1. Infection and pathogenesis

2. Other strains and novel pathological syndromes

3. Epidemiology

4. Drugs associated with reactivation

5. References

6. External links

The JC virus or John Cunningham virus is a type of human polyomavirus (formerly known as papovavirus). It was identified by electron microscopy in 1965 by ZuRhein and Chou,^[1] 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).^[2] 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).^[3]

Infection and pathogenesis

The initial site of infection may be the tonsils,^[4] or possibly the gastrointestinal tract.^[5] The virus then remains latent in the gastrointestinal tract^[5] and can also infect the tubular epithelial cells in the kidneys,^[6] 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-HT_2A serotonin receptor.^[7] JC viral DNA can be detected in both non-PML affected and PML-affected (see below) brain tissue.^[8]

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.^[3] Certain transcription factors present in the early promoter sequences of the JC virus can induce trophism 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.^[9] The protein encoded by these early sequences, T-antigen, also plays a key role in viral proliferation,^[10] 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.

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.^[11] 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.^[12]

Other strains and novel pathological syndromes

Although JC virus infection is classically associated with white matter demyelination and PML pathogenesis, recent literature has identified viral variants as etiological agents of other novel syndromes. For example, JCV has been found to infect the granule cell layer of the cerebellum, while sparing purkinje fibers, ultimately causing severe cerebellar atrophy.^[13] 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.

JCV also appears to mediate encephalopathy, due to infection of cortical pyramidal neurons (CPN) and astrocytes.^[13] 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 the agnogene, coding for a 10 amino acid truncated peptide, which is believed to mediate CPN tropism. Additionally, analysis of the sub-cellular localization of JC CPN virions in nuclei, cytoplasm, and axons suggests that the virus may travel through axons to increase infectivity.

The JCV virus may also be a causative agent of aseptic meningitis (JCVM), as JCV was the only pathogen identified in the CSF of certain patients with meningitis.^[13] Analysis of the JCVM variant revealed archetype-like regulatory regions with no mutations in coding sequences. The precise molecular mechanisms mediating JCV meningeal tropism remains to be found.

Epidemiology

The virus is very common in the general population, infecting 70% to 90% of humans; most people acquire JCV in childhood or adolescence.^[15][16][17] It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.^[18]

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.^[19] 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.

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) includes a statement that JC virus infection resulting in progressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug.^[20]

The boxed warning for the drug natalizumab (Tysabri) includes a statement that JC virus 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.^[21]

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 February 19, 2009, for the drug efalizumab (Raptiva) 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.

A boxed warning for brentuximab 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.^[22]

References

• {{cite journal | last1 = Zu Rhein | first1 = G.M. | last2 = Chou | first2 = S.M. | year = 1965 | title = Particles Resembling Papova Viruses in Human Cerebral Demyelinating Disease

• {{cite journal | last1 = Silverman | first1 = L. | last2 = Rubinstein | first2 = L.J. | year = 1965 | title = Electron microscopic observations on a case of progressive multifocal leukoencephalopathy| url = | journal = Acta Neuropathologica | volume = 5 | issue = 2| pages = 215–224 | doi=10.1007/bf00686519}}

External links

• [https://web.archive.org/web/20111227130140/http://rad.usuhs.edu/medpix/kiosk_image.html?imageid=3583&pt_id=0&recid=1043#pic JC Brain infection] MRI Diagnosis of PML

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