An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors

We recently reported identification of a previously undescribed gammaretrovirus genome, xenotropic murine leukemia virus-related virus (XMRV), in prostate cancer tissue from patients homozygous for a reduced activity variant of the antiviral enzyme RNase L. Here we constructed a full-length XMRV genome from prostate tissue RNA and showed that the molecular viral clone is replication-competent. XMRV replication in the prostate cancer cell line DU145 was sensitive to inhibition by IFN-β. However, LNCaP prostate cancer cells, which are deficient in JAK1 and RNase L, were resistant to the effects of IFN-β against XMRV. Furthermore, DU145 cells rendered deficient in RNase L with siRNA were partially resistant to IFN inhibition of XMRV. Expression in hamster cells of the xenotropic and polytropic retrovirus receptor 1 allowed these cells to be infected by XMRV. XMRV provirus integration sites were mapped in DNA isolated from human prostate tumor tissue to genes for two transcription factors (NFATc3 and CREB5) and to a gene encoding a suppressor of androgen receptor transactivation (APPBP2/PAT1/ARA67). Our studies demonstrate that XMRV is a virus that has infected humans and is susceptible to inhibition by IFN and its downstream effector, RNase L.

[1]  K. Hagino-Yamagishi,et al.  [Oncogene]. , 2019, Gan to kagaku ryoho. Cancer & chemotherapy.

[2]  Janet S. Sinsheimer,et al.  A High-Throughput Method for Cloning and Sequencing Human Immunodeficiency Virus Type 1 Integration Sites , 2006, Journal of Virology.

[3]  Anantha Marri,et al.  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 , 2006, Journal of Virology.

[4]  J. Derisi,et al.  Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant , 2006, PLoS pathogens.

[5]  M. Wabl,et al.  A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. , 2005, Blood.

[6]  R. Schreiber,et al.  IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. , 2005, Cancer research.

[7]  Hong-Chiang Chang,et al.  Androgen receptor (AR) NH2- and COOH-terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth. , 2005, Molecular endocrinology.

[8]  Monica Hultcrantz,et al.  RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection1 , 2005, The Journal of Immunology.

[9]  S. Goff.  Retrovirus restriction factors. , 2004, Molecular cell.

[10]  R. Silverman,et al.  HPC1/RNASEL Mediates Apoptosis of Prostate Cancer Cells Treated with 2′,5′-Oligoadenylates, Topoisomerase I Inhibitors, and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand , 2004, Cancer Research.

[11]  F. Bushman,et al.  Retroviral DNA Integration: ASLV, HIV, and MLV Show Distinct Target Site Preferences , 2004, PLoS biology.

[12]  S. Yeh,et al.  ARA67/PAT1 Functions as a Repressor To Suppress Androgen Receptor Transactivation , 2004, Molecular and Cellular Biology.

[13]  J. Carpten,et al.  Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. , 2003, Cancer research.

[14]  Shawn M. Burgess,et al.  Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration , 2003, Science.

[15]  Y. Takeuchi,et al.  Molecular cloning, complete sequence, and biological characterization of a xenotropic murine leukemia virus constitutively released from the human B-lymphoblastoid cell line DG-75. , 2003, Virology.

[16]  G. Rennert,et al.  A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. , 2002, American journal of human genetics.

[17]  Yasuhiro Takeuchi,et al.  PCR-based cloning and immunocytological titration of infectious porcine endogenous retrovirus subgroup A and B. , 2002, The Journal of general virology.

[18]  K. Klinger,et al.  Germline mutations in the ribonuclease L gene in families showing linkage with HPC1 , 2002, Nature Genetics.

[19]  L. Bromham,et al.  The Nucleotide Sequence of Koala (Phascolarctos cinereus) Retrovirus: a Novel Type C Endogenous Virus Related to Gibbon Ape Leukemia Virus , 2000, Journal of Virology.

[20]  G. Crabtree.  Generic Signals and Specific Outcomes Signaling through Ca2+, Calcineurin, and NF-AT , 1999, Cell.

[21]  J. Rasko,et al.  A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Kozak,et al.  Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  K. Hunter,et al.  Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmc1 , 1999, Nature Genetics.

[24]  S. Pimplikar,et al.  PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Arai,et al.  Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by tissue-specific splicing and is essential for transactivation activity in T cells. , 1998, Journal of immunology.

[26]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[27]  F. Shibasaki,et al.  Intramolecular Masking of Nuclear Import Signal on NF-AT4 by Casein Kinase I and MEKK1 , 1998, Cell.

[28]  R. Silverman,et al.  Interferon action and apoptosis are defective in mice devoid of 2′,5′‐oligoadenylate‐dependent RNase L , 1997, The EMBO journal.

[29]  P. S. Kim,et al.  Structure of a murine leukemia virus receptor-binding glycoprotein at 2.0 angstrom resolution. , 1997, Science.

[30]  T. Hoey,et al.  Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. , 1995, Immunity.

[31]  K. Arai,et al.  NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus , 1995, Molecular and cellular biology.

[32]  N. Nomura,et al.  Regulation of trans-activating capacity of CRE-BPa by phorbol ester tumor promoter TPA. , 1993, Oncogene.

[33]  T. Beaty,et al.  Hereditary prostate cancer: epidemiologic and clinical features. , 1993, The Journal of urology.

[34]  Robert H. Silverman,et al.  Expression cloning of 2-5A-dependent RNAase: A uniquely regulated mediator of interferon action , 1993, Cell.

[35]  N. Nomura,et al.  Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1. , 1993, The Journal of biological chemistry.

[36]  O. Danos,et al.  Receptor choice determinants in the envelope glycoproteins of amphotropic, xenotropic, and polytropic murine leukemia viruses , 1992, Journal of virology.

[37]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[38]  A. Fauci,et al.  Interferon-alpha but not AZT suppresses HIV expression in chronically infected cell lines. , 1989, Science.

[39]  T. Triche,et al.  Interferon inhibits mouse leukaemia virus release: an electron microscope study. , 1977, The Journal of general virology.

[40]  P. Pitha,et al.  Effect of interferon on exogenous, endogenous, and chroniv murine leukemia virus infection. , 1976, Virology.

[41]  R. Friedman,et al.  Inhibition of murine leukemia virus production in chronically infected AKR cells: a novel effect of interferon. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[42]  L. Wilkinson.  Immunity , 1891, The Lancet.

[43]  S. Goff,et al.  Assays for retroviral reverse transcriptase. , 1995, Methods in enzymology.

[44]  I. Kerr,et al.  pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[45]  V. Georgiev.  Virology , 1955, Nature.