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  • Review Article
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A cornucopia of human polyomaviruses

Nature Reviews Microbiology volume 11, pages 264–276 (2013)Cite this article

Subjects

Key Points

  • The recent discovery of nine new human polyomaviruses has reinvigorated the field of polyomavirus research.

  • Integration of the Merkel cell polyomavirus genome into the host cell genome seems to be the major risk factor for the development of Merkel cell carcinoma, a highly lethal cancer.

  • Polyomavirus large and small T antigens bind to and perturb numerous host cell proteins that promote cell cycle entry and viral replication.

  • It seems that polyomaviruses infect humans ubiquitously, and they tend to cause disease in immunosuppressed individuals.

  • The use of different host cell receptors by the different human polyomaviruses seems to dictate the pathology of these viruses.

  • The task is now to more clearly investigate the link between these viruses and both the normal microbiome and disease.

Abstract

During the past 6 years, focused virus hunting has led to the discovery of nine new human polyomaviruses, including Merkel cell polyomavirus, which has been linked to Merkel cell carcinoma, a lethal skin cell cancer. The discovery of so many new and highly divergent human polyomaviruses raises key questions regarding their evolution, tropism, latency, reactivation, immune evasion and contribution to disease. This Review describes the similarities and differences among the new human polyomaviruses and discusses how these viruses might interact with their human host.

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Figure 1: Genomic organization and structure of polyomaviruses.
Figure 2: Phylogenetic tree relating polyomaviruses from human and primate isolates.
Figure 3: The functional domains of polyomavirus large and small T antigens.
Figure 4: Glycan receptors used by polyomaviruses.
Figure 5: Merkel cell polyomavirus and Merkel cell carcinoma.

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References

  1. Johne, R., Enderlein, D., Nieper, H. & Muller, H. Novel polyomavirus detected in the feces of a chimpanzee by nested broad-spectrum PCR. J. Virol. 79, 3883–3887 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Groenewoud, M. J. et al. Characterization of novel polyomaviruses from Bornean and Sumatran orang-utans. J. Gen. Virol. 91, 653–658 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Deuzing, I. et al. Detection and characterization of two chimpanzee polyomavirus genotypes from different subspecies. Virol. J. 7, 347 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Leendertz, F. H. et al. African great apes are naturally infected with polyomaviruses closely related to Merkel cell polyomavirus. J. Virol. 85, 916–924 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Howley, P. M. & Livingston, D. M. Small DNA tumor viruses: large contributors to biomedical sciences. Virology 384, 256–259 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Gardner, S. D., Field, A. M., Coleman, D. V. & Hulme, B. New human papovavirus (BK) isolated from urine after renal transplantation. Lancet 1, 1253–1257 (1971).

    Article  CAS  PubMed  Google Scholar 

  7. Padgett, B. L., Walker, D. L., ZuRhein, G. M., Eckroade, R. J. & Dessel, B. H. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1, 1257–1260 (1971).

    Article  CAS  PubMed  Google Scholar 

  8. Kean, J. M., Rao, S., Wang, M. & Garcea, R. L. Seroepidemiology of human polyomaviruses. PLoS Pathog. 5, e1000363 (2009). The largest seroepidemiological study of the new viruses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walker, D. L. & Padgett, B. L. The epidemiology of human polyomaviruses. Prog. Clin. Biol. Res. 105, 99–106 (1983).

    CAS  PubMed  Google Scholar 

  10. Stolt, A., Sasnauskas, K., Koskela, P., Lehtinen, M. & Dillner, J. Seroepidemiology of the human polyomaviruses. J. Gen. Virol. 84, 1499–1504 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Knowles, W. A. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv. Exp. Med. Biol. 577, 19–45 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Knowles, W. A. et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J. Med. Virol. 71, 115–123 (2003).

    Article  PubMed  Google Scholar 

  13. Egli, A. et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J. Infect. Dis. 199, 837–846 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Ferenczy, M. W. et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin. Microbiol. Rev. 25, 471–506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kuypers, D. R. Management of polyomavirus-associated nephropathy in renal transplant recipients. Nature Rev. Nephrol. 8, 390–402 (2012).

