Polyomaviridae#The Polyoma Middle T-Antigen

File:Mpyv colorbydepth.png VP1, colored such that areas of the surface closer to the interior center appear blue and areas nearer to the surface appear red. Rendered from {{PDB|1SIE}}.]]

Polyomaviruses are non-enveloped double-stranded DNA viruses with circular genomes of around 5000 base pairs. With such a small size, they are ranked among the smallest known double stranded DNA viruses.{{cite journal | vauthors = Shackelton LA, Rambaut A, Pybus OG, Holmes EC |title= JC virus evolution and its association with human populations |journal= J Virol |date=October 2006 | volume = 80| issue = 20|pages=9928–9933|doi=10.1128/JVI.00441-06|pmid=17005670 |pmc= 1617318|doi-access=free}}

The genome is packaged in a viral capsid of about 40-50 nanometers in diameter, which is icosahedral in shape (T=7 symmetry).{{cite web | title = Viral Zone | url = http://viralzone.expasy.org/all_by_species/148.html | publisher = ExPASy | access-date=15 June 2015 }} The capsid is composed of 72 pentameric capsomeres of a protein called VP1, which is capable of self-assembly into a closed icosahedron;{{cite journal | vauthors = Salunke DM, Caspar DL, Garcea RL | title = Self-assembly of purified polyomavirus capsid protein VP1 | journal = Cell | volume = 46 | issue = 6 | pages = 895–904 | date = September 1986 | pmid = 3019556 | doi = 10.1016/0092-8674(86)90071-1 | s2cid = 25800023 }} each pentamer of VP1 is associated with one molecule of one of the other two capsid proteins, VP2 or VP3.{{cite journal | vauthors = DeCaprio JA, Garcea RL | title = A cornucopia of human polyomaviruses | journal = Nature Reviews. Microbiology | volume = 11 | issue = 4 | pages = 264–76 | date = April 2013 | pmid = 23474680 | pmc = 3928796 | doi = 10.1038/nrmicro2992 }}

File:Gaynor plospathogens 2007 WUvirusgenome.png, a human polyomavirus. The early region is shown on the left and contains the TAg (tumor antigen) proteins; the late region is on the right and contains the capsid proteins.{{cite journal | vauthors = Gaynor AM, Nissen MD, Whiley DM, Mackay IM, Lambert SB, Wu G, Brennan DC, Storch GA, Sloots TP, Wang D | title = Identification of a novel polyomavirus from patients with acute respiratory tract infections | journal = PLOS Pathogens | volume = 3 | issue = 5 | pages = e64 | date = May 2007 | pmid = 17480120 | pmc = 1864993 | doi = 10.1371/journal.ppat.0030064 | doi-access = free }}]]

The genome of a typical polyomavirus codes for between five and nine proteins, divided into two transcriptional regions called the early and late regions due to the time during infection in which they are transcribed. Each region is transcribed by the host cell's RNA polymerase II as a single pre-messenger RNA containing multiple genes. The early region usually codes for two proteins, the small and large tumor antigens, produced by alternative splicing. The late region contains the three capsid structural proteins VP1, VP2, and VP3, produced by alternative translational start sites. Additional genes and other variations on this theme are present in some viruses: for example, rodent polyomaviruses have a third protein called middle tumor antigen in the early region, which is extremely efficient at inducing cellular transformation; SV40 has an additional capsid protein VP4; some examples have an additional regulatory protein called agnoprotein expressed from the late region. The genome also contains a non-coding control or regulatory region containing the early and late regions' promoters, transcriptional start sites, and the origin of replication.{{Cite journal|last=International Agency for Research on Cancer|year=2013|title=Introduction to Polyomaviruses|url=https://monographs.iarc.fr/ENG/Monographs/vol104/mono104-0GI.pdf|journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|volume=104|pages=121–131}}

File:Mpyv vp1 gt1a 5cpw.png VP1 in complex with the GT1a glycan. GT1a is shown in yellow and the VP1 monomer with a white surface and a blue protein backbone. A complex network of hydrogen bonds, many water-mediated, is shown at the binding surface by orange lines, with participating protein residues shown as sticks. Mutations of the two residues shown in cyan at the bottom of the figure can significantly affect pathogenicity. From {{PDB|5CPW}}.]]

