Immunologic Research

, Volume 48, Issue 1–3, pp 27–39 | Cite as

Biology and pathophysiology of the new human retrovirus XMRV and its association with human disease

Article

Abstract

Xenotropic murine leukemia virus–related virus (XMRV) is a new human retrovirus originally identified in prostate cancer patients with a deficiency in the antiviral enzyme RNase L. XMRV has been detected with varying frequencies in cases of prostate cancer and chronic fatigue syndrome (CFS), as well as in a small proportion of healthy individuals. An etiologic link between XMRV infection and human disease, however, has yet to be established. Here, we summarize existing knowledge regarding the characteristics of XMRV replication, association of XMRV with prostate cancer and CFS, and potential mechanisms of XMRV pathophysiology. We also highlight several areas, such as the establishment of standardized assays and the development of animal models, as future directions to advance our current understanding of XMRV and its relevance to human disease.

Keywords

XMRV Prostate cancer Chronic fatigue syndrome Viral pathophysiology 

References

  1. 1.
    Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006;2:e25.PubMedCrossRefGoogle Scholar
  2. 2.
    Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA, Ganem D, DeRisi JL, Chow SA, Silverman RH. An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proc Natl Acad Sci USA. 2007;104:1655–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Silverman RH, Nguyen C, Weight CJ, Klein EA. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol. 2010: epub ahead of print.Google Scholar
  4. 4.
    Suzuki Y, Craigie R. The road to chromatin–nuclear entry of retroviruses. Nat Rev Microbiol. 2007;5:187–96.PubMedCrossRefGoogle Scholar
  5. 5.
    Mikkers H, Berns A. Retroviral insertional mutagenesis: tagging cancer pathways. Adv Cancer Res. 2003;88:53–99.PubMedCrossRefGoogle Scholar
  6. 6.
    Verdin E, Van Lint C. Internal transcriptional regulatory elements in HIV-1 and other retroviruses. Cell Mol Biol. 1995;41:365–9.PubMedGoogle Scholar
  7. 7.
    Holmes-Son ML, Appa RS, Chow SA. Molecular genetics and target site specificity of retroviral integration. Adv Genet. 2001;43:33–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou A, Hassel BA, Silverman RH. Expression cloning of 2–5A-dependent RNAse: a uniquely regulated mediator of interferon action. Cell. 1993;72:753–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Dong B, Silverman RH. 2–5A-dependent RNase molecules dimerize during activation by 2–5A. J Biol Chem. 1995;270:4133–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Malathi K, Dong B, Gale M, Silverman RH. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature. 2007;448:816–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhou A, Paranjape J, Brown TL, Nie H, Naik S, Dong B, Chang A, Trapp B, Fairchild R, Colmenares C, Silverman RH. Interferon action and apoptosis are defective in mice devoid of 2’, 5’-oligoadenylate-dependent RNase L. EMBO J. 1997;16:6355–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Flodstrom-Tullberg M, Hultcrantz M, Stotland A, Maday A, Tsai D, Fine C, Williams B, Silverman R, Sarvetnick N. RNaseL and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J Immunol. 2005;174:1171–7.PubMedGoogle Scholar
  13. 13.
    Samuel MA, Whitby K, Marri A, Williams BRG, Silverman RH, Diamond MS. PKR and RNase L contribute to protection against lethal West Nile virus infection by controlling early viral spread in the periphery and replication in neurons. J Virol. 2006;80:7009–19.PubMedCrossRefGoogle Scholar
  14. 14.
    Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Grönberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet. 2002;30:181–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Casey G, Neville PJ, Plummer SJ, Xiang Y, Krumroy LM, Klein EA, Catalona WJ, Nupponen N, Carpten JD, Trent JM, Silverman RH, Witte JS. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet. 2002;32:581–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Rennert H, Bercovich D, Hubert A, Abeliovich D, Rozovsky U, Bar-Shira A, Soloviov S, Schreiber L, Matzkin H, Rennert G, Kadouri L, Peretz T, Yaron Y. Orr-Urtreger A: A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Am J Hum Genet. 2002;71:981–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Rokman A, Ikonen T, Seppala EH, Nupponen N, Autio V, Mononen N, Bailey-Wilson J, Trent J, Carpten J, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP, Schleutker J. Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am J Hum Genet. 2002;70:1299–304.PubMedCrossRefGoogle Scholar