    Article  CAS  Google Scholar 

  16. Allander, T. et al. Identification of a third human polyomavirus. J. Virol. 81, 4130–4136 (2007). The discovery of KIPyV, the first new human polyomavirus to be discovered in 36 years.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gaynor, A. M. et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog. 3, e64 (2007). The discovery of WUPyV by next-generation sequencing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Siebrasse, E. A. et al. Identification of MW polyomavirus, a novel polyomavirus in human stool. J. Virol. 86, 10321–10326 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lim, E. S. et al. Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing. Virology 436, 295–303 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Haycox, C. L. et al. Trichodysplasia spinulosa–a newly described folliculocentric viral infection in an immunocompromised host. J. Investig. Dermatol. Symp. Proc. 4, 268–271 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. van der Meijden, E. et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog. 6, e1001024 (2010). The discovery of TSPyV using rolling-circle amplification to identify a virus that had been detected by electron microscopy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Feng, H., Shuda, M., Chang, Y. & Moore, P. S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008). The discovery of MCPyV as a result of the recognition that MCC occurs more frequently in immunocompromised patients than in non-immunocompromised individuals. Southern blotting also demonstrates the clonal integration of MCPyV in tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schowalter, R. M., Pastrana, D. V., Pumphrey, K. A., Moyer, A. L. & Buck, C. B. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7, 509–515 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Scuda, N. et al. A novel human polyomavirus closely related to the African green monkey-derived lymphotropic polyomavirus. J. Virol. 85, 4586–4590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reyes, A., Semenkovich, N. P., Whiteson, K., Rohwer, F. & Gordon, J. I. Going viral: next-generation sequencing applied to phage populations in the human gut. Nature Rev. Microbiol. 10, 607–617 (2012).

    Article  CAS  Google Scholar 

  26. Rector, A., Tachezy, R. & Van Ranst, M. A sequence-independent strategy for detection and cloning of circular DNA virus genomes by using multiply primed rolling-circle amplification. J. Virol. 78, 4993–4998 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sauvage, V. et al. Human polyomavirus related to African green monkey lymphotropic polyomavirus. Emerg. Infect. Dis. 17, 1364–1370 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu, G. et al. Discovery of a novel polyomavirus in acute diarrheal samples from children. PLoS ONE 7, e49449 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Buck, C. B. et al. Complete genome sequence of a tenth human polyomavirus. J. Virol. 86, 10887 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Johne, R. et al. Taxonomical developments in the family Polyomaviridae. Arch. Virol. 156, 1627–1634 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Pastrana, D. V. et al. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog. 5, e1000578 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Viscidi, R. P. et al. Age-specific seroprevalence of Merkel cell polyomavirus, BK virus, and JC virus. Clin. Vaccine Immunol. 18, 1737–1743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nguyen, N. L., Le, B. M. & Wang, D. Serologic evidence of frequent human infection with WU and KI polyomaviruses. Emerg. Infect. Dis. 15, 1199–1205 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gorelik, L., Goelz, S. & Sandrock, A. W. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N. Engl. J. Med. 361, 2487–2488; author reply 2489–2490 (2009). The worrisome reactivation of JCPyV in patients treated with immunomodulatory therapies.

    Article  PubMed  Google Scholar 

  35. Feltkamp, M. C., Kazem, S., van der Meijden, E., Lauber, C. & Gorbalenya, A. E. From Stockholm to Malawi: recent developments in studying human polyomaviruses. J. Gen. Virol. 94, 482–496 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Dalianis, T. & Garcea, R. L. Welcome to the Polyomaviridae. Semin. Cancer Biol. 19, 209–210 (2009).

    Article  PubMed  Google Scholar 

  37. Jiang, M., Abend, J. R., Johnson, S. F. & Imperiale, M. J. The role of polyomaviruses in human disease. Virology 384, 266–273 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Tooze, J. & Acheson, N. H. DNA Tumor Viruses (Cold Spring Harbor Laboratory, 1981).

