|Immunohistochemical detection of JC virus protein (stained brown) in a brain biopsy (glial cells demonstrating progressive multifocal leukoencephalopathy (PML))|
|Group:||Group I (dsDNA)|
The JC virus or John Cunningham virus (JCV, not to be confused with Jamestown Canyon virus that bears the same initials) is a type of human polyomavirus (formerly known as papovavirus) and is genetically similar to BK virus and SV40. It was identified by electron microscopy in 1965 by ZuRhein and Chou, and by Silverman and Rubinstein, and later isolated in culture and named using the two initials of a patient, John Cunningham, with progressive multifocal leukoencephalopathy (PML). The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with drugs intended to induce a state of immunosuppression (e.g. organ transplant patients).
The virus is very common in the general population, infecting 70% to 90% of humans; most people acquire JCV in childhood or adolescence. It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.
Minor genetic variations are found consistently in different geographic areas; thus, genetic analysis of JC virus samples has been useful in tracing the history of human migration. 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.
An alternative numbering scheme numbers the genotypes 1–8 with additional lettering. Types 1 and 4 are found in Europe 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 (excluding Inuit); 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.
Infection and pathogenesis
The initial site of infection may be the tonsils, or possibly the gastrointestinal tract. The virus then remains latent in the gastrointestinal tract  and can also infect the tubular epithelial cells in the kidneys, where it continues to reproduce, shedding virus particles in the urine.
JCV can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor. JC viral DNA can be detected in both non-PML affected and PML-affected (see below) brain tissue.
JCV found in the central nervous system of PML patients almost invariably have differences in promoter sequence to the JCV 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.
Immunodeficiency or immunosuppression allows JCV to reactivate. In the brain, it causes the usually fatal progressive multifocal leukoencephalopathy, or PML, by destroying oligodendrocytes. Whether this represents the reactivation of JCV within the CNS or seeding of newly reactivated JCV via blood or lymphatics is unknown. Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as JCV has been found in malignant colon tumors, but these findings are still controversial.
Drugs associated with reactivation
Since immunodeficiency causes this virus to progress to PML, immunosuppressants are contraindicated in those who are infected.
The boxed warning for the drug rituximab (Rituxan, co-marketed by Genentech BioOncology and Biogen Idec) includes a statement that JC virus infection resulting in progressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug.
The boxed warning for the drug natalizumab (Tysabri, marketed by Elan and developed by Biogen Idec) includes a statement that JC virus resulted in progressive multifocal leukoencephalopathy developing in three patients who received natalizumab in clinical trials.
The boxed warning had been included for the drugs Tecfidera and Gilenya, both of which have had incidences of PML resulting in death.
The boxed warning was added on Feb. 19, 2009, for the drug efalizumab (Raptiva, marketed in the U.S. by Genentech, and marketed in Europe by Swiss drugmaker Merck Serono) includes a statement that JC virus, 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.
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