Editor's Commentary - Recombinant origin of the retrovirus XMRV

BERKELEY, CA (UroToday.com) - A startling report in Science suggests that the xenotropic murine leukemia virus-related virus (XMRV) detected in human prostate cancer (CaP) tumors is a contaminant.

Researchers from the NCI, Tufts University and the University of California, Davis published the research in the online edition, June 2, 2011. Another article in the same issue reported that the association of XMRV with chronic fatigue syndrome is also a contaminant.

XMRV was first isolated from human CaP in 2006 and reported to be present in 6-27% of human prostate cancers and in the peripheral blood of 67% of chronic fatigue syndrome patients. Yet other studies have not been able to confirm these observations and it is known that xenotopic murine leukemia viruses (MLVs) can infect human tumors during passage through nude mice. The CWR22Rv1 human CaP cell line was established from a primary CaP tumor at Case Western Reserve University and passaged in nude mice. It harbors infectious XMRV identical in sequence to that obtained from patients and the proposed origin was from an XMRV-infected tumor. The investigators compared early and late passages of the CWR22Rv1 tumors. They verified that the xenograft samples and cell lines were all derived from the same person by performing short tandem repeat analysis of 7 loci.

They found that CWR22 xenografts had significantly fewer copies of XMRV compared to the CWR22Rv1 cells. The investigators found that the early passages did not contain XMRV, but did contain a previously undescribed pro-virus; pre-XMRV-1 that differs from XMRV by one base pair over a stretch of 3,211-nt sequence of the genome. It turns out that the preXMRV-1 is an endogenous murine provirus that is present in the NU/NU and Hsd strains used to propagate the xenografts, but neither of these strains contains XMRV. They could not find endogenous XMRV in 45 laboratory mouse strains and 44 wild mice. However, they did find a second previously undescribed endogenous provirus they called preXMRV-2. No early xenografts, but all late xenografts, and both cell lines were positive for XMRV. Further comparison of the preXMRV-1 and preMXRV-2 sequences revealed that the regions of near identity to XMRV are reciprocal and largely non-overlapping. This led to the hypothesis that the recombination between these two retroviruses resulted in the formation of XMRV. The data supported the hypothesis that virus derived from two previously undescribed murine endogenous retroviruses underwent retroviral recombination to generate XMRV during in vivo passaging of the CWR22 xenograft in nude mice. Only 6 recombinant template switches per replication cycle are needed to generate a recombinant that is virtually identical and ancestral to all XMRV sequences characterized to date from patients and cell lines. The probability of the switching events occurring independently is 1.3 x10-12.

Paprotka T, Delviks-Frankenberry KA, Cingöz O, Martinez A, Kung HJ, Tepper CG, Hu WS, Fivash MJ Jr, Coffin JM, Pathak VK



Science. 2011 Jul 1;333(6038):97-101

PubMed Abstract
PMID: 21628392

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