  18. 18.
    Downing SR, Hennessy KT, Abe M, Manola J, George DJ, Kantoff PW. 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. 2003;2:177–80.PubMedGoogle Scholar
  19. 19.
    Wiklund F, Jonsson BA, Brookes AJ, Stromqvist L, Adolfsson J, Emanuelsson M, Adami HO, Augustsson-Balter K, Gronberg H. Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin Cancer Res. 2004;10:7150–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Maier C, Haeusler J, Herkommer K, Vesovic Z, Hoegel J, Vogel W, Paiss T. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. Br J Cancer. 2005;92:1159–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Daugherty SE, Hayes RB, Yeager M, Andriole GL, Chatterjee N, Huang W, Isaacs WB, Platz E. RNASEL Arg462Gln polymorphism and prostate cancer in PLCO. Prostate. 2007;67:849–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang D, Coscoy L, Zylberberg M, Avila PC, Boushey HA, Ganem D, DeRisi JL. Microarray-based detection and genotyping of viral pathogens. Proc Natl Acad Sci USA. 2002;99:15687–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang D, Urisman A, Liu Y, Springer M, Ksiazek TG, Erdman DD, Mardis ER, Hickenbotham M, Magrini V, Eldred J, Latreille JP, Wilson RK, Ganem D, DeRisi JL. Viral discovery and sequence recovery using DNA microarrays. PLoS Biol. 2003;1:e2.PubMedCrossRefGoogle Scholar
  24. 24.
    Dunn GP, Sheehan KC, Old LJ, Schreiber RD. IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res. 2005;65:3447–53.PubMedGoogle Scholar
  25. 25.
    Xiang Y, Wang Z, Murakami J, Plummer S, Klein EA, Carpten JD, Trent JM, Isaacs WB, Casey G, Silverman RH. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2’, 5’-oligoadenylates. Cancer Res. 2003;63:6795–801.PubMedGoogle Scholar
  26. 26.
    Bhosle S, Suppiah S, Molinaro R, Liang Y, Arnold R, Diehl W, Makarova N, Blackwwell J, Petros J, Liotta D, Hunter E, Ly H. Evaluation of cellular determinants required for in vitro XMRV entry of human prostate cancer and non-cancerous cells. J Virol. 2010;84:6288–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Marin M, Tailor CS, Nouri A, Kozak SL, Kabat D. Polymorphisms of the cell surface receptor control mouse susceptibilities to xenotropic and polytropic leukemia viruses. J Virol. 1999;73:9362–8.PubMedGoogle Scholar
  28. 28.
    Van Hoeven NS, Miller AD. Use of different but overlapping determinants in a retrovirus receptor accounts for non-reciprocal interference between xenotropic and polytropic murine leukemia viruses. Retrovirology. 2005;2:76.PubMedCrossRefGoogle Scholar
  29. 29.
    Battini J, Rasko JE, Miller AD. 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. 1999;96:1385–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Tailor CS, Nouri A, Lee CG, Kozak C, Kabat D. Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc Natl Acad Sci USA. 1999;96:927–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Stieler K, Schulz C, Lavanya M, Aepfelbacher M, Stocking C, Fischer N. Host range and cellular tropism of the human exogenous gammaretrovirus XMRV. Virology. 2010;399:23–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Rodriguez JJ. Goff SP: xenotropic murine leukemia virus-related virus establishes an efficient spreading infection and exhibits enhanced transcriptional activity in prostate carcinoma cells. J Virol. 2010;84:2556–62.PubMedCrossRefGoogle Scholar
  33. 33.
    Laimins LA, Gruss P, Pozzatti R, Khoury G. Characterization of enhancer elements in the long terminal repeat of Moloney murine sarcoma virus. J Virol. 1984;49:183–9.PubMedGoogle Scholar
  34. 34.
    Celander D, Hus BL, Haseltine WA. Regulatory elements within the murine leukemia virus enhancer regions mediate glucocorticoid responsiveness. J Virol. 1998;62:1314–22.Google Scholar
  35. 35.
    Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT. Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci USA. 2004;101:4758–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Dong B, Silverman RH. Androgen stimulates transcription and replication of XMRV (xenotropic murine leukemia virus-related virus). J Virol. 2010;84:1648–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Cunha GR, Ricke W, Thomson A, Marker PC, Risbridger G, Hayward SW, Wang YZ, Donjacour AA, Kurita T. Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. J Steroid Biochem Mol Biol. 2004;92:221–36.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolf D, Goff SP. Host restriction factors blocking retroviral replication. Annu Rev Genet. 2008;42:143–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Groom HC, Yap MW, Galao RP, Neil SJ, Bishop KN. Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors. Proc Natl Acad Sci USA. 2010;107:5166–71.PubMedCrossRefGoogle Scholar
  40. 40.
    Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu W, Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol. 2010;84:5719–29.PubMedCrossRefGoogle Scholar
  41. 41.
    Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326:585–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Koning FA, Newman EN, Kim E, Kunstman KJ, Wolinsky SM, Malin MH. Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets. J Virol. 2009;83:9474–85.PubMedCrossRefGoogle Scholar
  43. 43.
    Peng G, Greenwell-Wild T, Nares S, Jin W, Lei K, Rangel ZG, Munson PJ, Wahl SM. Myeloid differentiation and susceptibility to HIV-1 are linked to APOBEC3G expression. Blood. 2007;110:393–400.PubMedCrossRefGoogle Scholar
  44. 44.
    Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002;418:646–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008;451:425–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. XMRV is present in malignant prostate epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci USA. 2009;106:16351–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA, Johnson NA, Bhosle SM, Liotta D, Hunter E, Marshall FF, Ly H, Molinaro RJ, Blackwell JL, Petros JA. XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. J Urol. 2010;75:755–61.CrossRefGoogle Scholar
  48. 48.
    Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher M, Schlomm T. Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J Clin Virol. 2008;43:277–83.PubMedCrossRefGoogle Scholar
  49. 49.
    Sfanos KS, Sauvageot J, Fedor HL, Dick JD, De Marzo AM, Isaacs WB. 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. 2008;68:306–20.PubMedCrossRefGoogle Scholar
  50. 50.
    D’Arcy F, Foley R, Perry A, Marignol L, Lawler M, Gaffney E, Watson R, Fitzpatrick J, Lynch T. No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation. Eur Urol Suppl. 2008;7:271.CrossRefGoogle Scholar
  51. 51.
    Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K, Kurth R, Bannert N. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology. 2009;6:92.PubMedCrossRefGoogle Scholar
  52. 52.
    Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Muller WE, Schroder HC, Carter WA. Upregulation of the 2–5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S96–104.PubMedGoogle Scholar
  53. 53.
    Suhadolnik RJ, Peterson DL, O’Brien K, Cheney PR, Herst CV, Reichenbach NL, Kon N, Horvath SE, Iacono KT, Adelson ME, De Meirleir K, De Becker P, Charubala R, Pfleiderer W. Biochemical evidence for a novel low molecular weight 2–5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res. 1997;17:377–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet. 1991;338:707–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D, Komaroff AL, Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987;139:3306–13.PubMedGoogle Scholar
  56. 56.
    Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010;5:e8519.PubMedCrossRefGoogle Scholar
  57. 57.
    Groom HT, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. 2010;7:10.PubMedCrossRefGoogle Scholar
  58. 58.
    van Kuppeveld FJ, De Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanin CM, Bleijenberg G, Netea MG, Galama JM, van der Meer JW. 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. 2010;340:c1018.PubMedCrossRefGoogle Scholar
  59. 59.
    Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC, Heneine W. Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. Retrovirology. 2010;7:57.PubMedCrossRefGoogle Scholar
  60. 60.
    Fukuta K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953–9.Google Scholar
  61. 61.