  39. Shuda, M. et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc. Natl Acad. Sci. USA 105, 16272–16277 (2008). Mutations in MCPyV large T antigen, found in MCC, disable the ability of the virus to replicate viral origin-containing DNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cheng, J., DeCaprio, J. A., Fluck, M. M. & Schaffhausen, B. S. Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens. Semin. Cancer Biol. 19, 218–228 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Raghava, S., Giorda, K. M., Romano, F. B., Heuck, A. P. & Hebert, D. N. The SV40 late protein VP4 is a viroporin that forms pores to disrupt membranes for viral release. PLoS Pathog. 7, e1002116 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rozenblatt-Rosen, O. et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487, 491–495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Krumbholz, A., Bininda-Emonds, O. R., Wutzler, P. & Zell, R. Phylogenetics, evolution, and medical importance of polyomaviruses. Infect. Genet. Evol. 9, 784–799 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Perez-Losada, M. et al. Comparing phylogenetic codivergence between polyomaviruses and their hosts. J. Virol. 80, 5663–5669 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Warden, C. D. & Lacey, S. F. Updated phylogenetic analysis of polyomavirus-host co-evolution. J. Bioinfo. Res. 1, 46–49 (2012).

    Google Scholar 

  46. Campbell, K. S. et al. DnaJ/hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication. Genes Dev. 11, 1098–1110 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. DeCaprio, J. A. et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54, 275–283 (1988).

    Article  CAS  PubMed  Google Scholar 

  48. Stubdal, H. et al. Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen. Mol. Cell. Biol. 17, 4979–4990 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu, X. et al. Merkel cell polyomavirus large T antigen disrupts lysosome clustering by translocating human Vam6p from the cytoplasm to the nucleus. J. Biol. Chem. 286, 17079–17090 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sowd, G. A. & Fanning, E. A wolf in sheep's clothing: SV40 co-opts host genome maintenance proteins to replicate viral DNA. PLoS Pathog. 8, e1002994 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yardimci, H. et al. Bypass of a protein barrier by a replicative DNA helicase. Nature 492, 205–209 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lilyestrom, W., Klein, M. G., Zhang, R., Joachimiak, A. & Chen, X. S. Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor. Genes Dev. 20, 2373–2382 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Welcker, M. & Clurman, B. E. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J. Biol. Chem. 280, 7654–7658 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Fine, D. A. et al. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. PLoS Pathog. 8, e1002949 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pallas, D. C. et al. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60, 167–176 (1990).

    Article  CAS  PubMed  Google Scholar 

  56. Pallas, D. C. et al. The third subunit of protein phosphatase 2A (PP2A), a 55-kilodalton protein which is apparently substituted for by T antigens in complexes with the 36- and 63-kilodalton PP2A subunits, bears little resemblance to T antigens. J. Virol. 66, 886–893 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shuda, M., Kwun, H. J., Feng, H., Chang, Y. & Moore, P. S. Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J. Clin. Invest. 121, 3623–3634 (2011). The finding that MCPyV small T antigen is expressed in most MCCs, is oncogenic and can promote phosphorylation of 4EBP1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Seo, G. J., Fink, L. H., O'Hara, B., Atwood, W. J. & Sullivan, C. S. Evolutionarily conserved function of a viral microRNA. J. Virol. 82, 9823–9828 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Seo, G. J., Chen, C. J. & Sullivan, C. S. Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression. Virology 383, 183–187 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Lee, S. et al. Identification and validation of a novel mature microRNA encoded by the Merkel cell polyomavirus in human Merkel cell carcinomas. J. Clin. Virol. 52, 272–275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sullivan, C. S., Grundhoff, A. T., Tevethia, S., Pipas, J. M. & Ganem, D. SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 435, 682–686 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Bauman, Y. et al. An identical miRNA of the human JC and BK polyoma viruses targets the stress-induced ligand ULBP3 to escape immune elimination. Cell Host Microbe 9, 93–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Salunke, D. M., Caspar, D. L. D. & Garcea, R. L. Self-assembly of purified polyomavirus capsid protein VP1. Cell 46, 895–904 (1986).

    Article  CAS  PubMed  Google Scholar 

  64. Montross, L. et al. Nuclear assembly of polyomavirus capsids in insect cells expressing the major capsid protein VP1. J. Virol. 65, 4991–4998 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cole, C. N., Landers, T., Goff, S. P., Manteuil-Brutlag, S. & Berg, P. Physical and genetic characterization of deletion mutants of simian virus 40 constructed in vitro. J. Virol. 24, 277–294 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Giorda, K. M., Raghava, S. & Hebert, D. N. The Simian virus 40 late viral protein VP4 disrupts the nuclear envelope for viral release. J. Virol. 86, 3180–3192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Neu, U., Stehle, T. & Atwood, W. J. The Polyomaviridae: contributions of virus structure to our understanding of virus receptors and infectious entry. Virology 384, 389–399 (2009). An excellent review of the polyomavirus receptors.

