An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors
- Beihua Dong*,
- Sanggu Kim†,
- Seunghee Hong*,‡,
- Jaydip Das Gupta*,
- Krishnamurthy Malathi*,
- Eric A. Klein§,
- Don Ganem¶,‖,**,
- Joseph L. DeRisi**,††,
- Samson A. Chow†,‡‡, and
- Robert H. Silverman*,§§
- *Department of Cancer Biology, Lerner Research Institute, and
- §Glickman Urologic Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195;
- †Biomedical Engineering Interdepartmental Program, University of California, Los Angeles, CA 90095;
- ‡Graduate Program in Molecular Virology, Case Western Reserve University, Cleveland, OH 44106;
- Departments of ††Biochemistry and Biophysics,
- ¶Microbiology, and
- ‖Medicine and
- **Howard Hughes Medical Institute, University of California, San Francisco, CA 94158; and
- ‡‡Department of Molecular and Medical Pharmacology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095
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Communicated by George R. Stark, Cleveland Clinic Foundation, Cleveland, OH, November 27, 2006 (received for review November 6, 2006)
Abstract
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.
Footnotes
- §§To whom correspondence should be addressed. E-mail: silverr{at}ccf.org
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Author contributions: B.D., S.K., S.H., J.D.G., S.A.C., and R.H.S. designed research; B.D., S.K., S.H., J.D.G., and S.A.C. performed research; K.M. and E.A.K. contributed new reagents/analytic tools; B.D., S.K., E.A.K., D.G., J.L.D., S.A.C., and R.H.S. analyzed data; and B.D., S.A.C., and R.H.S. wrote the paper.
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The authors declare no conflict of interest.
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Data deposition: The sequence of the molecular viral clone of XMRV VP62 reported in this paper has been deposited in the GenBank database (accession no. EF185282).
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See Commentary on page 1449.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0610291104/DC1.
- Abbreviations:
- CM,
- conditioned media;
- MLV,
- murine leukemia virus;
- RT,
- reverse transcriptase;
- XMRV,
- xenotropic MLV-related virus;
- XPR1,
- xenotropic and polytropic retrovirus receptor 1; 2–5A;
- 5′-phosphorylated,
- 2′–5′-linked oligoadenylates.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
