Human polyomavirus 2

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Human polyomavirus 2
JC-Virus.jpg
Immunohistochemical detection of Human polyomavirus 2 protein (stained brown) in a brain biopsy (glia demonstrating progressive multifocal leukoencephalopathy (PML))
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Monodnaviria
Kingdom: Shotokuvirae
Phylum: Cossaviricota
Class: Papovaviricetes
Order: Sepolyvirales
Family: Polyomaviridae
Genus: Betapolyomavirus
Species:
Human polyomavirus 2
Synonyms
  • JC polyomavirus [1]
  • JC virus [2]

Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus, is a type of human polyomavirus (formerly known as papovavirus). [3] It was identified by electron microscopy in 1965 by ZuRhein and Chou, [4] 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). [5] The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs (e.g. in organ transplant patients). [6]

Contents

Infection and pathogenesis

The initial site of infection may be the tonsils, [7] or possibly the gastrointestinal tract. [8] The virus then remains latent in the gastrointestinal tract [9] and can also infect the tubular epithelial cells in the kidneys, [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 against Human 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 the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor. [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 the central nervous system of PML patients almost invariably have differences in promoter sequence to Human 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 of Human 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 allows Human polyomavirus 2 to reactivate. In the brain, it causes the often fatal progressive multifocal leukoencephalopathy, or PML, by destroying oligodendrocytes. Whether this represents the reactivation of Human polyomavirus 2 within the CNS or seeding of newly reactivated Human polyomavirus 2 via blood or lymphatics is unknown. [18] Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as Human polyomavirus 2 has been found in malignant colon tumors, but these findings are still controversial. [19]

Other strains and novel pathological syndromes

Although Human polyomavirus 2 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, Human polyomavirus 2 has been found to infect the granule cell layer of the cerebellum, while sparing purkinje fibers, 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 mediate encephalopathy, due to infection of cortical pyramidal neurons (CPN) and astrocytes. [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 the agnogene, coding for a 10–amino-acid truncated peptide, which is believed to mediate CPN tropism. Additionally, analysis of the subcellular localization of JC CPN virions in nuclei, cytoplasm, and axons suggests that the virus may travel through axons to increase infectivity. [20]

Human polyomavirus 2 may also be a causative agent of aseptic meningitis (JCVM), as Human polyomavirus 2 was the only pathogen identified in the CSF 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 mediating Human polyomavirus 2 meningeal tropism remain to be found. [20]

Epidemiology

A map of the genome of Human polyomavirus 2, indicating the position of the tumor antigen genes (red), the three capsid protein genes (green and blue), the agnogene (yellow), and the non-coding control region (NCCR). Wharton plosone 2016.png
A map of the genome of Human polyomavirus 2, indicating the position of the tumor antigen genes (red), the three capsid protein genes (green and blue), the agnogene (yellow), and the non-coding control region (NCCR).

The virus is very common in the general population, infecting 70% to 90% of humans; most people acquire Human 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 of Human 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 (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. The geographic distribution of JC polyomavirus types may help to trace humans from different continents by JC genotyping. [27]

Drugs associated with reactivation

Since immunodeficiency causes this virus to progress to PML, immunosuppressants are contraindicated in those who are infected.[ citation needed ]

The boxed warning for the drug rituximab (Rituxan) includes a statement that Human polyomavirus 2 infection resulting in progressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug. [28]

The boxed warning for the drug natalizumab (Tysabri) includes a statement that Human 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 drugs Tecfidera and Gilenya, both of which have had incidences of PML resulting in death.[ citation needed ]

The boxed warning was added on February 19, 2009, for the drug efalizumab (Raptiva) includes a statement that Human 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 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. [30]

Related Research Articles

<span class="mw-page-title-main">Progressive multifocal leukoencephalopathy</span> Viral disease affecting human brains

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It is caused by the JC virus, which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities.

<span class="mw-page-title-main">Chorion</span> Outermost fetal membrane around the embryo in amniotes

The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida, known as the vitelline membrane in other animals. In insects, it is developed by the follicle cells while the egg is in the ovary. Some mollusks also have chorions as part of their eggs. For example, fragile octopus eggs have only a chorion as their envelope.

