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XMRV and prostate cancer—a 'final' perspective

Nature Reviews Urology volume 9, pages 111–118 (2012)Cite this article

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Abstract

XMRV was first described in 2006, when it was identified in samples isolated from prostate cancer tissues. However, studies have since shown that XMRV arose in the laboratory and was formed by genetic recombination between two viral genomes carried in the germline DNA of mice used during serial transplantation of the CWR22 prostate cancer xenograft. These new findings strongly imply that XMRV does not circulate in humans, but is only present in the laboratory. Thus, there is no reason to believe that it has any role in the etiology of prostate cancer or other diseases.

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Figure 1: Timeline of key studies and events in the XMRV controversy.
Figure 2: The recombinant origin of XMRV.

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References

  1. Voisset, C., Weiss, R. A. & Griffiths, D. J. Human RNA “rumor” viruses: the search for novel human retroviruses in chronic disease. Microbiol. Mol. Biol. Rev. 72, 157–196 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Weiss, R. A cautionary tale of virus and disease. BMC Biol. 8, 124 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Urisman, A. et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2, e25 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Carpten, J. et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat. Genet. 30, 181–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Dong, B. et al. An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proc. Natl Acad. Sci. USA 104, 1655–1660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ruscetti, S. K. Deregulation of erythropoiesis by the Friend spleen focus-forming virus. Int. J. Biochem. Cell Biol. 31, 1089–1109 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Pandhare-Dash, J., Mantri, C. K., Gong, Y., Chen, Z. & Dash, C. XMRV accelerates cellular proliferation, transformational activity, and invasiveness of prostate cancer cells by downregulating p27Kip1. Prostate doi:10.1002/pros.21491.

    Article  PubMed  Google Scholar 

  8. Schlaberg, R., Choe, D. J., Brown, K. R., Thaker, H. M. & Singh, I. R. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors Proc. Natl Acad. Sci. USA 106, 16351–16356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Arnold, R. S. et al. XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. Urology 75, 755–761 (2010).

    Article  PubMed  Google Scholar 

  10. Danielson, B. P., Ayala, G. E. & Kimata, J. T. Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the Southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. J. Infect. Dis. 202, 1470–1477 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Onlamoon, N. et al. Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J. Virol. 85, 4547–4557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sfanos, K. S. et al. A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms. Prostate 68, 306–320 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Fischer, N. et al. Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J. Clin. Virol. 43, 277–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. D'Arcy, F. et al. No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation. Eur. Urol. Suppl. 7, 271 (2008).

    Article  Google Scholar 

  15. Hohn, O. et al. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology 6, 92 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sakuma, T. et al. No evidence of XMRV in prostate cancer cohorts in the Midwestern United States. Retrovirology 8, 23 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Switzer, W. M., Jia, H., Zheng, H., Tang, S. & Heneine, W. No association of xenotropic murine leukemia virus-related viruses with prostate cancer. PLoS ONE 6, e19065 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aloia, A. L. et al. XMRV: a new virus in prostate cancer? Cancer Res. 70, 10028–10033 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martinez-Fierro, M. L. et al. Identification of viral infections in the prostate and evaluation of their association with cancer. BMC Cancer 10, 326 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Verhaegh, G. W. et al. Prevalence of human xenotropic murine leukemia virus-related gammaretrovirus (XMRV) in Dutch prostate cancer patients. Prostate 71, 415–420 (2011).

    Article  PubMed  Google Scholar 

  21. Furuta, R. et al. No association of xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in Japan. Retrovirology 8, 20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stieler, K. et al. No detection of XMRV in blood samples and tissue sections from prostate cancer patients in Northern Europe. PLoS ONE 6, e25592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Robinson, M. J. et al. No evidence of XMRV or MuLV sequences in prostate cancer, diffuse large B-Cell lymphoma, or the UK blood donor population. Adv. Virol. doi:10.1155/2012/782353.

