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The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome

Abstract

Xenotropic murine leukemia virus-related virus (XMRV) is an authentic, newly recognized human retrovirus first identified in prostate cancer tissues from men with a deficiency in the innate immunity gene RNASEL. At present, studies have detected XMRV at widely different rates in prostate cancer cases (0–27%) and in patients with chronic fatigue syndrome (CFS; 0–67%). Indirect or direct modes of carcinogenesis by XMRV have been suggested depending on whether the virus was found in stroma or malignant epithelium. Viral replication in the prostate might be affected by androgens, which stimulate XMRV through a transcriptional enhancer site in viral DNA. By contrast, host restriction factors, such as APOBEC3 and tetherin, inhibit virus replication. Immune dysfunction mediated by XMRV has been suggested as a possible factor in CFS. Recent studies show that some existing antiretroviral drugs suppress XMRV infections and diagnostic assays are under development. Although other retroviruses of the same genus as XMRV (gammaretroviruses) cause cancer and neurological disease in animals, whether XMRV is a cause of either prostate cancer or CFS remains unknown. Emerging science surrounding XMRV is contributing to our knowledge of retroviral infections while focusing intense interest on two major human diseases.

Key Points

  • Infection, inflammation and genetics are all risk factors in prostate cancer development

  • Xenotropic murine leukemia virus-related virus (XMRV) is a newly discovered retrovirus identified in some, but not all, studies of prostate cancer and chronic fatigue syndrome

  • A viral etiology is suspected but not proven for either disease

  • XMRV oncogenesis by insertional activation of host genes followed by androgen stimulation might lead to chronic inflammation and cell transformation in the prostate

  • XMRV could present opportunities for diagnosis, treatment and prevention of these diseases via development of biomarkers, antiretroviral therapies, and vaccines, respectively

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Figure 1: Phylogeny of nucleotide sequences of XMRV with other gammaretroviruses.
Figure 2: Structure of xenotropic murine leukemia virus-related virus.
Figure 3: Potential role of XMRV in prostate cancer and CFS.

References

  1. Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Fan, H. A new human retrovirus associated with prostate cancer. Proc. Natl Acad. Sci. USA 104, 1449–1450 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  4. 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 

  5. Nelson, W. G., De Marzo, A. M. & Isaacs, W. B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).

    CAS  PubMed  Google Scholar 

  6. De Marzo, A. M. et al. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 7, 256–269 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 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).

    CAS  Article  PubMed  Google Scholar 

  8. Dennis, L. K., Lynch, C. F. & Torner, J. C. Epidemiologic association between prostatitis and prostate cancer. Urology 60, 78–83 (2002).

    Article  PubMed  Google Scholar 

  9. Dennis, L. K. & Dawson, D. V. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology 13, 72–79 (2002).

    Article  PubMed  Google Scholar 

  10. Huang, W. Y. et al. Sexually transmissible infections and prostate cancer risk. Cancer Epidemiol. Biomarkers Prev. 17, 2374–2381 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Sutcliffe, S. et al. Sexually transmitted infections and prostatic inflammation/cell damage as measured by serum prostate specific antigen concentration. J. Urol. 175, 1937–1942 (2006).

    Article  PubMed  Google Scholar 

  12. Platz, E. A. & De Marzo, A. M. Epidemiology of inflammation and prostate cancer. J. Urol. 171, S36–S40 (2004).

    Article  PubMed  Google Scholar 

  13. Putzi, M. J. & De Marzo, A. M. Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology 56, 828–832 (2000).

    CAS  Article  PubMed  Google Scholar 

  14. Sfanos, K. S., Wilson, B. A., De Marzo, A. M. & Isaacs, W. B. Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer. Proc. Natl Acad. Sci. USA 106, 3443–3448 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Klein, E. A., Casey, G. & Silverman, R. Genetic susceptibility and oxidative stress in prostate cancer: integrated model with implications for prevention. Urology 68, 1145–1151 (2006).

    Article  PubMed  Google Scholar 

  16. Casey, G. et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat. Genet. 32, 581–583 (2002).

    CAS  Article  PubMed  Google Scholar 

  17. Rennert, H. et al. A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Am. J. Hum. Genet. 71, 981–984 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rokman, A. et al. Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am. J. Hum. Genet. 70, 1299–1304 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Downing, S. R. et al. Mutations in ribonuclease L gene do not occur at a greater frequency in patients with familial prostate cancer compared with patients with sporadic prostate cancer. Clin. Prostate Cancer 2, 177–180 (2003).