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2024, there are eight recognized genera. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.

<span class="mw-page-title-main">Cidofovir</span> Antiviral drug

Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes have multi-lobed nuclei. In humans, lymphocytes make up the majority of the PBMC population, followed by monocytes, and only a small percentage of dendritic cells.

<span class="mw-page-title-main">BK virus</span> Member of the polyomavirus family

The BK virus, also known as Human polyomavirus 1, is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed. BK virus is an abbreviation of the name of the first patient, from whom the virus was isolated in 1971.

<span class="mw-page-title-main">Chorionic villi</span> Villi that sprout from the chorion

Chorionic villi are villi that sprout from the chorion to provide maximal contact area with maternal blood.

Efalizumab is a formerly available medication designed to treat autoimmune diseases, originally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection. Efalizumab binds to the CD11a subunit of lymphocyte function-associated antigen 1 and acts as an immunosuppressant by inhibiting lymphocyte activation and cell migration out of blood vessels into tissues. Efalizumab was associated with fatal brain infections and was withdrawn from the market in 2009.

<span class="mw-page-title-main">Decoy cells</span> Virally infected epithelial cells found in urine

Decoy cells are virally infected epithelial cells that can be found in the urine. Decoy cells owe their name to their strong resemblance to cancer cells, and may as such confuse the diagnosis of either viral infection or urothelial malignancy. During 1950s, cytotechnologist Andrew Ricci observed cells mimicking cancer cells by they were not, in a group of persons working in some kinds of industries - they were referred to as “decoy cells”, analogous to “decoy ducks” used in hunting wild ducks, by Andrew Ricci, a cytotechnologist working renown cytopathologist Dr. Leopold G. Koss.

Merkel cell polyomavirus was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions, suggesting that it might be transmitted via a respiratory route. However, it has also been found elsewhere, such as in shedded healthy skin and gastrointestinal tract tissues, thus its precise mode of transmission remains unknown. In addition, recent studies suggest that this virus may latently infect the human sera and peripheral blood mononuclear cells.

Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for gene therapy, and to eliminate detrimental populations of neural cells.

Eugene O. "Gene" Major is a senior investigator at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the United States National Institutes of Health (NIH). Major conducts research into the neurological diseases including progressive multifocal leukoencephalopathy (PML), caused by JC virus and often found in immunosuppressed patients such as those with HIV/AIDS. Major has published over 140 scientific articles and reviews in the peer-reviewed literature and has contributed to Fields Virology, a standard virology textbook.

Trichodysplasia spinulosa polyomavirus is a member virus of Human polyomavirus 8 that infects human hosts. First discovered in 2010, TSPyV is associated with Trichodysplasia spinulosa, a rare skin disease only seen in immunocompromised patients. The virus causes hyperproliferation and enlargement of hair follicles by modulating PP2A protein phosphatase signaling pathways. TSPyV was the eighth human polyomavirus to be discovered, and one of four associated with human disease, out of 13 human polyomaviruses known as of the 2015 update to polyomavirus taxonomy released by the International Committee on Taxonomy of Viruses.

WU polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in samples of human respiratory secretions, originally from a child patient in Australia who presented with clinical signs of pneumonia and in whom other common respiratory viruses were not detected. Follow-up studies identified the presence of WU virus in respiratory secretion samples from patients in Australia and the United States, suggesting that, like other human polyomaviruses, WU virus is widely distributed.

KI polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in stored samples of human respiratory secretions collected by the Karolinska Institute, after which the virus is named.

<span class="mw-page-title-main">Agnoprotein</span> Viral protein found in some polyomaviruses

Agnoprotein is a protein expressed by some members of the polyomavirus family from a gene called the agnogene. Polyomaviruses in which it occurs include two human polyomaviruses associated with disease, BK virus and JC virus, as well as the simian polyomavirus SV40.

