Abstract
XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection.
Highlights
In 2006, sequences corresponding to a novel gammaretrovirus named xenotropic murine leukemia virus-related virus (XMRV) were identified in tissue from prostate cancer patients following radical prostatectomy [1]
The ViroChip microarray [2,3,44,45] was used to screen RNA samples isolated from prostate tumors collected prospectively from 39 individuals, of which 16 individuals were genotyped as harboring the R462Q RNAse L mutation (QQ), 10 individuals were heterozygous cases (RQ), and 13 were wild-type cases (RR)
We investigated the putative association between XMRV and prostate cancer using a combination of microarray, PCR, fluorescence in situ hybridization (FISH), serological, and deep sequencing approaches
Summary
In 2006, sequences corresponding to a novel gammaretrovirus named xenotropic murine leukemia virus-related virus (XMRV) were identified in tissue from prostate cancer patients following radical prostatectomy [1]. The initial study reported a link between RNAse L-variant prostate cancer and XMRV infection, most, but not all, subsequent studies have failed to detect such an association [9,10,11,12]. Since this initial discovery, XMRV and MLV-related virus sequences resembling polytropic MLVs (P-MLVs) were found in patients with chronic fatigue syndrome (CFS) [13,14]
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