    Article  CAS  PubMed  Google Scholar 

  68. Neu, U. et al. Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif. Cell Host Microbe 8, 309–319 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Erickson, K. D., Garcea, R. L. & Tsai, B. Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus. J. Virol. 83, 10275–10279 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Stehle, T. & Harrison, S. C. High-resolution structure of a polyomavirus VP1-oligosaccharide complex: implications for assembly and receptor binding. EMBO J. 16, 5139–5148 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stehle, T., Yan, Y., Benjamin, T. L. & Harrison, S. C. Structure of murine polyomavirus complexed with an oligosaccharide receptor fragment. Nature 369, 160–163 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Neu, U., Wang, J., Macejak, D., Garcea, R. L. & Stehle, T. Structures of the major capsid proteins of the human Karolinska Institutet and Washington University polyomaviruses. J. Virol. 85, 7384–7392 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Neu, U. et al. Structures of Merkel cell polyomavirus VP1 complexes define a sialic acid binding site required for infection. PLoS Pathog. 8, e1002738 (2012). The latest data on structural differences in the VP1 proteins of the new human polyomaviruses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Magaldi, T. G. et al. Mutations in the GM1 binding site of simian virus 40 VP1 alter receptor usage and cell tropism. J. Virol. 86, 7028–7042 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schowalter, R. M., Reinhold, W. C. & Buck, C. B. Entry tropism of BK and Merkel cell polyomaviruses in cell culture. PLoS ONE 7, e42181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gorelik, L. et al. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J. Infect. Dis. 204, 103–114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reid, C. E. et al. Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients. J. Infect. Dis. 204, 237–244 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sunyaev, S. R., Lugovskoy, A., Simon, K. & Gorelik, L. Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML). PLoS Genet. 5, e1000368 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dang, X., Wuthrich, C., Gordon, J., Sawa, H. & Koralnik, I. J. JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant. PLoS ONE 7, e35793 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Major, E. O., Amemiya, K., Tornatore, C. S., Houff, S. A. & Berger, J. R. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin. Microbiol. Rev. 5, 49–73 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Pfister, L. A., Letvin, N. L. & Koralnik, I. J. JC virus regulatory region tandem repeats in plasma and central nervous system isolates correlate with poor clinical outcome in patients with progressive multifocal leukoencephalopathy. J. Virol. 75, 5672–5676 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gosert, R. et al. Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology. J. Exp. Med. 205, 841–852 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pastrana, D. V. et al. Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. PLoS Pathog. 8, e1002650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Freund, R., Garcea, R. L., Sahli, R. & Benjamin, T. L. A single-amino-acid substitution in polyomavirus VP1 correlates with plaque size and hemagglutination behavior. J. Virol. 65, 350–355 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Bauer, P. H. et al. Genetic and structural analysis of a virulence determinant in polyomavirus VP1. J. Virol. 69, 7925–7931 (1995). The demonstration that MPyV spread in the host is dependent on receptor usage.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Bauer, P. H. et al. Discrimination between sialic acid-containing receptors and pseudoreceptors regulates polyomavirus spread in the mouse. J. Virol. 73, 5826–5832 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Giroglou, T., Florin, L., Schafer, F., Streeck, R. E. & Sapp, M. Human papillomavirus infection requires cell surface heparan sulfate. J. Virol. 75, 1565–1570 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Johnson, K. M. et al. Role of heparan sulfate in attachment to and infection of the murine female genital tract by human papillomavirus. J. Virol. 83, 2067–2074 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Buck, C. B., Pastrana, D. V., Lowy, D. R. & Schiller, J. T. Generation of HPV pseudovirions using transfection and their use in neutralization assays. Methods Mol. Med. 119, 445–462 (2005).