    Rosenberg N, Jolicoeur P. Retroviral pathogenesis. In: Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1997. p. 475–586.Google Scholar
  62. 62.
    Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348:255–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC, Ranzani M, Benedicenti F, Sergi LS, Ambrosi A, Ponzoni M, Doglioni C, Di Serio C, von Kalle C, Naldini L. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest. 2009;119:964–75.PubMedCrossRefGoogle Scholar
  64. 64.
    Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell. 2002;110:521–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science. 2003;300:1749–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Mitchell RS, Beitzel BF, Schroder AR, Shinn P, Chen H, Berry CC, Ecker JR, Bushman FD. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2004;2:e234.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim S, Kim Y, Liang T, Sinsheimer JS, Chow SA. A high-throughput method for cloning and sequencing human immunodeficiency virus type 1 integration sites. J Virol. 2006;80:11313–21.PubMedCrossRefGoogle Scholar
  68. 68.
    Crise B, Li Y, Yuan C, Morcock DR, Whitby D, Munroe DJ, Arthur LO, Wu X. Simian immunodeficiency virus integration preference is similar to that of human immunodeficiency virus type 1. J Virol. 2005;79:12199–204.PubMedCrossRefGoogle Scholar
  69. 69.
    Moalic Y, Blanchard Y, Felix H, Jestin A. Porcine endogenous retrovirus integration sites in the human genome: features in common with those of murine leukemia virus. J Virol. 2006;80:10980–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Nowrouzi A, Dittrich M, Klanke C, Heinkelein M, Rammling M, Dandekar T, von Kalle C, Rethwilm A. Genome-wide mapping of foamy virus vector integrations into a human cell line. J Gen Virol. 2006;87:1339–47.PubMedCrossRefGoogle Scholar
  71. 71.
    Derse D, Crise B, Li Y, Princler G, Lum N, Stewart C, McGrath CF, Hughes SH, Munroe DJ, Wu X. Human T-cell leukemia virus type 1 integration target sites in the human genome: comparison with those of other retroviruses. J Virol. 2007;81:6731–41.PubMedCrossRefGoogle Scholar
  72. 72.
    Faschinger A, Rouault F, Sollner J, Lukas A, Salmons B, Gunzburg WH, Indik S. Mouse mammary tumor virus integration site selection in human and mouse genomes. J Virol. 2008;83:1360–7.CrossRefGoogle Scholar
  73. 73.
    Kim S, Kim N, Dong B, Boren D, Lee SA, Das Gupta J, Gaughan C, Klein EA, Lee C, Silverman RH, Chow SA. Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J Virol. 2008;82:9964–77.PubMedCrossRefGoogle Scholar
  74. 74.
    Rakha EA, Green AR, Powe DG, Roylance R, Ellis IO. Chromosome 16 tumor-suppressor genes in breast cancer. Genes Chromosomes Cancer. 2006;45:527–35.PubMedCrossRefGoogle Scholar
  75. 75.
    Dong JT. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev. 2001;20:173–93.PubMedCrossRefGoogle Scholar
  76. 76.
    Moreau K, Torne-Celer C, Faure C, Verdier G, Ronfort C. In vivo retroviral integration: fidelity to size of the host DNA duplication might be reduced when integration occurs near sequences homologous to LTR ends. Virology. 2000;278:133–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Taganov K, Daniel R, Katz RA, Favorova O, Skalka AM. Characterization of retrovirus-host DNA junctions in cells deficient in nonhomologous-end joining. J Virol. 2001;75:9549–52.PubMedCrossRefGoogle Scholar
  78. 78.
    Oh J, Chang KW, Alvord WG, Hughes SH. Alternate polypurine tracts affect Rous sarcoma virus integration in vivo. J Virol. 2006;80:10281–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Oh J, Chang KW, Hughes SH. Mutations in the U5 sequences adjacent to the primer binding site do not affect tRNA cleavage by Rous sarcoma virus RNase H but do cause aberrant integrations in vivo. J Virol. 2006;80:451–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Muesing MA, Smith DH, Cabradilla CD, Benson CV, Lasky LA, Capon DJ. Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature. 1985;313:450–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Vincent KA, York HD, Quiroga M, Brown PO. Host sequences flanking the HIV provirus. 2 Acids Res. 1990;18:6045–7.CrossRefGoogle Scholar
  82. 82.
    Vink C, Groenink M, Elgersma Y, Fouchier RA, Tersmette M, Plasterk RH. Analysis of the junctions between human immunodeficiency virus type 1 proviral DNA and human DNA. J Virol. 1990;64:5626–7.PubMedGoogle Scholar
