Xenotropic murine leukemia virus-related virus

Xenotropic murine leukemia virus-related virus
Virus classification
Group: Group VI (ssRNA-RT)
Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus: Gammaretrovirus
Species: Xenotropic MuLV-related virus

Xenotropic murine leukemia virus-related virus (XMRV) is "a laboratory-derived mouse virus that was generated through recombination between two endogenous murine retroviruses during propagation of a prostate cancer xenograft in the mid-1990’s."[1][2][3] The chimeric virus was first described in 2006 as an apparently novel retrovirus and potential human pathogen.[4] Initial reports erroneously[1][2][3] 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.

XMRV has now been established as a laboratory contaminant.[2][3] 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 Most scientific publications claiming an association of XMRV with CFS or prostate cancer have been retracted, and allegations of research misconduct were leveled against at least one CFS investigator.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 has it been demonstrated 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.[5] 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[6] as retroviruses replicate their genomes with relatively low fidelity, leading to divergent viral sequences in a single host organism.[6][7] 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".[8][9]

Discovery

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.[10] 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%.[11] 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,[11] leading to the discovery of XMRV.

Disease association studies

Prostate cancer

In 2006 in the initial report on XMRV, the virus was detected in cancerous prostate tissues using a microarray containing samples of genetic material from about 950 viruses. The screen indicated the presence of a gammaretrovirus-like sequence in seven of eleven tumours homozygous for the R462Q mutation, but only in one of five tumours without the mutation. After isolation and cloning of the virus, an expanded screen found it present in 40% of tumours homozygous for R462Q and in only 1.5% of those not.[12] A 2009 study reported evidence of XMRV infection in 23% of subjects independent of the RNase L gene variation,[13] and detection of XMRV was again reported in a 2010 article.[14]

However, by 2009 numerous studies had failed to find evidence of XMRV in prostate cancer. Researchers in Germany found no XMRV-specific sequences in the DNA or RNA of samples from prostate cancer patients, and no XMRV-specific antibodies were detected in blood serum samples.[15] Another German study found no XMRV association with non-familial (sporadic) prostate cancer,[16] and no XMRV link was found in Irish prostate cancer patients with the R462Q mutation.[17] Similar results were reported in The Netherlands,[18] Japan,[19] and Mexico.[20] Geographical differences were initially suspected as the culprit in these discrepancies, because the positive results were obtained in the United States.[21] However, U.S. studies have also found no evidence of XMRV. In 2010 researchers at the National Cancer Institute,[22] Johns Hopkins[23] and the Mayo Clinic[24] tested over 1,000 samples from prostate cancer patients but found no evidence of the virus.

By 2010 a causal role of XMRV in cancer has not been established,[6] and XMRV does not appear to be capable of transforming cells directly.[25] In prostate cancer, XMRV protein has been found in tumour-associated but nonmalignant stromal cells, but in one study was not found in the actual prostate cancer cells, raising the possibility that the virus may indirectly support tumorigenesis.[26] However, in another study, XMRV proteins and nucleic acids were found in malignant cells.[6][13]

Chronic fatigue syndrome

In 2009, Lombardi et al. reported finding XMRV DNA in 67% of people with chronic fatigue syndrome (CFS) but in only 4% of healthy controls.[27] The authors reported that patient-derived XMRV could infect cells in vitro and stated that "These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS". The reported association of XMRV and CFS, published in Science, generated worldwide media coverage and subsequent conflicting study results. Independent laboratories from around the world have not detected XMRV in CFS patient groups or control populations, using blood samples[28][29][30][31][32][33][34][35][36][37] or cerebrospinal fluid.[38] Various PCR (Polymerase Chain Reaction) assays and antibody-based detection methods were used in these investigations. Some of the authors of the original CFS report suggested that the widespread failure to replicate their results was attributable to different PCR conditions or to different criteria used to classify patients.[39] However, several negative studies have been conducted with the same PCR primers used in the first investigation.[29][31][32] Another study using the original reaction conditions did not detect XMRV in UK patients who "not only had CFS, but had considerable disability".[36] Another study found no XMRV, but did report detection of murine leukemia virus related sequences in the blood of CFS patients.[40] Two reviews have argued that reconciliation of these differences is necessary.[41][42] The editor-in-chief of the journal Science in June 2011 published an expression of concern, stating that "the validity of the study by Lombardi et al. is now seriously in question".[43] In September 2011, the original authors published a "Partial Retraction" of their 2009 findings, in which they acknowledged that "some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA."[44] A full retraction was issued by Science on December 22, 2011.[45]

An international workshop was convened in September 2010 to aid in resolving the discrepancies.[46] At the meeting, it was announced that Ian Lipkin would oversee a multi-centre trial that would culminate in blinded testing of 150 CFS patients and 150 healthy but comparable donors by laboratories at the Whittemore Peterson Institute, the NIH and the CDC.[47] The results of this trial were made available in mid-2012, and concluded that XMRV was not present in either CFS patients or the control group.

