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Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (
taxonomically In biology, taxonomy () is the scientific study of naming, defining ( circumscribing) and classifying groups of biological organisms based on shared characteristics. Organisms are grouped into taxa (singular: taxon) and these groups are given ...
), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles (herpes zoster) in adults but rarely in children. VZV infections are
species In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
-specific to humans. The virus can survive in external environments for a few hours. VZV multiplies in the tonsils, and causes a wide variety of symptoms. Similar to the herpes simplex viruses, after primary infection with VZV (chickenpox), the virus lies dormant in neurons, including the cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia. Many years after the person has recovered from initial chickenpox infection, VZV can ''reactivate'' to cause shingles.


Epidemiology


Chickenpox

Primary varicella zoster virus infection results in
chickenpox Chickenpox, also known as varicella, is a highly contagious disease caused by the initial infection with varicella zoster virus (VZV). The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab ...
(varicella), which may result in complications including
encephalitis Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, ...
,
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...
(either direct
viral pneumonia Viral pneumonia is a pneumonia caused by a virus. Pneumonia is an infection that causes inflammation in one or both of the lungs. The pulmonary alveoli fill with fluid or pus making it difficult to breathe. Pneumonia can be caused by bacteria, vir ...
or secondary
bacterial pneumonia Bacterial pneumonia is a type of pneumonia caused by bacterial infection. Types Gram-positive ''Streptococcus pneumoniae'' () is the most common bacterial cause of pneumonia in all age groups except newborn infants. ''Streptococcus pneumoniae'' ...
), or
bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...
(either viral bronchitis or secondary bacterial bronchitis). Even when clinical symptoms of chickenpox have resolved, VZV remains dormant in the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
of the infected person (
virus latency Virus latency (or viral latency) is the ability of a pathogenic virus to lie dormant (latent) within a cell, denoted as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which is disti ...
), in the
trigeminal In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and chewing; ...
and
dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal ...
. VZV enters through the respiratory system. Having an incubation period of 10–21 days, averaging at 14 days. Targeting the skin and
peripheral nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...
, the period of illness is from 3 to 4 days. 1–2 days before the rash appears is when this virus is the most contagious. Signs and symptoms include vesicles that fill with pus, rupture, and scab before healing. Lesions most commonly occur on the face, throat, the lower back, the chest and shoulders.


Shingles

In about a third of cases, VZV reactivates in later life, producing a disease known as shingles or herpes zoster. The individual lifetime risk of developing herpes zoster is thought to be between 20% and 30%, or approximately 1 in 4 people. However, for people aged 85 and over, this risk increases to 1 in 2. In a study in Sweden by Nilsson et al. (2015) the annual incidence of herpes zoster infection is estimated at a total of 315 cases per 100,000 inhabitants for all ages and 577 cases per 100,000 for people 50 years of age or older. VZV can also infect the central nervous system, with a 2013 article reporting an incidence rate of 1.02 cases per 100,000 inhabitants in Switzerland, and an annual incidence rate of 1.8 cases per 100,000 inhabitants in Sweden. Shingles lesions and the associated pain, often described as burning, tend to occur on the skin that is innervated by one or two adjacent sensory nerves, almost always on one side of the body only. The skin lesions usually subside over the course of several weeks, while the pain often persists longer. In 10–15% of cases the pain persists more than three months, a chronic and often disabling condition known as
postherpetic neuralgia Postherpetic neuralgia (PHN) is neuropathic pain that occurs due to damage to a peripheral nerve caused by the reactivation of the varicella zoster virus (herpes zoster, also known as shingles). Typically, the nerve pain (neuralgia) is confined ...
. Other serious complications of varicella zoster infection include
Mollaret's meningitis Mollaret's meningitis is a recurrent or chronic inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. Since Mollaret's meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, ...
, zoster multiplex, and inflammation of arteries in the brain leading to stroke, myelitis, herpes ophthalmicus, or zoster sine herpete. In
Ramsay Hunt syndrome Three different neurological syndromes carry the name of Ramsay Hunt syndrome. Their only connection is that they were all first documented by the famous neurologist James Ramsay Hunt (1872–1937). * Ramsay Hunt syndrome type 1, also called ''Rams ...
, VZV affects the geniculate ganglion giving lesions that follow specific branches of the facial nerve. Symptoms may include painful blisters on the tongue and ear along with one-sided facial weakness and hearing loss. After infection during initial stages of pregnancy, the fetus can be severely damaged.
Reye's syndrome Reye syndrome is a rapidly worsening encephalopathy, brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While hepatotoxicity, liver toxicity typically occurs in the ...
can happen after initial infection, causing continuous vomiting and signs of brain dysfunction such as extreme drowsiness or combative behavior. In some cases, death or coma can follow. Reye's syndrome mostly affects children and teenagers; using aspirin during infection can increase this risk.


