Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome

Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 01/2010; 5(1):e8519. DOI: 10.1371/journal.pone.0008519
Source: PubMed


In October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the US were infected with a novel gamma retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer. This finding, if confirmed, would have a profound effect on the understanding and treatment of an incapacitating disease affecting millions worldwide. We have investigated CFS sufferers in the UK to determine if they are carriers of XMRV.
Patients in our CFS cohort had undergone medical screening to exclude detectable organic illness and met the CDC criteria for CFS. DNA extracted from blood samples of 186 CFS patients were screened for XMRV provirus and for the closely related murine leukaemia virus by nested PCR using specific oligonucleotide primers. To control for the integrity of the DNA, the cellular beta-globin gene was amplified. Negative controls (water) and a positive control (XMRV infectious molecular clone DNA) were included. While the beta-globin gene was amplified in all 186 samples, neither XMRV nor MLV sequences were detected.
XMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK. Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not.

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Available from: Simon Wessely, Dec 30, 2013
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    • "Despite these early reports and the excitement they generated in the CFS patient community, the association of XMRV with CFS has been disproven. Many studies have failed to detect XMRV in CFS cohorts around the globe.27,41,42,43,44,45,46,47,48,49,50,51,52 Surveys also have not identified XMRV infection in the general human population 53,54,55,56 or in humans at high risk for viral infections (e.g., HIV-1-infected individuals).57,58,59,60,61,62 "
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    ABSTRACT: Xenotropic murine leukemia virus-related virus (XMRV) was discovered in 2006 in a search for a viral etiology of human prostate cancer (PC). Substantial interest in XMRV as a potentially new pathogenic human retrovirus was driven by reports that XMRV could be detected in a significant percentage of PC samples, and also in tissues from patients with chronic fatigue syndrome (CFS). After considerable controversy, etiologic links between XMRV and these two diseases were disproven. XMRV was determined to have arisen during passage of a human PC tumor in immunocompromised nude mice, by activation and recombination between two endogenous murine leukemia viruses from cells of the mouse. The resulting XMRV had a xentropic host range, which allowed it replicate in the human tumor cells in the xenograft. This review describes the discovery of XMRV, and the molecular and virological events leading to its formation, XMRV infection in animal models and biological effects on infected cells. Lessons from XMRV for other searches of viral etiologies of cancer are discussed, as well as cautions for researchers working on human tumors or cell lines that have been passed through nude mice, includingpotential biohazards associated with XMRV or other similar xenotropic murine leukemia viruses (MLVs).
    Emerging Microbes and Infections 04/2014; 3(4):e. DOI:10.1038/emi.2014.25 · 2.26 Impact Factor
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    • "XMRV was also reported to be presence in patients with chronic fatigue syndrome (CFS) (Lombardi et al., 2009). However, the link between XMRV and CFS is unclear, because in other studies it has failed to detect XMRV infection in CFS patients (Erlwein et al., 2010; Groom et al., 2010; Switzer et al., 2010; van Kuppeveld et al., 2010; Knox et al., 2011; Satterfield et al., 2011; Shin et al., 2011). However, gammaretroviruses are known to induce cancer in animals, understanding XMRV or related MLV infections in human prostate cancer tissues will shed light on their potential contribution to human disease. "
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    ABSTRACT: Background: Multiple etiologies have been hypothesized for prostate cancer, including genetic defects and infectious agents. A recently reported gamaretrovirus, xenotropic murine leukemia virus-related virus (XMRV) has been reported to be detected in prostate cancer. However, this virus has not been detected in similar groups of patients in other studies. Herein, we sought to detect XMRV in prostate cancers and benign controls in Sanandaj, west of Iran. Materials and methods: In a case-control study, genomic DNA was extracted from formalin fixed and paraffin embedded prostate tissues from a total of 163 Iranian patients. We developed a conventional and a nested PCR assay using primers targeting to an env specific sequence of XMRV. PCR assays were carried out on 63 prostate cancers and 100 benign prostate hyperplasias. Results: Beta-actin sequences were successfully detected in the DNA extracts from all prostate tissues, confirming DNA extraction integrity. We did not detect XMRV in samples either from prostate cancers or benign prostate hyperplasias using XMRV specific primers. Conclusions: We conclude that in our population XMRV does not play a role in genesis of prostate cancer.
    Asian Pacific journal of cancer prevention: APJCP 11/2013; 14(11):6929-33. DOI:10.7314/APJCP.2013.14.11.6929 · 2.51 Impact Factor
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    • "XMRV was originally identified in human prostate cancer tissue and its association with human pathologies has been suggested in the last years. Recent data suggesting a recombination of two ancestor mouse XMRV sequences, called Pre-XMRV1 and Pre-XMRV2, in cell culture thereby generating XMRV [7] together with multiple studies not detecting XMRV sequences in human samples [11], [12], [14], [17], [18], [20], [32], [33], [34], [35], [36], [37] question an association of XMRV with human diseases. "
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    ABSTRACT: 22Rv1 is a common prostate cancer cell line used in xenograft mouse experiments as well as in vitro cell culture assays to study aspects of prostate cancer tumorigenesis. Recently, this cell line was shown to harbor multiple copies of a gammaretrovirus, called XMRV, integrated in its genome. While the original prostate cancer xenograft CWR22 is free of any retrovirus, subsequently generated cell lines 22Rv1 and CWR-R1, carry this virus and additionally shed infectious gammaretroviral particles in their supernatant. Although XMRV most likely was generated by recombination events in cell culture this virus has been demonstrated to infect human cells in vitro and 22Rv1 as well as CWR-R1 cells are now considered biosafety 2 reagents. Here, we demonstrate that 22Rv1 cells with reduced retroviral transcription show reduced tumor angiogenesis and increased necrosis of the primary tumor derived from xenografted cells in scid mice when compared to the parental cell line. The presence of XMRV transcripts significantly increases secretion of osteopontin (OPN), CXCL14, IL13 and TIMP2 in 22Rv1 cells. Furthermore, these data are supported by in vitro cell invasion and differentiation assays. Collectively, our data suggest that the presence of XMRV transcripts at least partially contributes to 22Rv1 characteristics observed in vitro and in vivo with regard to migration, invasion and tumor angiogenesis. We propose that data received with 22Rv1 cells or equivalent cells carrying xenotropic gammaretroviruses should be carefully controlled including other prostate cancer cell lines tested for viral sequences.
    PLoS ONE 07/2012; 7(7). DOI:10.1371/journal.pone.0042321 · 3.23 Impact Factor
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