    CAS  PubMed  Google Scholar 

  90. Schowalter, R. M., Pastrana, D. V. & Buck, C. B. Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry. PLoS Pathog. 7, e1002161 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Broekema, N. M. & Imperiale, M. J. Efficient propagation of archetype BK and JC polyomaviruses. Virology 422, 235–241 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Dalianis, T., Ramqvist, T., Andreasson, K., Kean, J. M. & Garcea, R. L. K. I. WU and Merkel cell polyomaviruses: a new era for human polyomavirus research. Semin. Cancer Biol. 19, 270–275 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Bialasiewicz, S. et al. Presence of the newly discovered human polyomaviruses KI and WU in Australian patients with acute respiratory tract infection. J. Clin. Virol. 41, 63–68 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bialasiewicz, S., Whiley, D. M., Lambert, S. B., Nissen, M. D. & Sloots, T. P. Detection of BK, JC, WU, or KI polyomaviruses in faecal, urine, blood, cerebrospinal fluid and respiratory samples. J. Clin. Virol. 45, 249–254 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Han, T. H., Chung, J. Y., Koo, J. W., Kim, S. W. & Hwang, E. S. WU polyomavirus in children with acute lower respiratory tract infections, South Korea. Emerg. Infect. Dis. 13, 1766–1768 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Neske, F. et al. WU polyomavirus infection in children, Germany. Emerg. Infect. Dis. 14, 680–681 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ren, L. et al. WU polyomavirus in fecal specimens of children with acute gastroenteritis, China. Emerg. Infect. Dis. 15, 134–135 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Le, B. M. et al. Clinical and epidemiologic characterization of WU polyomavirus infection, St. Louis, Missouri. Emerg. Infect. Dis. 13, 1936–1938 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Wattier, R. L. et al. Role of human polyomaviruses in respiratory tract disease in young children. Emerg. Infect. Dis. 14, 1766–1768 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rao, S., Garcea, R. L., Robinson, C. C. & Simoes, E. A. WU and KI polyomavirus infections in pediatric hematology/oncology patients with acute respiratory tract illness. J. Clin. Virol. 52, 28–32 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Debiaggi, M. et al. Molecular epidemiology of KI and WU polyomaviruses in infants with acute respiratory disease and in adult hematopoietic stem cell transplant recipients. J. Med. Virol. 82, 153–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Dang, X. et al. Infrequent detection of KI, WU and MC polyomaviruses in immunosuppressed individuals with or without progressive multifocal leukoencephalopathy. PLoS ONE 6, e16736 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mourez, T. et al. Polyomaviruses KI and WU in immunocompromised patients with respiratory disease. Emerg. Infect. Dis. 15, 107–109 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Tolstov, Y. L. et al. Asymptomatic primary Merkel cell polyomavirus infection among adults. Emerg. Infect. Dis. 17, 1371–1380 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Norja, P., Ubillos, I., Templeton, K. & Simmonds, P. No evidence for an association between infections with WU and KI polyomaviruses and respiratory disease. J. Clin. Virol. 40, 307–311 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Payungporn, S. et al. Prevalence and molecular characterization of WU/KI polyomaviruses isolated from pediatric patients with respiratory disease in Thailand. Virus Res. 135, 230–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Toker, C. Trabecular carcinoma of the skin. Arch. Dermatol. 105, 107–110 (1972).

    Article  CAS  PubMed  Google Scholar 

  108. Koljonen, V. et al. Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. Br. J. Cancer 101, 1444–1447 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. de Giorgi, V., Benemei, S., Grazzini, M., Lotti, T. & Geppetti, P. Rapid growth of Merkel cell carcinoma during etanercept treatment of psoriatic arthritis: cause or coincidence? Acta Derm. Venereol. 91, 354–355 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Paulson, K. G., Iyer, J. G. & Nghiem, P. Asymmetric lateral distribution of melanoma and Merkel cell carcinoma in the United States. J. Am. Acad. Dermatol. 65, 35–39 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ohnishi, Y. et al. Merkel cell carcinoma and multiple Bowen's disease: incidental association or possible relationship to inorganic arsenic exposure? J. Dermatol. 24, 310–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Sahi, H. et al. Increased incidence of Merkel cell carcinoma among younger statin users. Cancer Epidemiol. 36, 421–424 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Rodig, S. J. et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J. Clin. Invest. 122, 4645–4653 (2012). This study raises the possibility that all MCCs contain MCPyV.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schmitt, M., Wieland, U., Kreuter, A. & Pawlita, M. C-terminal deletions of Merkel cell polyomavirus large T-antigen, a highly specific surrogate marker for virally induced malignancy. Int. J. Cancer 131, 2863–2868 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Kraus, I. et al. The majority of viral-cellular fusion transcripts in cervical carcinomas cotranscribe cellular sequences of known or predicted genes. Cancer Res. 68, 2514–2522 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Duncavage, E. J. et al. Hybrid capture and next-generation sequencing identify viral integration sites from formalin-fixed, paraffin-embedded tissue. J. Mol. Diagn. 13, 325–333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shuda, M. et al. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int. J. Cancer 125, 1243–1249 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bhatia, K., Goedert, J. J., Modali, R., Preiss, L. & Ayers, L. W. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int. J. Cancer 126, 2240–2246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Houben, R. et al. An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int. J. Cancer 130, 847–856 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Arora, R. et al. Survivin is a therapeutic target in Merkel cell carcinoma. Sci. Transl. Med. 4, 133ra56 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Busam, K. J. et al. Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am. J. Surg. Pathol. 33, 1378–1385 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Schrama, D. et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J. Invest. Dermatol. 131, 1631–1638 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Paik, J. Y. et al. Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population. Hum. Pathol. 42, 1385–1390 (2011).

