| Human polyomavirus 2 | |
|---|---|
 | |
| Immunohistochemical detection ofHuman polyomavirus 2 protein (stained brown) in a brain biopsy (glia demonstratingprogressive multifocal leukoencephalopathy) | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Monodnaviria |
| Kingdom: | Shotokuvirae |
| Phylum: | Cossaviricota |
| Class: | Papovaviricetes |
| Order: | Sepolyvirales |
| Family: | Polyomaviridae |
| Genus: | Betapolyomavirus |
| Species: | Human polyomavirus 2 |
| Synonyms | |
Human polyomavirus 2, commonly referred to as theJC virus orJohn Cunningham virus, is a type of humanpolyomavirus (formerly known aspapovavirus).[3] It was identified by electron microscopy in 1965 by ZuRhein and Chou,[4] and by Silverman and Rubinstein.[citation needed] It was later isolated in culture and named using the initials of a patient by the name of John Cunningham from whom it was isolated and had developedprogressive multifocal leukoencephalopathy (PML).[5] The virus causes leukoencephalopathy and other diseases only in cases ofimmunodeficiency, as inAIDS or during treatment withimmunosuppressive drugs (e.g. inorgan transplant patients).[6]
The initial site of infection may be thetonsils,[7] or possibly thegastrointestinal tract.[8] The virus then remains latent in the gastrointestinal tract[9] and can also infect the tubularepithelial cells in thekidneys,[10] where it continues to reproduce,shedding virus particles in the urine. In addition, recent studies suggest that this virus may latently infect the human semen[11] as well as the chorionic villi tissues.[12] Serum antibodies againstHuman polyomavirus 2 have also been found in spontaneous abortion-affected women as well as in women who underwent voluntary interruption of pregnancy.[13]
Human polyomavirus 2 can cross theblood–brain barrier into thecentral nervous system, where it infectsoligodendrocytes andastrocytes, possibly through the5-HT2Aserotoninreceptor.[14]Human polyomavirus 2 DNA can be detected in both non-PML affected and PML-affected (see below) brain tissue.[15]
Human polyomavirus 2 found in thecentral nervous system of PML patients almost invariably have differences inpromoter sequence toHuman polyomavirus 2 found in healthy individuals. It is thought that these differences in promoter sequence contribute to the fitness of the virus in the CNS and thus to the development of PML.[6] Certain transcription factors present in the early promoter sequences ofHuman polyomavirus 2 can induce tropism and viral proliferation that leads to PML. The Spi-B factor was shown to be crucial in initiating viral replication in certain strains of transgenic mice.[16] The protein encoded by these early sequences, T-antigen, also plays a key role in viral proliferation,[17] directing the initiation of DNA replication for the virus as well as performing a transcriptional switch to allow for the formation of the various capsid and regulatory proteins needed for viral fitness. Further research is needed to determine the exact etiological role of T-antigen, but there seems to be a connection to the early initiation of the active virus from its archetypal dormant state.[citation needed]
Immunodeficiency or immunosuppression allowsHuman polyomavirus 2 to reactivate. In thebrain, it causes the often fatalprogressive multifocal leukoencephalopathy, or PML, by destroying oligodendrocytes. Whether this represents the reactivation ofHuman polyomavirus 2 within the CNS or seeding of newly reactivatedHuman polyomavirus 2 via blood or lymphatics is unknown.[18] Several studies since 2000 have suggested that the virus is also linked tocolorectal cancer, asHuman polyomavirus 2 has been found in malignantcolon tumors, but these findings are still controversial.[19]
AlthoughHuman polyomavirus 2 infection is classically associated with white matterdemyelination and PML pathogenesis, recent literature has identified viral variants as etiological agents of other novel syndromes. For example,Human polyomavirus 2 has been found to infect thegranule cell layer of thecerebellum, while sparingPurkinje cells, ultimately causing severe cerebellar atrophy.[20] This syndrome, called JCV granule cell layer neuronopathy (JCV GCN), is characterized by a productive and lytic infection by a JC variant with a mutation in the VP1 coding region.[citation needed]