  83. 83.
    Shoemaker C, Goff S, Gilboa E, Paskind M, Mitra SW, Baltimore D. Structure of a cloned circular Moloney murine leukemia virus DNA molecule containing an inverted segment: implications for retrovirus integration. Proc Natl Acad Sci USA. 1980;77:3932–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Shoemaker C, Hoffman J, Goff SP, Baltimore D. Intramolecular integration within Moloney murine leukemia virus. J Virol. 1981;40:164–72.PubMedGoogle Scholar
  85. 85.
    Shimotohno K, Mizutani S, Temin HM. Sequence of retrovirus provirus resembles that of bacterial transposable elements. Nature. 1980;285:550–4.PubMedCrossRefGoogle Scholar
  86. 86.
    Kim S, Rusmevichientong A, Dong B, Remenyi R, Silverman RH, Chow SA. Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus. PLoS One. 2010;5:e10255.PubMedCrossRefGoogle Scholar
  87. 87.
    Nelson WG, De Marzo AM, Issacs WB. Prostate cancer. N Engl J Med. 2003;349:366–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Knouf EC, Metzger MJ, Mitchell PS, Arroyo JD, Chevillet JR, Tewari M, Miller JD. 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. 2009;83:7353–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Moreau-Gachelin F. Multi-stage Friend murine erythroleukemia: molecular insights into oncogenic cooperation. Retrovirology. 2008;5:99.PubMedCrossRefGoogle Scholar
  90. 90.
    Fan H, Palmarini M, DeMartini JC. Transformation and oncogenesis by Jaagsiekte sheep retrovirus. Curr Top Microbiol Immunol. 2003;275:139–77.PubMedGoogle Scholar
  91. 91.
    Metzger MJ, Holguin CJ, Mendoza R, Miller AD. The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. J Virol. 2010;84:1874–80.PubMedCrossRefGoogle Scholar
  92. 92.
    Cunha GR, Hayward SW, Wang YZ, Ricke WA. Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer. 2003;107:1–10.PubMedCrossRefGoogle Scholar
  93. 93.
    Memarzadeh S, Xin L, Mulholland DJ, Mansukhani A, Wu H, Teitell MA, Witte ON. Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor. Cancer Cell. 2007;12:572–85.PubMedCrossRefGoogle Scholar
  94. 94.
    Chisari FV. Rous-Whipple award lecture. Viruses, immunity, and cancer: lessons from hepatitis B. Am J Pathol. 2000;156:1117–32.PubMedGoogle Scholar
  95. 95.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.PubMedCrossRefGoogle Scholar
  96. 96.
    De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256–69.PubMedCrossRefGoogle Scholar
  97. 97.
    Waters DJ, Sakr WA, Hayden DW, Lang CM, McKinney L, Murphy GP, Radinsky R, Ramoner R, Richardson RC, Tindall DJ. Workgroup 4: spontaneous prostate carcinoma in dogs and nonhuman primates. Prostate. 1998;36:64–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Waters DJ, Bostwick DG. Prostatic intraepithelial neoplasia occurs spontaneously in the canine prostate. J Urol. 1997;157:713–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Lucia MS, Bostwick DG, Bosland M, Cockett AT, Knapp DW, Leav I, Pollard M, Rinker-Schaeffer C, Shirai T, Watkins BA. Workgroup I: rodent models of prostate cancer. Prostate. 1998;36:49–55.PubMedCrossRefGoogle Scholar
  100. 100.
    Abate-Shen C, Shen MM. Mouse models of prostate carcinogenesis. Trends Genet. 2002;18:S1–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Hong S, Klein EA, Das Gupta J, Hanke K, Weight CJ, Nguyen C, Gaughan C, Kim K, Bannert N, Kirchhoff F, Munch J, Silverman RH. Fibrils of prostatic acid phosphatase fragments boost infections by XMRV, a human retrovirus associated with prostate cancer. J Virol. 2009;83:6995–7003.PubMedCrossRefGoogle Scholar
  102. 102.
    Fischer N, Schulz C, Stieler K, Hohn O, Lange C, Drosten C, Aepfelbacher M. Xenotropic murine leukemia virus-related gammaretrovirus in respiratory tract. Emerg Infect Dis. 2010;16:1000–2.PubMedGoogle Scholar
  103. 103.
    Sakuma R, Sakuma T, Ohmine S, Silverman RH, Ikeda Y. Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology. 2010;397:1–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF. Raltegravir is a potent inhibitor of XMRV, a virus implicated in prostate cancer and chronic fatigue syndrome. PLoS One. 2010;5:e9948.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Molecular and Medical PharmacologyMolecular Biology InstituteLos AngelesUSA
  2. 2.UCLA AIDS Institute, UCLA School of MedicineLos AngelesUSA

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