The polyomavirus life cycle begins with entry into a host cell. Cellular receptors for polyomaviruses are sialic acid residues of glycans, commonly gangliosides. The attachment of polyomaviruses to host cells is mediated by the binding of VP1 to sialylated glycans on the cell surface.{{cite journal | vauthors = Buch MH, Liaci AM, O'Hara SD, Garcea RL, Neu U, Stehle T | title = Structural and Functional Analysis of Murine Polyomavirus Capsid Proteins Establish the Determinants of Ligand Recognition and Pathogenicity | journal = PLOS Pathogens | volume = 11 | issue = 10 | pages = e1005104 | date = October 2015 | pmid = 26474293 | pmc = 4608799 | doi = 10.1371/journal.ppat.1005104 | doi-access = free }} In some particular viruses, additional cell-surface interactions occur; for example, the JC virus is believed to require interaction with the 5HT2A receptor and the Merkel cell virus with heparan sulfate.{{cite journal | vauthors = Schowalter RM, Pastrana DV, Buck CB | title = Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry | journal = PLOS Pathogens | volume = 7 | issue = 7 | pages = e1002161 | date = July 2011 | pmid = 21829355 | pmc = 3145800 | doi = 10.1371/journal.ppat.1002161 | doi-access = free }} However, in general virus-cell interactions are mediated by commonly occurring molecules on the cell surface, and therefore are likely not a major contributor to individual viruses' observed cell-type tropism. After binding to molecules on the cell surface, the virion is endocytosed and enters the endoplasmic reticulum - a behavior unique among known non-enveloped viruses{{cite journal | vauthors = Inoue T, Tsai B | title = How viruses use the endoplasmic reticulum for entry, replication, and assembly | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 1 | pages = a013250 | date = January 2013 | pmid = 23284050 | pmc = 3579393 | doi = 10.1101/cshperspect.a013250 }} - where the viral capsid structure is likely to be disrupted by action of host cell disulfide isomerase enzymes.{{cite journal | vauthors = Gjoerup O, Chang Y | title = Update on human polyomaviruses and cancer | journal = Advances in Cancer Research | volume = 106 | pages = 1–51 | date = 2010 | pmid = 20399955 | doi = 10.1016/S0065-230X(10)06001-X | isbn = 9780123747716 }}

The details of transit to the nucleus are not clear and may vary among individual polyomaviruses. It has been frequently reported that an intact, albeit distorted, virion particle is released from the endoplasmic reticulum into the cell cytoplasm, where the genome is released from the capsid, possibly due to the low calcium concentration in the cytoplasm. Both expression of viral genes and replication of the viral genome occur in the nucleus using host cell machinery. The early genes - comprising at minimum the small tumor antigen (ST) and large tumor antigen (LT) - are expressed first, from a single alternatively spliced messenger RNA strand. These proteins serve to manipulate the host's cell cycle - dysregulating the transition from G1 phase to S phase, when the host cell's genome is replicated - because host cell DNA replication machinery is needed for viral genome replication. The precise mechanism of this dysregulation depends on the virus; for example, SV40 LT can directly bind host cell p53, but murine polyomavirus LT does not.{{cite journal | doi = 10.1128/JVI.05034-11 | pmid = 21835797 | pmc = 3187521 | title = Comparisons between Murine Polyomavirus and Simian Virus 40 Show Significant Differences in Small T Antigen Function | volume=85 | issue = 20 | year=2011 | journal=Journal of Virology | pages=10649–10658 | vauthors=Andrabi S, Hwang JH, Choe JK, Roberts TM, Schaffhausen BS}} LT induces DNA replication from the viral genome's non-coding control region (NCCR), after which expression of the early mRNA is reduced and expression of the late mRNA, which encodes the viral capsid proteins, begins. As these interactions begin, the LTs belonging to several polyomaviruses, including Merkel cell polyomavirus, present oncogenic potential.{{cite journal | vauthors = Rotondo JC, Bononi I, Puozzo A, Govoni M, Foschi V, Lanza G, Gafà R, Gaboriaud P, Touzé FA, Selvatici R, Martini F, Tognon M | title = Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF | journal = Clinical Cancer Research | volume = 23| issue = 14 | pages = 3929–3934 | date = July 2017 | url=https://clincancerres.aacrjournals.org/content/23/14/3929| pmid = 28174236 | doi = 10.1158/1078-0432.CCR-16-2899 | doi-access = free | hdl = 11392/2378829 | hdl-access = free }}

Several mechanisms have been described for regulating the transition from early to late gene expression, including the involvement of the LT protein in repressing the early promoter, the expression of un-terminated late mRNAs with extensions complementary to early mRNA, and the expression of regulatory microRNA.

Expression of the late genes results in accumulation of the viral capsid proteins in the host cell cytoplasm. Capsid components enter the nucleus in order to encapsidate new viral genomic DNA. New virions may be assembled in viral factories. The mechanism of viral release from the host cell varies among polyomaviruses; some express proteins that facilitate cell exit, such as the agnoprotein or VP4. In some cases high levels of encapsidated virus result in cell lysis, releasing the virions.