    Article  PubMed  Google Scholar 

  124. Sihto, H. et al. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma. Clin. Cancer Res. 17, 4806–4813 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Hafner, C. et al. Activation of the PI3K/AKT pathway in Merkel cell carcinoma. PLoS ONE 7, e31255 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nardi, V. et al. Activation of PI3K signaling in Merkel cell carcinoma. Clin. Cancer Res. 18, 1227–1236 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lill, C. et al. P53 mutation is a rare event in Merkel cell carcinoma of the head and neck. Eur. Arch. Otorhinolaryngol. 268, 1639–1646 (2011).

    Article  PubMed  Google Scholar 

  128. Waltari, M. et al. Association of Merkel cell polyomavirus infection with tumor p53, KIT, stem cell factor, PDGFR-alpha and survival in Merkel cell carcinoma. Int. J. Cancer 129, 619–628 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Asioli, S., Righi, A., Volante, M., Eusebi, V. & Bussolati, G. p63 expression as a new prognostic marker in Merkel cell carcinoma. Cancer 110, 640–647 (2007).

    Article  PubMed  Google Scholar 

  130. Asioli, S. et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas. Mod. Pathol. 24, 1451–1461 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Hall, B. J. et al. Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome. J. Cutan. Pathol. 39, 911–917 (2012).

    Article  PubMed  Google Scholar 

  132. Lim, C. S. et al. Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma. Ann. Surg. Oncol. 19, 3325–3334 (2012).

    Article  PubMed  Google Scholar 

  133. Higaki-Mori, H. et al. Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma. Hum. Pathol. 43, 2282–2291 (2012).

    Article  PubMed  Google Scholar 

  134. Paulson, K. G. et al. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients. Cancer Res. 70, 8388–8397 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Iyer, J. G. et al. Merkel cell polyomavirus-specific CD8+ and CD4+ T-cell responses identified in Merkel cell carcinomas and blood. Clin. Cancer Res. 17, 6671–6680 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Paulson, K. G. et al. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J. Clin. Oncol. 29, 1539–1546 (2011). This study shows that patients with MCC who have a strong immune response have an improved prognosis compared with immunocompromised patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Tolstov, Y. L. et al. Lack of evidence for direct involvement of Merkel cell polyomavirus (MCV) in chronic lymphocytic leukemia (CLL). Blood 115, 4973–4974 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Reisinger, D. M. et al. Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma. J. Am. Acad. Dermatol. 63, 400–403 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Rollison, D. E. et al. Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 21, 74–81 (2012).

    Article  PubMed  Google Scholar 

  140. Abend, J. R., Jiang, M. & Imperiale, M. J. BK virus and human cancer: innocent until proven guilty. Semin. Cancer Biol. 19, 252–260 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Pino, L. et al. Bladder transitional cell carcinoma and BK virus in a young kidney transplant recipient. Transpl. Infect. Dis. 15, e25–e27 (2012).