Human polyomavirus 2 also appears to mediateencephalopathy, due to infection of corticalpyramidal neurons (CPN) andastrocytes.[20] Analysis of the JCV CPN variant revealed differences from JCV GCN: no mutations were found in the VP1 coding region; however, a 143–base-pair deletion was identified in theagnogene, coding for a 10–amino-acid truncatedpeptide, which is believed to mediate CPNtropism. Additionally, analysis of the subcellular localization of JC CPNvirions in nuclei, cytoplasm, and axons suggests that the virus may travel through axons to increase infectivity.[20]
Human polyomavirus 2 may also be acausative agent ofaseptic meningitis (JCVM), asHuman polyomavirus 2 was the only pathogen identified in theCSF of certain patients with meningitis. Analysis of the JCVM variant revealed archetype-like regulatory regions with no mutations in coding sequences. The precise molecular mechanisms mediatingHuman polyomavirus 2 meningealtropism remain to be found.[20]
The virus is very common in the general population, infecting 70% to 90% of humans; most people acquireHuman polyomavirus 2 in childhood or adolescence.[22][23][24] It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.[8]
Minor genetic variations are found consistently in different geographic areas; thus, genetic analysis ofHuman polyomavirus 2 samples has been useful in tracing the history of human migration.[25] 14 subtypes or genotypes are recognised each associated with a specific geographical region. Three are found in Europe (a, b and c). A minor African type—Af1—occurs in Central and West Africa. The major African type—Af2—is found throughout Africa and also in West and South Asia. Several Asian types are recognised B1-a, B1-b, B1-d, B2, CY, MY and SC.[citation needed]
An alternative numbering scheme numbers the genotypes 1–8 with additional lettering. Types 1 and 4 are found in Europe[26] and in indigenous populations in northern Japan, North-East Siberia and northern Canada. These two types are closely related. Types 3 and 6 are found in sub-Saharan Africa: type 3 was isolated in Ethiopia, Tanzania and South Africa. Type 6 is found in Ghana. Both types are also found in the Biaka Pygmies and Bantus from Central Africa. Type 2 has several variants: subtype 2A is found mainly in the Japanese population and Native Americans (excludingInuit); 2B is found in Eurasians; 2D is found in Indians and 2E is found in Australians and western Pacific populations. Subtype 7A is found in southern China and South-East Asia. Subtype 7B is found in northern China, Mongolia and Japan Subtype 7C is found in northern and southern China. Subtype 8 is found in Papua New Guinea and the Pacific Islands. The geographic distribution of JC polyomavirus types may help to trace humans from different continents by JC genotyping.[27]
Since immunodeficiency causes this virus to progress to PML, immunosuppressants arecontraindicated in those who are infected.[citation needed]
The boxed warning for the drugrituximab (Rituxan) includes a statement thatHuman polyomavirus 2 infection resulting inprogressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug.[28]
The boxed warning for the drugnatalizumab (Tysabri) includes a statement thatHuman polyomavirus 2 resulted in progressive multifocal leukoencephalopathy developing in three patients who received natalizumab in clinical trials. This is now one of the most common causes of PML.[29]
The boxed warning had been included for the drugsTecfidera andGilenya, both of which have had incidences of PML resulting in death.[citation needed]
The boxed warning was added on February 19, 2009, for the drugefalizumab (Raptiva) includes a statement thatHuman polyomavirus 2, resulting in progressive multifocal leukoencephalopathy, developed in three patients who received efalizumab in clinical trials. The drug was pulled off the U.S. market because of the association with PML on April 10, 2009.[citation needed]
A boxed warning forbrentuximab vedotin (Adcetris) was issued by the FDA on January 13, 2011 after two cases of PML were reported, bringing the total number of associated cases to three.[30]
It has been observed that several region-specific subtypes of this virus occur in different populations. Based on this observation, the subtypes of this virus have now been used to study human migration patterns.[31] Currently more than 30 genotypes of this virus are known.[32]
To rename the following taxon (or taxa): Current name Proposed name JC polyomavirus Human polyomavirus 2
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