The large tumor antigen plays a key role in regulating the viral life cycle by binding to the viral origin of DNA replication where it promotes DNA synthesis. Also as the polyomavirus relies on the host cell machinery to replicate the host cell needs to be in s-phase for this to begin. Due to this, large T-antigen also modulates cellular signaling pathways to stimulate progression of the cell cycle by binding to a number of cellular control proteins.{{cite journal | vauthors = White MK, Gordon J, Reiss K, Del Valle L, Croul S, Giordano A, Darbinyan A, Khalili K | title = Human polyomaviruses and brain tumors | journal = Brain Research. Brain Research Reviews | volume = 50 | issue = 1 | pages = 69–85 | date = December 2005 | pmid = 15982744 | doi = 10.1016/j.brainresrev.2005.04.007 | s2cid = 20990837 }} This is achieved by a two prong attack of inhibiting tumor suppressing genes p53 and members of the retinoblastoma (pRB) family,{{cite journal | vauthors = Kazem S, van der Meijden E, Wang RC, Rosenberg AS, Pope E, Benoit T, Fleckman P, Feltkamp MC | title = Polyomavirus-associated Trichodysplasia spinulosa involves hyperproliferation, pRB phosphorylation and upregulation of p16 and p21 | journal = PLOS ONE | volume = 9 | issue = 10 | pages = e108947 | year = 2014 | pmid = 25291363 | pmc = 4188587 | doi = 10.1371/journal.pone.0108947 | bibcode = 2014PLoSO...9j8947K | doi-access = free }} and stimulating cell growth pathways by binding cellular DNA, ATPase-helicase, DNA polymerase α association, and binding of transcription preinitiation complex factors.{{cite journal | vauthors = Kelley WL, Georgopoulos C | title = The T/t common exon of simian virus 40, JC, and BK polyomavirus T antigens can functionally replace the J-domain of the Escherichia coli DnaJ molecular chaperone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 8 | pages = 3679–84 | date = April 1997 | pmid = 9108037 | pmc = 20500 | doi = 10.1073/pnas.94.8.3679 | bibcode = 1997PNAS...94.3679K | doi-access = free }} This abnormal stimulation of the cell cycle is a powerful force for oncogenic transformation.{{citation needed|date=November 2022}}

The small tumor antigen protein is also able to activate several cellular pathways that stimulate cell proliferation. Polyomavirus small T antigens commonly target protein phosphatase 2A (PP2A),{{cite journal | vauthors = Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM | title = Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A | journal = Cell | volume = 60 | issue = 1 | pages = 167–76 | date = January 1990 | pmid = 2153055 | doi = 10.1016/0092-8674(90)90726-u | s2cid = 2007706 }} a key multisubunit regulator of multiple pathways including Akt, the mitogen-activated protein kinase (MAPK) pathway, and the stress-activated protein kinase (SAPK) pathway.{{cite journal | vauthors = Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M | title = The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation | journal = Cell | volume = 75 | issue = 5 | pages = 887–97 | date = December 1993 | pmid = 8252625 | doi = 10.1016/0092-8674(93)90533-V | doi-access = free }}{{cite journal | vauthors = Watanabe G, Howe A, Lee RJ, Albanese C, Shu IW, Karnezis AN, Zon L, Kyriakis J, Rundell K, Pestell RG | title = Induction of cyclin D1 by simian virus 40 small tumor antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 23 | pages = 12861–6 | date = November 1996 | pmid = 8917510 | pmc = 24011 | doi = 10.1073/pnas.93.23.12861 | bibcode = 1996PNAS...9312861W | doi-access = free }} Merkel cell polyomavirus small T antigen encodes a unique domain, called the LT-stabilization domain (LSD), that binds to and inhibits the FBXW7 E3 ligase regulating both cellular and viral oncoproteins.{{cite journal | vauthors = Kwun HJ, Shuda M, Feng H, Camacho CJ, Moore PS, Chang Y | title = Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7 | journal = Cell Host & Microbe | volume = 14 | issue = 2 | pages = 125–35 | date = August 2013 | pmid = 23954152 | pmc = 3764649 | doi = 10.1016/j.chom.2013.06.008 }} Unlike for SV40, the MCV small T antigen directly transforms rodent cells in vitro.{{cite journal | vauthors = Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS | title = Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator | journal = The Journal of Clinical Investigation | volume = 121 | issue = 9 | pages = 3623–34 | date = September 2011 | pmid = 21841310 | pmc = 3163959 | doi = 10.1172/JCI46323 }}

