|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) 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 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 percent 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 has differences in promoter (genetics) 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 contraindicative to those 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 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.
In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration. A further trial lead to non significant results between standard of care arm and mefloquine arm. This study found no evidence of anti-JCV activity by mefloquine.
On November 30, 2010, Cytheris announced that they had eradicated the JC virus from a PML patient, using their human interleukin-7 investigational drug (CYT107) combined with Chimerix's investigational, orally-available lipid conjugate prodrug of cidofovir known as brincidofovir. However, this therapy was attempted only once and further studies are needed to determine if this is a viable alternative.
- BL, Walker DL et al. (1971). "Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy". Lancet 1 (7712): 1257–60. doi:10.1016/S0140-6736(71)91777-6. PMID 4104715.
- Ferenczy, MW; Marshall, LJ; Nelson, CD; Atwood, WJ; Nath, A; Khalili, K; Major, EO (July 2012). "Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.". Clin. Microbiol. Rev. 25 (3): 471–506. doi:10.1128/CMR.05031-11. PMID 22763635.
- Hansjügen T. Agostini, Caroline F. Ryschkewitsch, Rachel Mory, Elyse J. Singer and Gerald L. Stoner (1997). "JC Virus (JCV) genotypes in brain tissue from patients with progressive multifocal leukoencephalopathy (PML) and in urine from controls without PML: increased frequency of JCV Type 2 in PML". The Journal of Infectious Diseases (Oxford University Press) 176 (1): 1–8. doi:10.1086/514010. JSTOR 30107072.
- Laura A. Shackelton, Andrew Rambaut, Oliver G. Pybus, and Edward C. Holmes (2006). "JC Virus evolution and its association with human populations". Journal of Virology (American Society for Microbiology) 80 (20): 9928–9933. doi:10.1128/JVI.00441-06. PMC 1617318. PMID 17005670.
- Padgett, B.L. and Walker, D.L. (1973). "Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy". J. Infect. Dis. 127 (4): 467–470. doi:10.1093/infdis/127.4.467. PMID 4571704.
- Bofill-Mas, S., Formiga-Cruz, M., Clemente-Casares, P., Calafell, F. and Girones, R. (2001). "Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA". J. Virol. 75 (21): 10290–10299. doi:10.1128/JVI.75.21.10290-10299.2001. PMC 114603. PMID 11581397.
- Pavesi, A. (2005). "Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times". J. Gen. Virol. 86 (Pt 5): 1315–1326. doi:10.1099/vir.0.80650-0. PMID 15831942.
- Monaco, M.C., Jensen, P.N., Hou, J., Durham, L.C. and Major, E.O. (1998). "Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection". J. Virol. 72 (12): 9918–9923. PMC 110504. PMID 9811728.
- Ricciardiello, L., Laghi, L., Ramamirtham, P., Chang, C.L., Chang, D.K., Randolph, A.E. and Boland, C.R. (2000). "JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract". Gastroenterology 119 (5): 1228–1235. doi:10.1053/gast.2000.19269. PMID 11054380.
- Harvey, R. (2007) Microbiology Philadelphia, Lippincott Williams & Wilkins.
- Elphick, G.F., Querbes, W., Jordan, J.A., Gee, G.V., Eash, S., Manley, K., Dugan, A., Stanifer, M., Bhatnagar, A., Kroeze, W.K., Roth, B.L. and Atwood, W.J. (2004). "The human polyomavirus, JCV, uses serotonin receptors to infect cells". Science 306 (5700): 1380–1383. doi:10.1126/science.1103492. PMID 15550673.
- White, F.A., 3rd., Ishaq, M., Stoner, G.L. and Frisque, R.J. (1992). "JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy". J. Virol. 66 (10): 5726–5734. PMC 241447. PMID 1326640.
- Theodoropoulos, G., Panoussopoulos, D., Papaconstantinou, I., Gazouli, M., Perdiki, M., Bramis, J. and Lazaris, ACh. (2005). "Assessment of JC polyoma virus in colon neoplasms". Dis. Colon. Rectum. 48 (1): 86–91. doi:10.1007/s10350-004-0737-2. PMID 15690663.
- "Adcetris (brentuximab vedotin): Drug Safety Communication—Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity". U.S. FDA. Retrieved 14 January 2012.
- Gofton TE, Al-Khotani1 A, O'Farrell B, Ang LC, McLachlan RS (June 2010). "Mefloquine in the treatment of progressive multifocal leukoencephalopathy". J Neurol Neurosurg Psychiatry 82 (4): 452–455. doi:10.1136/jnnp.2009.190652. PMID 20562463.
- Clifford, D. B.; Nath, A.; Cinque, P.; Brew, B. J.; Zivadinov, R.; Gorelik, L.; Zhao, Z.; Duda, P. (2013). "A study of mefloquine treatment for progressive multifocal leukoencephalopathy: Results and exploration of predictors of PML outcomes". Journal of NeuroVirology 19 (4): 351–358. doi:10.1007/s13365-013-0173-y. PMC 3758507. PMID 23733308.
- "Cytheris Announces Publication of Clinical Case Study Combining Recombinant Human Interleukin-7 (CYT107) with Antiviral Agent CMX001 as Potential Treatment for Progressive Multifocal Leukoencephalopathy (PML)". BusinessWire. November 30, 2010. Retrieved October 22, 2011.
- Zu Rhein, G.M., and S.M. Chou Science 148,1477–1479 (1965).
- Silverman,L. and Rubinstein, L.J. Acta Neuropathologica 5,215–224 (1965).