Morphology

VZV is closely related to the herpes simplex viruses (HSV), sharing much genome homology. The known
envelope An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card. Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a sh ...
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s (gB, gC, gE, gH, gI, gK, gL) correspond with those in HSV; however, there is no equivalent of the HSV gD protein. VZV also fails to produce the LAT (latency-associated transcripts) that play an important role in establishing HSV ''latency'' (herpes simplex virus). VZV virions are spherical and 180–200 nm in diameter. Their lipid envelope encloses the 100 nm nucleocapsid of 162
hexameric In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relati ...
and
pentameric A pentamer is an entity composed of five sub-units. In chemistry, it applies to molecules made of five monomers. In biochemistry, it applies to macromolecules, in particular to pentameric proteins, made of five proteic sub-units. In microbiolo ...
capsomeres arranged in an icosahedral form. Its DNA is a single, linear, double-stranded molecule, 125,000  nt long. The capsid is surrounded by loosely associated proteins known collectively as the tegument; many of these proteins play critical roles in initiating the process of virus reproduction in the infected cell. The tegument is in turn covered by a lipid envelope studded with glycoproteins that are displayed on the exterior of the virion, each approximately 8 nm long.


Genomes

The genome was first sequenced in 1986. It is a linear duplex DNA molecule, a laboratory strain has 124,884 base pairs. The genome has two predominant isomers, depending on the orientation of the S segment, P (prototype) and IS (inverted S) which are present with equal frequency for a total frequency of 90–95%. The L segment can also be inverted resulting in a total of four linear isomers (IL and ILS). This is distinct from HSV's equiprobable distribution, and the discriminatory mechanism is not known. A small percentage of isolated molecules are circular genomes, about which little is known. (It is known that HSV circularizes on infection.) There are at least 70
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
s in the genome.


Evolution

Commonality with HSV1 and HSV2 indicates a common ancestor; five genes (out of about 70) do not have corresponding HSV genes. Relation with other human herpes viruses is less strong, but many homologues and conserved gene blocks are still found. There are at least five
clade A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term, ...
s of this virus. Clades 1 and 3 include European/North American strains; clade 2 are Asian strains, especially from Japan; and clade 5 appears to be based in
India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
. Clade 4 includes some strains from Europe but its geographic origins need further clarification. There are also four genotypes that do not fit into these clades. Allocation of VZV strains to clades required sequence of whole virus genome. Practically all molecular epidemiological data on global VZV strains distribution are obtained with targeted sequencing of selected regions. Phylogenetic analysis of VZV genomic sequences resolves wild-type strains into nine genotypes (E1, E2, J, M1, M2, M3, M4, VIII and IX). Complete sequences for M3 and M4 strains are unavailable, but targeted analyses of representative strains suggest they are stable, circulating VZV genotypes. Sequence analysis of VZV isolates identified both shared and specific markers for every genotype and validated a unified VZV genotyping strategy. Despite high genotype diversity no evidence for intra-genotypic recombination was observed. Five of seven VZV genotypes were reliably discriminated using only four single nucleotide polymorphisms (SNP) present in ORF22, and the E1 and E2 genotypes were resolved using SNP located in ORF21, ORF22 or ORF50. Sequence analysis of 342 clinical varicella and zoster specimens from 18 European countries identified the following distribution of VZV genotypes: E1, 221 (65%); E2, 87 (25%); M1, 20 (6%); M2, 3 (1%); M4, 11 (3%). No M3 or J strains were observed. Of 165 clinical varicella and zoster isolates from Australia and New Zealand typed using this approach, 67 of 127 eastern Australian isolates were E1, 30 were E2, 16 were J, 10 were M1, and 4 were M2; 25 of 38 New Zealand isolates were E1, 8 were E2, and 5 were M1. The mutation rate for synonymous and nonsynonymous mutation rates among the herpesviruses have been estimated at 1 × 10−7 and 2.7 × 10−8 mutations/site/year, respectively, based on the highly conserved gB gene.


Treatment

Within the human body it can be treated by a number of drugs and therapeutic agents including
acyclovir Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following t ...
for chickenpox,
famciclovir Famciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is a prodrug form of penciclovir with improved oral bioavailability. Famciclovir is mark ...
,
valaciclovir Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken ...
for the shingles,
zoster-immune globulin VZV (varicella zoster virus) globulin or VZV antibodies is an immune system medication that is used mostly for Immunosuppression, immunosuppressed patients who have been or may be exposed to the varicella zoster virus. It shortens the course of Cuta ...
(ZIG), and
vidarabine Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses. Discovery In the 1950s two nucleosides were isolated from the Caribbean sea sponge, sponge ''Tethya c ...
. Acyclovir is frequently used as the drug of choice in primary VZV infections, and beginning its administration early can significantly shorten the duration of any symptoms. However, reaching an effective serum concentration of acyclovir typically requires intravenous administration, making its use more difficult outside of a hospital.