The middle tumor antigen is used in model organisms developed to study cancer, such as the MMTV-PyMT system where middle T is coupled to the MMTV promoter. There it functions as an oncogene, while the tissue where the tumor develops is determined by the MMTV promoter.{{citation needed|date=November 2022}}

The polyomavirus capsid consists of one major component, major capsid protein VP1, and one or two minor components, minor capsid proteins VP2 and VP3. VP1 pentamers form the closed icosahedral viral capsid, and in the interior of the capsid each pentamer is associated with one molecule of either VP2 or VP3.{{cite journal | vauthors = Chen XS, Stehle T, Harrison SC | title = Interaction of polyomavirus internal protein VP2 with the major capsid protein VP1 and implications for participation of VP2 in viral entry | language = en | journal = The EMBO Journal | volume = 17 | issue = 12 | pages = 3233–40 | date = June 1998 | pmid = 9628860 | pmc = 1170661 | doi = 10.1093/emboj/17.12.3233 }} Some polyomaviruses, such as Merkel cell polyomavirus, do not encode or express VP3. The capsid proteins are expressed from the late region of the genome.

The agnoprotein is a small multifunctional phospho-protein found in the late coding part of the genome of some polyomaviruses, most notably BK virus, JC virus, and SV40. It is essential for proliferation in the viruses that express it and is thought to be involved in regulating the viral life cycle, particularly replication and viral exit from the host cell, but the exact mechanisms are unclear.{{cite journal | vauthors = Sariyer IK, Saribas AS, White MK, Safak M | title = Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content | journal = Virology Journal | volume = 8 | pages = 255 | date = May 2011 | pmid = 21609431 | pmc = 3127838 | doi = 10.1186/1743-422X-8-255 | doi-access = free }}{{cite journal | vauthors = Saribas AS, Coric P, Hamazaspyan A, Davis W, Axman R, White MK, Abou-Gharbia M, Childers W, Condra JH, Bouaziz S, Safak M | title = Emerging From the Unknown: Structural and Functional Features of Agnoprotein of Polyomaviruses | journal = Journal of Cellular Physiology | volume = 231 | issue = 10 | pages = 2115–27 | date = October 2016 | pmid = 26831433 | doi = 10.1002/jcp.25329 | pmc = 5217748 }}

The polyomaviruses are members of group I (dsDNA viruses). The classification of polyomaviruses has been the subject of several proposed revisions as new members of the group are discovered. Formerly, polyomaviruses and papillomaviruses, which share many structural features but have very different genomic organizations, were classified together in the now-obsolete family Papovaviridae.{{cite web|title=ICTV Taxonomy Website|url=https://ictv.global/taxonomy }} (The name Papovaviridae derived from three abbreviations: Pa for Papillomavirus, Po for Polyomavirus, and Va for "vacuolating."){{cite journal|last1=International Agency for Research on Cancer|title=IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Malaria and Some Polyomaviruses (SV40, BK, JC, and Merkel Cell Viruses).|journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|date=2013|volume=104|url=https://www.ncbi.nlm.nih.gov/books/NBK294248/}} The polyomaviruses were divided into three major clades (that is, genetically related groups): the SV40 clade, the avian clade, and the murine polyomavirus clade.{{cite journal | vauthors = Pérez-Losada M, Christensen RG, McClellan DA, Adams BJ, Viscidi RP, Demma JC, Crandall KA | title = Comparing phylogenetic codivergence between polyomaviruses and their hosts | journal = Journal of Virology | volume = 80 | issue = 12 | pages = 5663–9 | date = June 2006 | pmid = 16731904 | pmc = 1472594 | doi = 10.1128/JVI.00056-06 }}

The family contains the following genera:{{cite web|title=Virus Taxonomy: 2024 Release|url=https://ictv.global/taxonomy|publisher=International Committee on Taxonomy of Viruses|access-date=5 March 2025}}

• Alphapolyomavirus
• Betapolyomavirus
• Deltapolyomavirus
• Epsilonpolyomavirus
• Etapolyomavirus
• Gammapolyomavirus
• Thetapolyomavirus
• Zetapolyomavirus

