Abstract

Abstract : Xenotropic murine leukemia virus related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV). We analyzed 334 consecutive prostate resection specimens, using a qPCR assay and immunohistochemistry with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike previously reported. This result increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide new evidence for an association of XMRV with malignant cells and with more aggressive tumors. XMRV displayed robust expression and infection in LNCaP prostate tumor cells. The transcriptional activity of the XMRV LTR was found to be higher than the MoMLV LTR in both LNCaP and WPMY-1 cells. The U3 promoter of XMRV and a glucocorticoid response element (GRE) in the U3 were required for transcriptional activity. Co-expression of the androgen receptor and stimulation with androgen stimulated XMRV-LTR dependent transcription in 293T cells and the GRE was required for this activity. Our data suggest that XMRV replicates more efficiently in certain prostate tumor cells in part due to the transcriptional environment in the prostate tumor cells.

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