  24. Waugh, E. M. et al. The retrovirus XMRV is not directly involved in the pathogenesis of common types of lymphoid malignancy. Cancer Epidemiol. Biomarkers Prev. 20, 2232–2236 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Balada, E., Castro-Marrero, J., Felip, L., Vilardell-Tarres, M. & Ordi-Ros, J. Xenotropic murine leukemia virus-related virus (XMRV) in patients with systemic lupus erythematosus. J. Clin. Immunol. 31, 584–587 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Lintas, C. et al. Lack of infection with XMRV or other MLV-related viruses in blood, post-mortem brains and paternal gametes of autistic individuals. PLoS ONE 6, e16609 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gray, E. R. et al. No evidence of XMRV or related retroviruses in a London HIV-1-positive patient cohort. PLoS ONE 6, e18096 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Barnes, E. et al. Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections. J. Infect. Dis. 202, 1482–1485 (2011).

    Article  Google Scholar 

  29. Tang, S. et al. Absence of detectable xenotropic murine leukemia virus-related virus in plasma or peripheral blood mononuclear cells of human immunodeficiency virus Type 1-infected blood donors or individuals in Africa. Transfusion 51, 463–468 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Maggi, F. et al. Xenotropic murine leukaemia virus-related virus is not found in peripheral blood cells from treatment-naive human immunodeficiency virus-positive patients. Clin. Microbiol. Infect. doi:10.1111/j.1469-0691.2011.03580.x.

    Article  CAS  PubMed  Google Scholar 

  31. Schmitt, M., Hofler, D., Koleganova, N. & Pawlita, M. Human polyomaviruses and other human viruses in neuroendocrine tumors. Cancer Epidemiol. Biomarkers Prev. 20, 1558–1561 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Cornelissen, M. et al. Lack of detection of XMRV in seminal plasma from HIV-1 infected men in The Netherlands. PLoS ONE 5, e12040 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jeziorski, E. et al. No evidence for XMRV association in pediatric idiopathic diseases in France. Retrovirology 7, 63 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Satterfield, B. C., Garcia, R. A., Gurrieri, F. & Schwartz, C. E. PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism. Mol. Autism 1, 14 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. McCormick, A. L., Brown, R. H., Cudkowicz, M. E., Al-Chalabi, A. & Garson, J. A. Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology 70, 278–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Lombardi, V. C. et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326, 585–589 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Erlwein, O. et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5, e8519 (2011).

    Article  Google Scholar 

  38. Groom, H. et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 7, 10 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lo, S.-C. et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc. Natl Acad. Sci. USA 107, 15874–15879 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hue, S. et al. Disease-associated XMRV sequences are consistent with laboratory contamination. Retrovirology 7, 111 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oakes, B. et al. Contamination of human DNA samples with mouse DNA can lead to false detection of XMRV-like sequences. Retrovirology 7, 109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Robinson, M. J. et al. Mouse DNA contamination in human tissue tested for XMRV. Retrovirology 7, 108 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sato, E., Furuta, R. A. & Miyazawa, T. An endogenous murine leukemia viral genome contaminant in a commercial RT-PCR kit is amplified using standard primers for XMRV. Retrovirology 7, 110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tuke, P. W., Tettmar, K. I., Tamuri, A., Stoye, J. P. & Tedder, R. S. PCR master mixes harbour murine DNA sequences. Caveat emptor! PLoS ONE 6, e19953 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Erlwein, O. et al. DNA extraction columns contaminated with murine sequences. PLoS ONE 6, e23484 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Simmons, G. et al. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: A multi-laboratory study. Science 334, 814–817 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bubbers, J. E. & Lilly, F. Selective incorporation of H-2 antigenic determinants into Friend virus particles. Nature 266, 458–459 (1977).