Description of additional viruses is ongoing. These include the sea otter polyomavirus 1{{cite journal | vauthors = Siqueira JD, Ng TF, Miller M, Li L, Deng X, Dodd E, Batac F, Delwart E | title = Endemic infection of stranded southern sea otters (Enhydra lutris nereis) with novel parvovirus, polyomavirus, and adenovirus | journal = Journal of Wildlife Diseases | volume = 53 | issue = 3 | pages = 532–542 | date = July 2017 | pmid = 28192039 | doi = 10.7589/2016-04-082 | s2cid = 46740584 }} and Alpaca polyomavirus{{cite journal | vauthors = Dela Cruz FN, Li L, Delwart E, Pesavento PA | title = A novel pulmonary polyomavirus in alpacas (Vicugna pacos) | journal = Veterinary Microbiology | volume = 201 | pages = 49–55 | year = 2017 | pmid = 28284622 | doi = 10.1016/j.vetmic.2017.01.005 }} Another virus is the giant panda polyomavirus 1.{{cite journal | vauthors = Qi D, Shan T, Liu Z, Deng X, Zhang Z, Bi W, Owens JR, Feng F, Zheng L, Huang F, Delwart E, Hou R, Zhang W | title = A novel polyomavirus from the nasal cavity of a giant panda (Ailuropoda melanoleuca) | journal = Virology Journal | volume = 14 | issue = 1 | pages = 207 | year = 2017 | pmid = 29078783 | pmc = 5658932 | doi = 10.1186/s12985-017-0867-5 | doi-access = free }} Another virus has been described from sigmodontine rodents.{{cite journal | doi = 10.1007/s00705-018-3913-8 | pmid=29931397 | volume=163 | title=A novel polyomavirus in sigmodontine rodents from São Paulo State, Brazil | year=2018 | journal=Archives of Virology | pages=2913–2915 | vauthors=Gonçalves Motta Maia F, Marciel de Souza W, Sabino-Santos G, Jorge Fumagalli M, Modha S, Ramiro Murcia P, Tadeu Moraes Figueiredo L| issue=10 | s2cid=49351836 }} Another - tree shrew polyomavirus 1 - has been described in the tree shrew.{{cite journal | vauthors = Liu P, Qiu Y, Xing C, Zhou JH, Yang WH, Wang Q, Li JY, Han X, Zhang YZ, Ge XY | year = 2019 | title = Detection and genome characterization of two novel papillomaviruses and a novel polyomavirus in tree shrew (Tupaia belangeri chinensis) in China | journal = Virol J | volume = 16 | issue = 1| page = 35 | doi=10.1186/s12985-019-1141-9| pmid = 30885224 | pmc = 6423848 | doi-access = free }}

Most polyomaviruses do not infect humans. Of the polyomaviruses cataloged as of 2017, a total of 14 were known with human hosts. However, some polyomaviruses are associated with human disease, particularly in immunocompromised individuals. MCV is highly divergent from the other human polyomaviruses and is most closely related to murine polyomavirus. Trichodysplasia spinulosa-associated polyomavirus (TSV) is distantly related to MCV. Two viruses—HPyV6 and HPyV7—are most closely related to KI and WU viruses, while HPyV9 is most closely related to the African green monkey-derived lymphotropic polyomavirus (LPV).{{citation needed|date=November 2022}}

A fourteenth virus has been described.{{cite journal | vauthors = Gheit T, Dutta S, Oliver J, Robitaille A, Hampras S, Combes JD, McKay-Chopin S, Le Calvez-Kelm F, Fenske N, Cherpelis B, Giuliano AR, Franceschi S, McKay J, Rollison DE, Tommasino M | title = Isolation and characterization of a novel putative human polyomavirus | journal = Virology | volume = 506 | pages = 45–54 | year = 2017 | pmid = 28342387 | doi = 10.1016/j.virol.2017.03.007 | pmc = 9265179 | doi-access = free }} Lyon IARC polyomavirus is related to raccoon polyomavirus.{{citation needed|date=November 2022}}

The following 14 polyomaviruses with human hosts had been identified and had their genomes sequenced as of 2017:

Deltapolyomavirus contains only the four human viruses shown in the above table. The Alpha and Beta groups contain viruses that infect a variety of mammals. The Gamma group contains the avian viruses. Clinically significant disease associations are shown only where causality is expected.{{cite journal | vauthors = Dalianis T, Hirsch HH | title = Human polyomaviruses in disease and cancer | journal = Virology | volume = 437 | issue = 2 | pages = 63–72 | date = March 2013 | pmid = 23357733 | doi = 10.1016/j.virol.2012.12.015 | doi-access = }}

Antibodies to the monkey lymphotropic polyomavirus have been detected in humans suggesting that this virus - or a closely related virus - can infect humans.{{cite journal | vauthors = Van Ghelue M, Khan MT, Ehlers B, Moens U | title = Genome analysis of the new human polyomaviruses | journal = Reviews in Medical Virology | volume = 22 | issue = 6 | pages = 354–77 | date = November 2012 | pmid = 22461085 | doi = 10.1002/rmv.1711 | doi-access = free }}