    Article  PubMed  Google Scholar 

  142. Vilkin, A. et al. Presence of JC virus DNA in the tumor tissue and normal mucosa of patients with sporadic colorectal cancer (CRC) or with positive family history and Bethesda criteria. Dig. Dis. Sci. 57, 79–84 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Garcea, R. L. & Imperiale, M. J. Simian virus 40 infection of humans. J. Virol. 77, 5039–5045 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Poulin, D. L. & DeCaprio, J. A. Is there a role for SV40 in human cancer? J. Clin. Oncol. 24, 4356–4365 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Dela Cruz, F. N. Jr et al. Novel polyomavirus associated with brain tumors in free-ranging Raccoons, Western United States. Emerg. Infect. Dis. 19, 77–84 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Swanson, P. A., Lukacher, A. E. & Szomolanyi-Tsuda, E. Immunity to polyomvirus infection: the polyomavirus–mouse model. Semin. Cancer Biol. 19, 244–251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. zur Hausen, H. & Gissmann, L. Lymphotropic papovaviruses isolated from African green monkey and human cells. Med. Microbiol. Immunol. 167, 137–153 (1979).

    Article  CAS  PubMed  Google Scholar 

  148. Kanda, T. & Takemoto, K. K. Monkey B-lymphotropic papovavirus mutant capable of replicating in T-lymphoblastoid cells. J. Virol. 55, 96–100 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Woolford, L. et al. A novel virus detected in papillomas and carcinomas of the endangered western barred bandicoot (Perameles bougainville) exhibits genomic features of both the Papillomaviridae and Polyomaviridae. J. Virol. 81, 13280–13290 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sehr, P., Zumbach, K. & Pawlita, M. A generic capture ELISA for recombinant proteins fused to glutathione S-transferase: validation for HPV serology. J. Immunol. Methods 253, 153–162 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Viscidi, R. P. & Clayman, B. Serological cross reactivity between polyomavirus capsids. Adv. Exp. Med. Biol. 577, 73–84 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Randhawa, P. et al. Identification of species-specific and cross-reactive epitopes in human polyomavirus capsids using monoclonal antibodies. J. Gen. Virol. 90, 634–639 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Waterboer, T. et al. Multiplex human papillomavirus serology based on in situ-purified glutathione S-transferase fusion proteins. Clin. Chem. 51, 1845–1853 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Edgar, R. C. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5, 113 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nature Methods 7, 335–336 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Price, M. N., Dehal, P. S. & Arkin, A. P. FastTree 2 – approximately maximum-likelihood trees for large alignments. PLoS ONE 5, e9490 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Carter, J. J. et al. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J. Natl Cancer Inst. 101, 1510–1522 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gorelik, L. et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann. Neurol. 68, 295–303 (2010).

    Article  PubMed  Google Scholar 

  159. Faust, H., Pastrana, D. V., Buck, C. B., Dillner, J. & Ekstrom, J. Antibodies to Merkel cell polyomavirus correlate to presence of viral DNA in the skin. J. Infect. Dis. 203, 1096–1100 (2011).

    Article  CAS  PubMed  Google Scholar 

  160. van der Meijden, E. et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg. Infect. Dis. 17, 1355–1363 (2011).

    PubMed  PubMed Central  Google Scholar 

  161. Nicol, J. T. et al. Seroprevalence and cross-reactivity of human polyomavirus 9. Emerg. Infect. Dis. 18, 1329–1332 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Trusch, F. et al. Seroprevalence of human polyomavirus 9 and cross-reactivity to African green monkey-derived lymphotropic polyomavirus. J. Gen. Virol. 93, 698–705 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by US Public Health Service grants P01CA050661, RO1CA93804 and R01CA63113 to J.A.D. and RO1CA37667 to R.L.G. The authors thank D. McDonald for assistance with the bioinformatics.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; and Department of Medicine, Harvard Medical School,

    James A. DeCaprio

  2. Department of Medicine, Brigham and Women's Hospital, 450 Brookline Avenue, Mayer 440, Boston, 02215, Massachusetts, USA

    James A. DeCaprio

  3. Department of Molecular, Cellular, & Developmental Biology, and The Biofrontiers Institute, University of Colorado at Boulder, Jennie Smoly Caruthers Biotechnology Building, Room D212, Campus Box 596, Boulder, 80309-0596, Colorado, USA

    Robert L. Garcea

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DeCaprio, J., Garcea, R. A cornucopia of human polyomaviruses. Nat Rev Microbiol 11, 264–276 (2013). https://doi.org/10.1038/nrmicro2992

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