Human polyomavirus 7 (HPyV7) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2010 and is a common component of the skin flora in healthy adults. There is limited evidence from case reports linking the virus to a skin rash occurring in immunocompromised organ transplant recipients.

Igor Koralnik is an American physician, neurologist and scientist. He is one of the first physicians to study the neurologic complications caused by the human immunodeficiency virus (HIV) and is a leading researcher in the investigation of the polyomavirus JC, which causes progressive multifocal leukoencephalopathy (PML), a disease of the central nervous system that occurs in immunosuppressed individuals.

References

  1. ↑ Calvignac-Spencer, Sébastien; et al. (22 October 2015). "Revision on the family Polyomaviridae(76 species, four genera)" (PDF). International Committee on Taxonomy of Viruses (ICTV). Retrieved 26 April 2019. To rename the following taxon (or taxa): Current name Proposed name JC polyomavirus Human polyomavirus 2
  2. ↑ ICTV 7th Report van Regenmortel, M.H.V., Fauquet, C.M., Bishop, D.H.L., Carstens, E.B., Estes, M.K., Lemon, S.M., Maniloff, J., Mayo, M.A., McGeoch, D.J., Pringle, C.R. and Wickner, R.B. (2000). Virus taxonomy. Seventh report of the International Committee on Taxonomy of Viruses. Academic Press, San Diego. p245 https://ictv.global/ictv/proposals/ICTV%207th%20Report.pdf
  3. ↑ Rotondo JC, Candian T, Selvatici R, Mazzoni E (2017). "Tracing Males From Different Continents by Genotyping JC Polyomavirus in DNA From Semen Samples". J Cell Physiol. 232 (5): 982–985. doi:10.1002/jcp.25686. PMID   27859215. S2CID   25331955.
  4. ↑ Zurhein, G; Chou, S. M. (1965). "Particles Resembling Papova Viruses in Human Cerebral Demyelinating Disease". Science. 148 (3676): 1477–9. Bibcode:1965Sci...148.1477R. doi:10.1126/science.148.3676.1477. PMID   14301897. S2CID   35870720.
  5. ↑ Padgett 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.
  6. 1 2 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. PMC   3416490 . PMID   22763635.
  7. ↑ 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): 9918–23. doi:10.1128/JVI.72.12.9918-9923.1998. PMC   110504 . PMID   9811728.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. 1 2 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): 10290–9. doi:10.1128/JVI.75.21.10290-10299.2001. PMC   114603 . PMID   11581397.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ 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): 1228–35. doi:10.1053/gast.2000.19269. PMID   11054380.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Cornelissen, Cynthia Nau; Harvey, Richard A.; Fisher, Bruce D. (2012). "X. Opportunistic Infections of HIV: JC Virus (JCV)". Microbiology. Illustrated Reviews. Vol. 3. Lippincott Williams & Wilkins. p. 389. ISBN   978-1-60831-733-2.
  11. ↑ Rotondo JC, Candian T, Selvatici R, Mazzoni E (2017). "Tracing Males From Different Continents by Genotyping JC Polyomavirus in DNA From Semen Samples". J Cell Physiol. 232 (5): 982–985. doi:10.1002/jcp.25686. PMID   27859215. S2CID   25331955.
  12. ↑ Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M (2019). "Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion". Hum Reprod. 34 (3): 433–440. doi:10.1002/jcp.27490. hdl: 11392/2397717 . PMID   30590693. S2CID   53106591.
  13. ↑ Tagliapietra A, Rotondo JC, Bononi I, Mazzoni E, Magagnoli F, Maritati M (2019). "Footprints of BK and JC polyomaviruses in specimens from females affected by spontaneous abortion". Hum Reprod. 34 (3): 433–440. doi:10.1002/jcp.27490. hdl: 11392/2397717 . PMID   30590693. S2CID   53106591.