All the polyomaviruses are highly common childhood and young adult infections.{{cite journal | vauthors = Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH | title = Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors | journal = The Journal of Infectious Diseases | volume = 199 | issue = 6 | pages = 837–46 | date = March 2009 | pmid = 19434930 | doi = 10.1086/597126 | doi-access = free }} Most of these infections appear to cause little or no symptoms. These viruses are probably lifelong persistent among almost all adults. Diseases caused by human polyomavirus infections are most common among immunocompromised people; disease associations include BK virus with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus (MCV) with Merkel cell cancer.

{{Main|SV40}}

SV40 replicates in the kidneys of monkeys without causing disease, but can cause cancer in rodents under laboratory conditions. In the 1950s and early 1960s, well over 100 million people may have been exposed to SV40 due to previously undetected SV40 contamination of polio vaccine, prompting concern about the possibility that the virus might cause disease in humans.{{cite journal | vauthors = Poulin DL, DeCaprio JA | title = Is there a role for SV40 in human cancer? | journal = Journal of Clinical Oncology | volume = 24 | issue = 26 | pages = 4356–65 | date = September 2006 | pmid = 16963733 | doi = 10.1200/JCO.2005.03.7101 }}{{cite journal | vauthors = zur Hausen H | title = SV40 in human cancers--an endless tale? | journal = International Journal of Cancer | volume = 107 | issue = 5 | pages = 687 | date = December 2003 | pmid = 14566815 | doi = 10.1002/ijc.11517 | doi-access = }} Although it has been reported as present in some human cancers, including brain tumors, bone tumors, mesotheliomas, and non-Hodgkin's lymphomas,{{cite journal | vauthors = Gazdar AF, Butel JS, Carbone M | title = SV40 and human tumours: myth, association or causality? | journal = Nature Reviews. Cancer | volume = 2 | issue = 12 | pages = 957–64 | date = December 2002 | pmid = 12459734 | doi = 10.1038/nrc947 | s2cid = 8878662 }} accurate detection is often confounded by high levels of cross-reactivity for SV40 with widespread human polyomaviruses. Most virologists dismiss SV40 as a cause for human cancers.{{cite journal | vauthors = Carroll-Pankhurst C, Engels EA, Strickler HD, Goedert JJ, Wagner J, Mortimer EA | title = Thirty-five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal period | journal = British Journal of Cancer | volume = 85 | issue = 9 | pages = 1295–7 | date = November 2001 | pmid = 11720463 | pmc = 2375249 | doi = 10.1054/bjoc.2001.2065 }}{{cite journal | vauthors = Shah KV | title = SV40 and human cancer: a review of recent data | journal = International Journal of Cancer | volume = 120 | issue = 2 | pages = 215–23 | date = January 2007 | pmid = 17131333 | doi = 10.1002/ijc.22425 | s2cid = 20679358 | doi-access = free }}

The diagnosis of polyomavirus almost always occurs after the primary infection as it is either asymptomatic or sub-clinical. Antibody assays are commonly used to detect presence of antibodies against individual viruses.{{cite journal | vauthors = Drachenberg CB, Hirsch HH, Ramos E, Papadimitriou JC | title = Polyomavirus disease in renal transplantation: review of pathological findings and diagnostic methods | journal = Human Pathology | volume = 36 | issue = 12 | pages = 1245–55 | date = December 2005 | pmid = 16311117 | doi = 10.1016/j.humpath.2005.08.009 }} Competition assays are frequently needed to distinguish among highly similar polyomaviruses.{{cite book |last1=Viscidi |first1=Raphael P. |last2=Clayman |first2=Barbara | name-list-style = vanc |year=2006 |chapter=Serological Cross Reactivity between Polyomavirus Capsids|chapter-url=https://books.google.com/books?id=Wz2aOQvHEPQC&pg=PA73 |pages=73–84 |doi=10.1007/0-387-32957-9_5 |pmid=16626028 |editor1-first=Nasimul |editor1-last=Ahsan |title=Polyomaviruses and Human Diseases |series=Advances in Experimental Medicine and Biology |volume=577 |isbn=978-0-387-29233-5}}

In cases of progressive multifocal leucoencephalopathy (PML), a cross-reactive antibody to SV40 T antigen (commonly Pab419) is used to stain tissues directly for the presence of JC virus T antigen. PCR can be used on a biopsy of the tissue or cerebrospinal fluid to amplify the polyomavirus DNA. This allows not only the detection of polyomavirus but also which sub type it is.{{cite journal | vauthors = Drews K, Bashir T, Dörries K | title = Quantification of human polyomavirus JC in brain tissue and cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy by competitive PCR | journal = Journal of Virological Methods | volume = 84 | issue = 1 | pages = 23–36 | date = January 2000 | pmid = 10644084 | doi = 10.1016/S0166-0934(99)00128-7 }}

There are three main diagnostic techniques used for the diagnosis of the reactivation of polyomavirus in polyomavirus nephropathy (PVN): urine cytology, quantification of the viral load in both urine and blood, and a renal biopsy.