    Article  CAS  PubMed  Google Scholar 

  48. Ott, D. E. Cellular proteins detected in HIV-1. Rev. Med. Virol. 18, 159–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Paprotka, T. et al. Recombinant origin of the retrovirus XMRV. Science 333, 97–101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Paine, E., Garcia, J., Philpott, T. C., Shaw, G. & Ratner, L. Limited sequence variation in human T-lymphotropic virus type 1 isolates from North American and African patients. Virology 182, 111–123 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Overbaugh, J. & Bangham, C. R. Selection forces and constraints on retroviral sequence variation. Science 292, 1106–1109 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Knouf, E. C. et al. Multiple integrated copies and high-level production of the human retrovirus XMRV (xenotropic murine leukemia virus-related virus) from 22Rv1 prostate carcinoma cells. J. Virol. 83, 7353–7356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Todaro, G. J., Arnstein, P., Parks, W. P., Lennette, E. H. & Huebner, R. J. A Type-C virus in human rhabdomyosarcoma cells after inoculation into NIH swiss mice treated with antithymocyte serum. Proc. Natl Acad. Sci. USA 70, 859–862 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sfanos, K. S. et al. Identification of replication competent murine gammaretroviruses in commonly used prostate cancer cell lines. PLoS ONE 6, e20874 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhuang, J., Mukherjee, S., Ron, Y. & Dougherty, J. P. High rate of genetic recombination in murine leukemia virus: Implications for influencing proviral ploidy. J. Virol. 80, 6706–6711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Knox, K. et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science 333, 94–97 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Alberts, B. Editorial expression of concern. Science 333, 35 (2011).

    Article  PubMed  Google Scholar 

  58. Silverman, R. H. et al. Partial retraction. Science 334, 176 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Garson, J. A., Kellam, P. & Towers, G. J. Analysis of XMRV integration sites from human prostate cancer tissues suggests PCR contamination rather than genuine human infection. Retrovirology 8, 13 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rusmevichientong, A., Das Gupta, J., Elias, P. S., Silverman, R. H. & Chow, S. A. Analysis of single nucleotide polymorphisms in XMRV patient-derived integration sites reveals contamination from cell lines acutely infected by XMRV. J. Virol. 85, 12830–12834 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Groom, H. C. T., Yap, M. W., Galao, R. P., Neil, S. J. D. & Bishop, K. N. Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors. Proc. Natl Acad. Sci. USA 107, 5166–5171 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stieler, K. & Fischer, N. Apobec 3G efficiently reduces infectivity of the human exogenous gammaretrovirus XMRV. PLoS ONE 5, e11738 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Paprotka, T. et al. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J. Virol. 84, 5719–5729 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cohen, J. More negative data for link between mouse virus and human disease. Science 331, 1253–1254 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Coffin, J. M., Hughes, S. H. & Varmus, H. E. (eds) Retroviruses (Cold Spring Harbor Laboratory Press, Plainview, 1997).

    Google Scholar 

  66. Rein, A. Murine leukemia viruses: objects and organisms. Adv. Virol. doi:10.1155/2011/403419.

    Article  Google Scholar 

  67. Cingöz, O. & Coffin, J. M. Endogenous murine leukemia viruses: relationship to XMRV and related sequences detected in human DNA samples. Adv. Virol. doi:10.1155/2011/940210.

    Article  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Dr Saraswati Sukumar for helpful discussions. Research by A. Aloia and A. Rein is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Karen S. Sfanos

  2. HIV Drug Resistance Program, National Cancer Institute, Building 535, Room 211, 1050 Boyles Street, Frederick, 21702-1201, MD, USA

    Amanda L. Aloia & Alan Rein

  3. The Brady Urological Research Institute and The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, 21231, MD, USA

    Angelo M. De Marzo

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All authors researched data for the article, made substantial contributions to discussions of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Karen S. Sfanos.

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Sfanos, K., Aloia, A., De Marzo, A. et al. XMRV and prostate cancer—a 'final' perspective. Nat Rev Urol 9, 111–118 (2012). https://doi.org/10.1038/nrurol.2011.225

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