  14. ↑ 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): 1380–3. Bibcode:2004Sci...306.1380E. doi:10.1126/science.1103492. PMID   15550673. S2CID   36657062.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ 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): 5726–4. doi:10.1128/JVI.66.10.5726-5734.1992. PMC   241447 . PMID   1326640.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  16. ↑ Marshall, Leslie J.; Dunham, Lisa; Major, Eugene O. (December 2010). "Transcription factor Spi-B binds unique sequences present in the tandem repeat promoter/enhancer of JC virus and supports viral activity". The Journal of General Virology. 91 (Pt 12): 3042–3052. doi:10.1099/vir.0.023184-0. ISSN   0022-1317. PMC   3052566 . PMID   20826618.
  17. ↑ Wollebo, Hassen S.; White, Martyn K.; Gordon, Jennifer; Berger, Joseph R.; Khalili, Kamel (April 2015). "Persistence and pathogenesis of the neurotropic polyomavirus JC". Annals of Neurology. 77 (4): 560–570. doi:10.1002/ana.24371. ISSN   0364-5134. PMC   4376594 . PMID   25623836.
  18. ↑ Progressive Multifocal Leukoencephalopathy in HIV at eMedicine
  19. ↑ 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. S2CID   23357519.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. 1 2 3 4 Miskin DP and Koralnik IJ (2015). "Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area". Curr Opin Neurol. 28 (3): 288–294. doi:10.1097/wco.0000000000000201. PMC   4414882 . PMID   25887767.
  21. ↑ Wharton, Keith A.; Quigley, Catherine; Themeles, Marian; Dunstan, Robert W.; Doyle, Kathryn; Cahir-McFarland, Ellen; Wei, Jing; Buko, Alex; Reid, Carl E.; Sun, Chao; Carmillo, Paul; Sur, Gargi; Carulli, John P.; Mansfield, Keith G.; Westmoreland, Susan V.; Staugaitis, Susan M.; Fox, Robert J.; Meier, Werner; Goelz, Susan E.; Major, Eugene Oliver (18 May 2016). "JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection". PLOS ONE. 11 (5): e0155897. Bibcode:2016PLoSO..1155897W. doi: 10.1371/journal.pone.0155897 . PMC   4871437 . PMID   27191595.
  22. ↑ Agostini, H.T.; Ryschkewitsch, C.F.; Mory, R.; Singer, E.J.; Stoner, G.L. (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". J. Infect. Dis. 176 (1): 1–8. doi: 10.1086/514010 . JSTOR   30107072. PMID   9207343.
  23. ↑ Shackelton, L.A.; Rambaut, A.; Pybus, O.G.; Holmes, E.C. (2006). "JC Virus evolution and its association with human populations". Journal of Virology. 80 (20): 9928–33. doi:10.1128/JVI.00441-06. PMC   1617318 . PMID   17005670.
  24. ↑ Padgett, B.L.; 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.
  25. ↑ Pavesi, A. (2005). "Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times". J. Gen. Virol. 86 (Pt 5): 1315–26. doi: 10.1099/vir.0.80650-0 . PMID   15831942.
  26. ↑ Rotondo JC, Candian T, Selvatici R, Mazzoni E (2017). "Tracing Males From Different Continents by Genotyping JC Polyomavirus in DNA From Semen Samples". J Cell Physiol. 232 (5): 982–985. doi:10.1002/jcp.25686. PMID   27859215. S2CID   25331955.
  27. ↑ Rotondo JC, Candian T, Selvatici R, Mazzoni E (2017). "Tracing Males From Different Continents by Genotyping JC Polyomavirus in DNA From Semen Samples". J Cell Physiol. 232 (5): 982–985. doi:10.1002/jcp.25686. PMID   27859215. S2CID   25331955.
  28. ↑ gene.com/gene/products/information/pdf/rituxan-prescribing.pdf
  29. ↑ Major, Eugene O; Yousry, Tarek A; Clifford, David B (May 2018). "Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned". The Lancet Neurology. 17 (5): 467–480. doi:10.1016/s1474-4422(18)30040-1. ISSN   1474-4422. PMID   29656742. S2CID   4891186.
  30. ↑ "Adcetris (brentuximab vedotin): Drug Safety Communication—Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity". U.S. FDA. Retrieved 14 January 2012.
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