The reactivation of polyomavirus in the kidneys and urinary tract causes the shedding of infected cells, virions, and/or viral proteins in the urine. This allows urine cytology to examine these cells, which if there is polyomavirus inclusion of the nucleus, is diagnostic of infection.{{cite journal | vauthors = Nickeleit V, Hirsch HH, Binet IF, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ | title = Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease | journal = Journal of the American Society of Nephrology | volume = 10 | issue = 5 | pages = 1080–9 | date = May 1999 | doi = 10.1681/ASN.V1051080 | pmid = 10232695 | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=10232695 | doi-access = free }} Also as the urine of an infected individual will contain virions and/or viral DNA, quantitation of the viral load can be done through PCR.{{cite journal | vauthors = Randhawa PS, Vats A, Zygmunt D, Swalsky P, Scantlebury V, Shapiro R, Finkelstein S | title = Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy | journal = Transplantation | volume = 74 | issue = 4 | pages = 485–8 | date = August 2002 | pmid = 12352906 | doi = 10.1097/00007890-200208270-00009 | s2cid = 30574884 | doi-access = free }} This is also true for the blood.

Renal biopsy can also be used if the two methods just described are inconclusive or if the specific viral load for the renal tissue is desired. Similarly to the urine cytology, the renal cells are examined under light microscopy for polyomavirus inclusion of the nucleus, as well as cell lysis and viral partials in the extra cellular fluid. The viral load as before is also measure by PCR.{{citation needed|date=February 2015}}

Tissue staining using a monoclonal antibody against MCV T antigen shows utility in differentiating Merkel cell carcinoma from other small, round cell tumors.{{cite journal | vauthors = Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, Bini J, Arora R, Hanson NC, Tassello JA, Frosina D, Moore P, Chang Y | title = Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas | journal = The American Journal of Surgical Pathology | volume = 33 | issue = 9 | pages = 1378–85 | date = September 2009 | pmid = 19609205 | pmc = 2932664 | doi = 10.1097/PAS.0b013e3181aa30a5 }} Blood tests to detect MCV antibodies have been developed and show that infection with the virus is widespread although Merkel cell carcinoma patients have exceptionally higher antibody responses than asymptomatically infected persons.{{cite journal | vauthors = Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS | title = Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays | journal = International Journal of Cancer | volume = 125 | issue = 6 | pages = 1250–6 | date = September 2009 | pmid = 19499548 | pmc = 2747737 | doi = 10.1002/ijc.24509 }}{{cite journal | vauthors = Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB | title = Quantitation of human seroresponsiveness to Merkel cell polyomavirus | journal = PLOS Pathogens | volume = 5 | issue = 9 | pages = e1000578 | date = September 2009 | pmid = 19750217 | pmc = 2734180 | doi = 10.1371/journal.ppat.1000578 | doi-access = free }}{{cite journal | vauthors = Carter JJ, Paulson KG, Wipf GC, Miranda D, Madeleine MM, Johnson LG, Lemos BD, Lee S, Warcola AH, Iyer JG, Nghiem P, Galloway DA | title = Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma | journal = Journal of the National Cancer Institute | volume = 101 | issue = 21 | pages = 1510–22 | date = November 2009 | pmid = 19776382 | pmc = 2773184 | doi = 10.1093/jnci/djp332 }}

The JC virus offers a promising genetic marker for human evolution and migration.{{cite book |author1=Elizabeth Matisoo-Smith |author2=K. Ann Horsburgh |title=DNA for Archaeologists |publisher=Routledge |date=2012 |isbn=978-1598746815}}{{cite journal | vauthors = Sugimoto C, Kitamura T, Guo J, Al-Ahdal MN, Shchelkunov SN, Otova B, Ondrejka P, Chollet JY, El-Safi S, Ettayebi M, Grésenguet G, Kocagöz T, Chaiyarasamee S, Thant KZ, Thein S, Moe K, Kobayashi N, Taguchi F, Yogo Y |title= Typing of urinary JC virus DNA offers a novel means of tracing human migrations |journal= Proc Natl Acad Sci U S A |date=August 19, 1997 | volume = 94| issue =17 |pages=9191–9196|doi=10.1073/pnas.94.17.9191

|pmid=9256458|pmc=23108|doi-access = free|bibcode= 1997PNAS...94.9191S }} It is carried by 70–90 percent of humans and is usually transmitted from parents to offspring. This method does not appear to be reliable for tracing the recent African origin of modern humans.{{citation needed|date=November 2022}}