Other conditions

XMRV has been proposed as a cause for conditions including autism, fibromyalgia, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease.[48][49] However, there is currently no evidence to support these hypotheses. No XMRV was found in 230 autistic children or in 204 controls,[50] nor was XMRV detected in fibromyalgia[51] or MS patients[34][52] or in children with idiopathic diseases.[53] In one study, XMRV was detected in a small percentage of patients with weakened immune systems,[54] but other studies found no evidence of XMRV in immunosuppression.[32][55] Out of more than 500 HIV-1-positive people, none was positive for XMRV,[56] nor was XMRV found in systemic lupus erythematosus patients.[57]

Contamination and artifact

From the first reports of XMRV and disease associations, scientists were concerned that the positive findings could be artifactual, for example as the result of contamination with nucleic acids from mice or mouse viruses.[9] Most proposed retrovirus-disease associations have been prompted by accidental detection of contaminants,[58] and initially promising results were later disproven or failed replication.[9] Virologist Robin Weiss suggested in 2010 that XMRV is likely to be one of these "rumour viruses".[59] By 2011, the suspicion of contamination had increased with an increasing number of negative studies as well as investigations demonstrating contamination.[21][60][61][62][63][64][65]

The results of several studies support the contamination hypothesis.[9] Scientists reported that they found ample sources of contamination in laboratory reagents,[66] tissue samples[58] and blood.[67] Samples that were positive for XMRV were also positive for mouse DNA contaminants.[24] Another article reported on the striking identity of XMRV genomic sequences and their similarity to xenotropic MLVs in several human cell lines.[8] The authors conclude that XMRV contaminated 22Rv1 cell cultures, likely during passage in athymic mice. (Production of laboratory cell lines may involve passaging of tumours in mice.) Identical XMRV integration sites were also found, a phenomenon never before reported for a retrovirus and strongly suggestive of contamination.[60] It has been recommended that studies of XMRV should include more diverse and stringent PCR testing and phylogenetic analysis to detect occurrence of mouse DNA contamination from laboratory sources.[9]

Responding to indications of contamination, the group that reported an association of XMRV with CFS stated that its evidence was not restricted to nucleic acids, but also included antibody-based detection.[68] Their study used murine leukaemia virus antibodies and antigens, not XMRV-specific reagents.[27] Multiple studies have failed to detect XMRV by PCR or antibody-based methods.[15][37][65] In one study, several samples that were PCR-negative contained antibodies that interacted with XMRV. However, the authors found that these antibodies were non-specific and also interacted with other viruses.[29] Mayo Clinic researchers also reported on non-specific anti-XMRV antibodies.[24] In another study, only low reactivity with XMRV antigens was found, with no differences between cases and controls. The authors noted that establishing a cutoff for seropositivity was impossible, as no positive sera are available.[69] A study that included samples from the original XMRV-CFS report found no XMRV in patients or controls by PCR, antibody-based methods or viral culture. The authors discovered that some PCR reagents were contaminated with low levels of mouse nucleic acid but pointed out that this could not explain the high XMRV positive rates reported initially.[65]

Blood supply controversy

Transmission of XMRV to or between humans has not been documented. Speculated modes of transmission include sexual[70][71][72] and airborne[54] routes, but the mode of human transmission, if any, has not yet been investigated.[6] A study in the Netherlands found no XMRV in the semen of HIV-positive men.[73] Both cell-associated and cell-free transmission have been reported in vitro.[27] 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).[74]

Judy Mikovits of the Whittemore Peterson Institute has stated that XMRV has "almost certainly entered the U.S. blood supply system, but did not know whether it would be susceptible to the same heat treatments that successfully kill off the AIDS virus in blood products."[75] 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.[76][77][78] The preliminary phase of this project yielded inconclusive data. Although four patients tested positive at two of the sites, no patient was positive after repeated testing.[68][79]

The association of XMRV and CFS reported in Science prompted Health Canada,[75][80][81] the New Zealand Blood Service,[82] the Australian Red Cross Blood Service,[83] and the American Red Cross[84] in 2010, to disallow blood donations from individuals with CFS. On June 18, 2010, the American Association of Blood Banks, recommended actively discouraging potential donors who have been diagnosed by a physician as having CFS from donating blood or blood components.[85] As of November 1, 2010, people with CFS are no longer able to donate blood in the UK.[86]

Writing in Cell Host & Microbe, retrovirologists Mark Wainberg and Kuan-Teh Jeang argued that a "scrupulously cautious" risk-benefit analysis is needed to assess the benefits and costs of testing or discarding blood on the basis of XMRV-positive results, taking into account the fact that some individuals and companies could profit from mandatory testing. They drew a parallel with the recent MMR-autism scare, in which conflicts of interest played a role.[87]

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