymidine analogue, is preferred in parts of Europe for its convenient once-daily dosing and its effect on pain, although it is not used everywhere.

Resistance is uncommon and is seen mainly in advanced HIV infection after prolonged exposure, usually through mutation of the thymidine kinase. Resistant virus remains susceptible to foscarnet and to cidofovir, which inhibit the DNA polymerase without needing viral activation and are the salvage agents, limited chiefly by nephrotoxicity. A crucial limitation runs through all of this: antivirals shorten the acute illness and reduce acute pain but do not prevent postherpetic neuralgia, which is managed separately with agents such as gabapentin or pregabalin, tricyclic antidepressants, and topical lidocaine.

Prevention and public health

Vaccination

Two kinds of vaccine exist. The live-attenuated Oka-strain varicella vaccine, the first ever licensed against a human herpesvirus, prevents chickenpox and is given as two doses, alone or combined with measles, mumps and rubella. Its attenuation reduces replication in the skin while leaving the virus able to induce strong T-cell immunity; vaccinated people rarely develop a mild rash and only then can occasionally transmit the vaccine virus. Because it is a live vaccine, it is contraindicated in pregnancy and in severe immunosuppression.

Prevention of shingles has changed decisively. The earlier approach used a high-potency live Oka vaccine (Zostavax), but its efficacy fell with advancing age and it could not be given to the immunocompromised. It has been superseded by the recombinant zoster vaccine (Shingrix), a glycoprotein E subunit with the AS01B adjuvant given as two doses, which produces high and durable protection of around 90% that does not wane with age and, being non-live, is safe and effective in immunocompromised people, the group at greatest need.

Infection prevention and control

VZV is the only human herpesvirus that is reliably transmitted through the air, so both airborne and contact precautions apply. Hospitalised patients with chickenpox or disseminated zoster should be isolated in a negative-pressure room, and even localised zoster in an inpatient warrants precautions because the lesions can transmit chickenpox to susceptible people. A patient is contagious from one to two days before the rash appears, which complicates control, and susceptible staff and contacts are best identified and managed in advance.

Post-exposure prophylaxis

A susceptible person at high risk of severe disease who is exposed to VZV can be protected. Varicella-zoster immunoglobulin, given as soon as possible after exposure, is the mainstay for high-risk susceptible contacts: the immunocompromised, susceptible pregnant women, and newborns whose mothers develop varicella around delivery. It attenuates rather than always prevents disease. For healthy susceptible people, post-exposure vaccination can prevent or modify illness, and antiviral prophylaxis during the incubation period is an alternative in selected cases.

South African context

South Africa carries the epidemiological signature of a high-HIV-prevalence, partly tropical setting. In advanced HIV infection VZV causes more severe, prolonged and disseminated chickenpox, far higher rates of zoster including in young adults, and the sight-threatening progressive outer retinal necrosis, so an episode of shingles in a young person is a recognised pointer to underlying HIV. The reduced transmissibility of the virus in warmer regions also leaves a greater share of South African adolescents and adults susceptible than in temperate, high-income countries, and susceptible than they would be under a universal childhood programme.

The varicella vaccine is not part of the routine public-sector Expanded Programme on Immunisation, so most population immunity is acquired through natural infection rather than vaccination, and varicella vaccination is largely confined to the private sector and to specific at-risk indications. Management of complicated and immunocompromised disease, and post-exposure prophylaxis of high-risk contacts, follow the national paediatric standard treatment guidelines, under which complicated varicella and any varicella in an immunocompromised child are treated with aciclovir, started as early as possible and given intravenously when disease is severe.

The same guidelines set out who should receive post-exposure prophylaxis and with what.

Post-exposure prophylaxis of varicella by exposed group (South African paediatric guidance)

Exposed group	Prophylaxis	Timing
Neonate whose mother develops varicella from 5 days before to 2 days after delivery	Varicella-zoster immunoglobulin (oral aciclovir if immunoglobulin unavailable)	Within 96 hours of exposure
Immunocompromised child over 28 days, exposed	Oral aciclovir	Through the second week after exposure
Hospitalised susceptible immunocompetent child, to limit spread	Post-exposure varicella vaccine, or oral aciclovir	Vaccine within 72 hours of exposure
Susceptible pregnant woman, exposed	Varicella-zoster immunoglobulin	Within 96 hours of exposure

In neonates, prophylaxis reduces but does not reliably prevent disease, so exposed infants are monitored and treated promptly if chickenpox develops.

References and recommended reading

• Gershon AA, Gershon MD. Varicella-Zoster Virus. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The principal source for the virology, replication, pathogenesis, clinical spectrum, diagnosis and antiviral management set out here.
• Arvin AM, Abendroth A. Varicella-Zoster Virus. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The current reference for the primary-infection and latency models, including the latency-associated transcript, the cerebral vasculopathy, and the contemporary zoster-vaccine landscape.
• Royal College of Obstetricians and Gynaecologists. Chickenpox in Pregnancy (Green-top Guideline No. 13). London: RCOG; 2015. The source for the management of maternal varicella in pregnancy.
• National Department of Health, South Africa. Hospital Level (Paediatric) Standard Treatment Guidelines and Essential Medicines List, 5th edition. Pretoria: National Department of Health; 2023. The source for the South African treatment and post-exposure prophylaxis regimens.