    CAS  Article  PubMed  Google Scholar 

  20. Wiklund, F. et al. Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin. Cancer Res. 10, 7150–7156 (2004).

    CAS  Article  PubMed  Google Scholar 

  21. Maier, C. et al. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. Br. J. Cancer 92, 1159–1164 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Li, H. & Tai, B. C. RNASEL gene polymorphisms and the risk of prostate cancer: a meta-analysis. Clin. Cancer Res. 12, 5713–5719 (2006).

    CAS  Article  PubMed  Google Scholar 

  23. Silverman, R. H. Viral encounters with OAS and RNase L during the IFN antiviral response. J. Virol. 81, 12720–12729 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Xiang, Y. et al. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. Cancer Res. 63, 6795–6801 (2003).

    CAS  PubMed  Google Scholar 

  25. Malathi, K., Paranjape, J. M., Ganapathi, R. & Silverman, R. H. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 64, 9144–9151 (2004).

    CAS  Article  PubMed  Google Scholar 

  26. Castelli, J. C. et al. The role of 2'-5' oligoadenylate-activated ribonuclease L in apoptosis. Cell Death Differ. 5, 313–320 (1998).

    CAS  Article  PubMed  Google Scholar 

  27. Wang, D. et al. Microarray-based detection and genotyping of viral pathogens. Proc. Natl Acad. Sci. USA 99, 15687–15692 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Kim, S. et al. Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J. Virol. 82, 9964–9977 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. 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).

    CAS  Article  PubMed  Google Scholar 

  34. Goff, S. in Retroviridae: The Retroviruses and Their Replication Fields Virology 5th edn (eds Knipe, D. & Howley, P. M.) 1999–2069 (Lippincott, Williams & Wilkins, 2007).

    Google Scholar 

  35. Li, W. H., Gu, Z., Wang, H. & Nekrutenko, A. Evolutionary analyses of the human genome. Nature 409, 847–849 (2001).

    CAS  Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  37. Groom, H. C. 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 

  38. Furuta, R. A. The prevalence of xenotropic murine leukemia virus-related virus in healthy blood donors in Japan. Presented at the Cold Spring Harbor Laboratory meeting on retroviruses, 18–23 May, 2009.

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

    CAS  Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  41. Devanur, L. D. & Kerr, J. R. Chronic fatigue syndrome. J. Clin. Virol. 37, 139–150 (2006).

    CAS  Article  PubMed  Google Scholar 

  42. Suhadolnik, R. J. et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J. Interferon Cytokine Res. 17, 377–385 (1997).

    CAS  Article  PubMed  Google Scholar 

  43. Demettre, E. et al. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J. Biol. Chem. 277, 35746–35751 (2002).

    CAS  Article  PubMed  Google Scholar 

  44. Erlwein, O. et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5, e8519 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. van Kuppeveld, F. J. et al. Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 340, c1018 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. McCormick, A. L. et al. Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology 70, 278–283 (2008).

    CAS  Article  PubMed  Google Scholar 

  47. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Coffin, J. M. & Stoye, J. P. Virology. A new virus for old diseases? Science 326, 530–531 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Proietti, F. A., Carneiro-Proietti, A. B., Catalan-Soares, B. C. & Murphy, E. L. Global epidemiology of HTLV-I infection and associated diseases. Oncogene 24, 6058–6068 (2005).

    CAS  Article  PubMed  Google Scholar 

  50. Courouce, A. M., Pillonel, J., Lemaire, J. M., Maniez, M. & Brunet, J. B. Seroepidemiology of HTLV-I/II in universal screening of blood donations in France. Aids 7, 841–847 (1993).

    CAS  Article  PubMed  Google Scholar 

  51. Tlsty, T. D. & Hein, P. W. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr. Opin. Genet. Dev. 11, 54–59 (2001).