Murine polyomavirus was the first polyomavirus discovered, having been reported by Ludwik Gross in 1953 as an extract of mouse leukemias capable of inducing parotid gland tumors.{{cite journal | vauthors = Gross L | title = A filterable agent, recovered from Ak leukemic extracts, causing salivary gland carcinomas in C3H mice | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 83 | issue = 2 | pages = 414–21 | date = June 1953 | pmid = 13064287 | doi = 10.3181/00379727-83-20376 | s2cid = 34223353 }} The causative agent was identified as a virus by Sarah Stewart and Bernice Eddy, after whom it was once called "SE polyoma".{{cite journal | vauthors = Stewart SE, Eddy BE, Borgese N | title = Neoplasms in mice inoculated with a tumor agent carried in tissue culture | journal = Journal of the National Cancer Institute | volume = 20 | issue = 6 | pages = 1223–43 | date = June 1958 | pmid = 13549981 | doi=10.1093/jnci/20.6.1223}}{{cite journal | vauthors = Eddy BE, Stewart SE | title = Characteristics of the SE polyoma virus | journal = American Journal of Public Health and the Nation's Health | volume = 49 | issue = 11 | pages = 1486–92 | date = November 1959 | pmid = 13819251 | pmc = 1373056 | doi = 10.2105/AJPH.49.11.1486 }}{{cite journal | vauthors = Schowalter RM, Pastrana DV, Buck CB | title = Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry | journal = PLOS Pathogens | volume = 7 | issue = 7 | pages = e1002161 | date = July 2011 | pmid = 21829355 | doi = 10.1371/journal.ppat.1002161 | pmc=3145800 | doi-access = free }} The term "polyoma" refers to the viruses' ability to produce multiple (poly-) tumors (-oma) under certain conditions. The name has been criticized as a "meatless linguistic sandwich" ("meatless" because both morphemes in "polyoma" are affixes) giving little insight into the viruses' biology; in fact, subsequent research has found that most polyomaviruses rarely cause clinically significant disease in their host organisms under natural conditions.{{cite journal | vauthors = Gottlieb KA, Villarreal LP | title = Natural biology of polyomavirus middle T antigen | journal = Microbiology and Molecular Biology Reviews | volume = 65 | issue = 2 | pages = 288–318; second and third pages, table of contents | date = June 2001 | pmid = 11381103 | pmc = 99028 | doi = 10.1128/mmbr.65.2.288-318.2001 }}

Dozens of polyomaviruses have been identified and sequenced as of 2017, infecting mainly birds and mammals. Two polyomaviruses are known to infect fish, the black sea bass{{cite journal | vauthors = Peretti A, FitzGerald PC, Bliskovsky V, Pastrana DV, Buck CB | title = Genome Sequence of a Fish-Associated Polyomavirus, Black Sea Bass (Centropristis striata) Polyomavirus 1 | journal = Genome Announcements | volume = 3 | issue = 1 | pages = e01476-14 | date = January 2015 | pmid = 25635011 | pmc = 4319505 | doi = 10.1128/genomeA.01476-14 }} and gilthead seabream.{{cite journal | vauthors = López-Bueno A, Mavian C, Labella AM, Castro D, Borrego JJ, Alcami A, Alejo A | title = Concurrence of Iridovirus, Polyomavirus, and a Unique Member of a New Group of Fish Papillomaviruses in Lymphocystis Disease-Affected Gilthead Sea Bream | journal = Journal of Virology | volume = 90 | issue = 19 | pages = 8768–79 | date = October 2016 | pmid = 27440877 | pmc = 5021401 | doi = 10.1128/JVI.01369-16 }} A total of fourteen polyomaviruses are known to infect humans.

{{Reflist|30em}}

• [http://www.ictv.global/report/polyomaviridae ICTV Report: Polyomaviridae]
• [http://www.expasy.org/viralzone/all_by_species/58.html Viralzone: Polyomavirus]
• [http://ictvonline.org/virusTaxonomy.asp ICTV]

{{Baltimore classification}}

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Category:Infectious causes of cancer

Category:Virus families