[Note: See also “ASCO GU: Novel Retrovirus Mimics HIV Transmission,” MedPageToday, Mar 6.]
Background: Xenotropic Murine Leukemia Related Virus (XMRV) is a novel gammaretrovirus discovered in prostate tissue of men genetically predisposed to prostate cancer. A growing body of evidence suggests a potential causative role in prostate cancer.
Methods: XMRV was isolated and cloned from prostate tissue of unselected men with prostate cancer who underwent radical prostatectomy, with initial identification accomplished by hybridization to a DNA microarray containing conserved sequences of known viruses. Live virus was injected intravenously into rhesus macaques for acute and chronic infection studies. Tissue distribution of XMRV was studied by immunohistochemistry (using a rhesus-derived monoclonal to ENV protein) and RT-PCR based assays. Effect of androgen on XMRV growth was assessed by infection of LnCap and DU145 cells using virus mutated in the androgen response element (ARE) promoter region as control. Chromosomal integration sites were mapped from human prostates using a PCR-based approached that produced biotinylated-ds DNA and isolated by binding to streptavidin-agarose Dynabeads. Expressed prostatic secretions (EPS) were obtained by milking radical prostatectomy specimens. The presence of XMRV in EPS was assessed by qRT-PCR.
1. Preliminary observations suggest that XMRV is detectable by immunohistochemistry in prostate epithelium;
2. XMRV preferentially integrates into host chromosomes at transcriptionally active sites;
3. IV injection of XMRV produces viremia and persistent infection in rhesus macaques with a robust immune response;
4. The XMRV promoter contains a consensus ARE;
5. Androgen stimulates transcription and replication of XMRV independent of cell growth;
6. XMRV is present in 15% of EPS from unselected cases of prostate cancer;
7. Human semen and semen-derived enhancers substantially increase XMRV in both prostate stroma and epithelium.
• XMRV is infective in primates and produces an immune response.
• The presence of XMRV in EPS and effect of semen on infectivity suggest sexual transmission.
• The presence of an ARE and the stimulatory effect of androgen suggests that XMRV integration into host DNA could impart androgen stimulation on cellular genes, serving as a potential oncogenic mechanism.
Source: 2010 Genitourinary Cancers Symposium (Abstract 117), Mar 5-7, 2010. Klein EA, Villinger F, Das Gupta J, Magi-Galluzzi C, Hong S, Nguyen C, Weight CJ, Schochetman G, Hackett J, Silverman R. Cleveland Clinic Foundation, Cleveland, OH; Yerkes Primate Center, Atlanta, GA; Cleveland Clinic, Cleveland, OH; Abbott Diagnostics, Abbott Park, IL.