    CAS  Article  PubMed  Google Scholar 

  52. Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Kim, S. et al. Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus. PLoS ONE 5, e10255 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Dong, B. & Silverman, R. H. Androgen stimulates transcription and replication of XMRV (xenotropic murine leukemia virus-related virus). J. Virol. 84, 1648–1651 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Rodriguez, J. J. & Goff, S. P. Xenotropic murine leukemia virus-related virus establishes an efficient spreading infection and exhibits enhanced transcriptional activity in prostate carcinoma cells. J. Virol. 84, 2556–2562 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Stieler, K. et al. Host range and cellular tropism of the human exogenous gammaretrovirus XMRV. Virology 399, 23–30 (2010).

    CAS  Article  PubMed  Google Scholar 

  57. Sharma, P. et al. Organ and cell lineage dissemination of XMRV in rhesus macaques during acute and chronic infection. Presented at the 17th Conference on Retroviruses and Opportunistic Infections, 2010.

  58. Mani, R. S. et al. Induced chromosomal proximity and gene fusions in prostate cancer. Science 326, 1230 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Metzger, M. J., Holguin, C. J., Mendoza, R. & Miller, A. D. The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. J. Virol. 84, 1874–1880 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Schlecht-Louf, G. et al. Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proc. Natl Acad. Sci. USA 107, 3782–3787 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Battini, J. L., Rasko, J. E. & Miller, A. D. A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. Proc. Natl Acad. Sci. USA 96, 1385–1390 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Yan, Y., Liu, Q. & Kozak, C. A. Six host range variants of the xenotropic/polytropic gammaretroviruses define determinants for entry in the XPR1 cell surface receptor. Retrovirology 6, 87 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Groom, H. C., Yap, M. W., Galao, R. P., Neil, S. J. & 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Munch, J. et al. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell 131, 1059–1071 (2007).

    Article  PubMed  Google Scholar 

  66. Roan, N. R. et al. The cationic properties of SEVI underlie its ability to enhance HIV infection. J. Virol. 285, 1861–1869 (2008).

    Google Scholar 

  67. Hong, S. et al. Fibrils of prostatic acid phosphatase fragments boost infections by XMRV, a human retrovirus associated with prostate cancer. J. Virol. 83, 6995–7003 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Singh, I., Gorzynski, J. E., Drobrysheva, D., Bassit, L. & Shinazi, R. F. Raltegravir is a potent inhibitor of XMRV, a virus implicated in prostate cancer and chronic fatigue syndrome. PLoS ONE 5, e948 (2010).

    Google Scholar 

  69. Sakuma, R., Sakuma, T., Ohmine, S., Silverman, R. H. & Ikeda, Y. Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology 397, 1–6 (2009).

    Article  PubMed  Google Scholar 

  70. Qui, X. et al. XMRV: examination of viral kinetics, tissue tropism, and serological markers of infection. Presented at the 17th Conference on Retroviruses and Opportunistic Infections, 2010.

  71. Barquinero, J., Eixarch, H. & Perez-Melgosa, M. Retroviral vectors: new applications for an old tool. Gene Ther. 11 (Suppl. 1), S3–S9 (2004).

    CAS  Article  PubMed  Google Scholar 

  72. Dong, B., Silverman, R. H. & Kandel, E. S. A natural human retrovirus efficiently complements vectors based on murine leukemia virus. PLoS ONE 3, e3144 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Stang, A. et al. Unintended spread of a biosafety level 2 recombinant retrovirus. Retrovirology 6, 86 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Denner, J. Detection of a gammaretrovirus, XMRV, in the human population: open questions and implications for xenotransplantation. Retrovirology 7, 16 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Feng, H., Shuda, M., Chang, Y. & Moore, P. S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Cobbs, C. S. et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 62, 3347–3350 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to gratefully acknowledge financial support for our research studies from the NIH (NCI), grant CA103943, US Department of Defense, grant W81XWH-07-1-338, Mal and Lea Bank, the Charlotte Geyer Foundation, the Milton and Tamar Maltz Family Foundation, and Abbott Laboratories.

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Correspondence to Robert H. Silverman.

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All authors hold patents, or have patent applications pending, with Abbott Laboratories. In addition, Robert H. Silverman has been a consultant for, and received grant/research support from, Abbott Laboratories.

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Silverman, R., Nguyen, C., Weight, C. et al. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol 7, 392–402 (2010). https://doi.org/10.1038/nrurol.2010.77

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