Xenotropic murine leukemia virus–related virus
|Xenotropic murine leukemia virus-related virus|
Xenotropic murine leukemia virus-related virus
Xenotropic murine leukemia virus–related virus (XMRV) is a retrovirus which was first described in 2006 as an apparently novel human pathogen found in tissue samples from men with prostate cancer. Initial reports erroneously linked the virus to prostate cancer and later to chronic fatigue syndrome (CFS), leading to considerable interest in the scientific and patient communities, investigation of XMRV as a potential cause of multiple medical conditions, and public-health concerns about the safety of the donated blood supply.
Subsequent research established that XMRV was in fact a laboratory contaminant, rather than a novel pathogen. XMRV was generated unintentionally in the laboratory, through genetic recombination between two mouse retroviruses during propagation of a prostate-cancer cell line in the mid-1990s. False-positive detection of XMRV may also occur because of contamination of clinical specimens and laboratory reagents with other mouse retroviruses or related nucleic acids. Most scientific publications claiming an association of XMRV with CFS or prostate cancer have been retracted, and allegations of research misconduct were leveled against at least one CFS investigator. There is no evidence that XMRV can infect humans, nor that XMRV is associated with or causes any human disease.
Classification and genome
XMRV is a murine leukemia virus (MLV) that formed through the recombination of the genomes of two parent MLVs known as preXMRV-1 and preXMRV-2. MLVs belong to the virus family Retroviridae and the genus gammaretrovirus and have a single-stranded RNA genome that replicates through a DNA intermediate. The name XMRV was given because the discoverers of the virus initially thought that it was a novel potential human pathogen that was related to but distinct from MLVs. The XMRV particle is approximately spherical and 80 to 100 nm in diameter.Several XMRV genomic sequences have been published to date. These sequences are almost identical, an unusual finding as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism. In 2010 the results of phylogenetic analyses of XMRV and related murine retroviruses led a group of researchers to conclude that XMRV "might not be a genuine human pathogen". Xenotropic viruses (xenos Gr. foreign; tropos Gr. turning) were initially discovered in the New Zealand Black (NZB) mouse and later found to be present in many other mouse strains including wild mice.
XMRV was discovered in the laboratories of Joseph DeRisi at the University of California, San Francisco, and Robert Silverman and Eric Klein of the Cleveland Clinic. Silverman had previously cloned and investigated the enzyme ribonuclease L (RNase L), part of the cell’s natural defense against viruses. When activated, RNase L degrades cellular and viral RNA to halt viral replication. In 2002, the "hereditary prostate cancer 1" locus (HPC1) was mapped to the RNase L gene, implicating it in the development of prostate cancer. The cancer-associated "R462Q" mutation results in a glutamine instead of an arginine at position 462 of the RNase L enzyme, reducing its catalytic activity. A man with two copies of this mutation has twice the risk of prostate cancer; one copy raises the risk by 50%. Klein and Silverman hypothesized that "the putative linkage of RNase L alterations to HPC might reflect enhanced susceptibility to a viral agent" and conducted a viral screen of prostate cancer samples, leading to the discovery of XMRV.
Disease association studies
Contamination and artifact
Initially promising results were later disproven or failed replication.
Blood supply controversy
XMRV is closely related to several known xenotropic mouse viruses. These viruses recognize and enter cells of non-rodent species by means of the cell-surface xenotropic and polytropic murine leukemia virus receptor (XPR1).
Only fractionated plasma is heat treated, blood for transfusion is not. A United States federal consortium is now working to determine the prevalence of XMRV in the blood supply and the suitability of different detection methods.
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