Vaccination

A live attenuated VZV Oka/Merck strain
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
is available and is marketed in the United States under the trade name Varivax. It was developed by Merck, Sharp & Dohme in the 1980s from the Oka strain virus isolated and attenuated by
Michiaki Takahashi was a Japanese virologist, best known for inventing the first chickenpox vaccine. He developed the "Oka" vaccine by producing v-Oka, a live-attenuated virus strain of varicella zoster virus. Life Born at Higashisumiyoshi-ku, Osaka, Japan, on F ...
and colleagues in the 1970s. It was submitted to the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) for approval in 1990 and was approved in 1995. Since then, it has been added to the recommended vaccination schedules for children in
Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
, the United States, and many other countries. Varicella vaccination has raised concerns in some that the immunity induced by the vaccine may not be lifelong, possibly leaving adults vulnerable to more severe disease as the immunity from their childhood immunization wanes. Vaccine coverage in the United States in the population recommended for vaccination is approaching 90%, with concomitant reductions in the incidence of varicella cases and hospitalizations and deaths due to VZV. So far, clinical data has proved that the vaccine is effective for over ten years in preventing varicella infection in healthy individuals, and when
breakthrough infection A breakthrough infection is a case of illness in which a vaccinated individual becomes infected with the illness, because the vaccine has failed to provide complete immunity against the pathogen (currently only viruses). Breakthrough infections ha ...
s do occur, illness is typically mild. In 2006, the CDC's
Advisory Committee on Immunization Practices The Advisory Committee on Immunization Practices (ACIP) is a committee within the United States Centers for Disease Control and Prevention (CDC) that provides advice and guidance on effective control of vaccine-preventable diseases in the U.S. c ...
(ACIP) recommended a second dose of vaccine before school entry to ensure the maintenance of high levels of varicella immunity. In 2006, the FDA approved
Zostavax A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and ...
for the prevention of shingles. Zostavax is a more concentrated formulation of the Varivax vaccine, designed to elicit an immune response in older adults whose immunity to VZV wanes with advancing age. A systematic review by the
Cochrane Library The Cochrane Library (named after Archie Cochrane) is a collection of databases in medicine and other healthcare specialties provided by Cochrane and other organizations. At its core is the collection of Cochrane Reviews, a database of system ...
shows that Zostavax reduces the incidence of shingles by almost 50%.
Shingrix A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and ...
is a ''V. zoster'' subunit vaccine (glycoprotein E) developed by
GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
which was approved in the United States by the FDA in October 2017. The ACIP recommended Shingrix for adults over the age of 50, including those who have already received Zostavax. The committee voted that Shingrix is preferred over Zostavax for the prevention of zoster and related complications because phase 3 clinical data showed vaccine efficacy of >90% against shingles across all age groups, as well as sustained efficacy over a four-year follow-up. Unlike Zostavax, which is given as a single shot, Shingrix is given as two intramuscular doses, two to six months apart. This vaccine has shown to be immunogenic and safe in adults with human immunodeficiency virus.


History

Chickenpox-like rashes were recognized and described by ancient civilizations; the relationship between zoster and chickenpox was not realized until 1888. In 1943, the similarity between virus particles isolated from the lesions of zoster and those from chickenpox was noted. In 1974 the first chickenpox vaccine was introduced. The varicella zoster virus was first isolated by Evelyn Nicol while she was working at Cleveland City Hospital. Thomas Huckle Weller also isolated the virus and found evidence that the same virus was responsible for both chickenpox and herpes zoster. The etymology of the name of the virus comes from the two diseases it causes, varicella and herpes zoster. The word ''varicella'' is possibly derived from ''variola'', a term for
smallpox Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
coined by Rudolph Augustin Vogel in 1764.


See also

* Herpes simplex virus *
Progressive outer retinal necrosis Progressive outer retinal necrosis (PORN) syndrome is a form of chorioretinitis, an infection in the retina, the back of the eye. The disease is most commonly caused by the varicella zoster virus and is found almost exclusively in patients with HI ...
*
Simian varicella virus ''Cercopithecine alphaherpesvirus 9'' (CeHV-9) is a species of virus in the genus ''Varicellovirus'', subfamily ''Alphaherpesvirinae'', family ''Herpesviridae'', and order ''Herpesvirales''. Pathology ''Cercopithecine alphaherpesvirus 9'' infe ...


References


External links

* {{DEFAULTSORT:Varicella Zoster Virus Chickenpox Varicelloviruses Animal viral diseases