‘Chronic fatigue syndrome is not caused by XMRV virus, study shows’ – British Medical Journal

December 23, 2010

From the British Medical Journal, 22 December 2010 (Story by Jo Carlowe).

The XMRV virus, which has been implicated as a possible cause of chronic fatigue syndrome, is not the cause of the disease, an overview of four research papers has concluded.

The new findings, from researchers at University College London, the Wellcome Trust Sanger Institute, and the University of Oxford, show that cell samples used in previous research were contaminated with mouse DNA and that this was the source of the XMRV (xenotropic murine leukaemia virus-related virus). The papers are all open access and are available at www.retrovirology.com/.

The virus was first linked to chronic fatigue syndrome in a study published inScience in October 2009 (2009:326;585-9, doi:10.1126/science.1179052), which found that blood samples from patients with the syndrome carried traces of the XMRV virus.

The author of one of the studies, Greg Towers, a Wellcome Trust senior research fellow at University College London, said, “Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome.

“It is vital to understand that we are not saying chronic fatigue syndrome does not have a virus cause—we cannot answer that yet—but we know it is not this virus causing it.”

Professor Towers and his colleagues say that more rigorous methods are needed to prevent contamination of cell and DNA samples and that more consistent standards are required for identifying viruses and other organisms as the cause of a disease.

Paul Kellam, a coauthor and virus genomics group leader at the Sanger Institute, explained, “Increasingly we are using DNA based methods to accelerate our understanding of the role of pathogens in disease. These will drive our understanding of infection, but we must ensure that we close the circle from identification to association and then causation.

“The strongest lesson is that we must fully use robust guidelines and discriminatory methods to ascribe a cause to a disease.”

Reacting to the findings, Anthony Cleare, reader in affective disorders at the Institute of Psychiatry of King’s College London, said, “The original paper linking infection with the XMRV virus with chronic fatigue syndrome (CFS) received widespread publicity. However, if this latest paper is correct, and XMRV is a laboratory contaminant rather than a virus that infects humans, it could explain why later studies have not confirmed any link between XMRV and CFS. Patients with CFS need much more certainty before accepting a link between XMRV and their illness.”

Tim Peto, consultant in infectious diseases at the University of Oxford, said, “It came as a great surprise when XMRV was first suggested as being linked to chronic fatigue syndrome, and it was imperative that further tests be done to see if the findings could be repeated.

“There have now been a number of attempts which have failed to find the retrovirus in other samples, and this research suggests that in fact XMRV is probably a contamination from mouse DNA. These latest findings add to the evidence, and it now seems really very, very unlikely that XMRV is linked to chronic fatigue syndrome.”

A spokesman for the ME (myalgic encephalopathy) Association said that the organisation was keeping an open mind. He said, “Whether this study kills the theory that there is a close link between XMRV and chronic fatigue syndrome stone dead we just don’t know at this stage. There are still a large number of very serious investigations being carried out into this retrovirus, and the next set of results may show something completely different.”

8 thoughts on “‘Chronic fatigue syndrome is not caused by XMRV virus, study shows’ – British Medical Journal”

  1. Regarding the paper Disease-associated XMRV sequences are consistent with laboratory contamination cited in the above BMJ article, there are a number of glaring inaccuracies:

    • Hue et al claim that their PCR primers were specific to XMRV. This claim is false (Urisman et al, 2006; Dong et al, 2007)
    • Hue et al claim that there is no significant variation between the viral sequences isolated from patients. This is a false claim. Fully sequenced clones from two patients display a 2% sequence variation. The gag sequences isolated from other patients show considerable variation (despite containing the characteristic 24 bp deletion in glycogag) and polymorphism. The same is true of pol sequences (Urisman et al, 2006).
    • Hue et al have underestimated the sequence variability in fully assembled clones by 100% (Urisman et al, 2006).
    • Hue et al claim that the X-MLV-like sequence in 22RV1 cell lines is a clone. This is a false claim. The virus expressed by the 22RV1 cell line is XMRV (Knouff et al, 2009).
    • Hue et al claim that the sequences of XMRV expressed in the 22RV1 cell line are ancestral to the sequences found in XMRV sequences recently found in prostate cancer patients. This claim is true.
    • Hue et al claim that this is clear evidence that XMRV is a laboratory contaminant. This claim is false. The 22RV1 cell line originated in one patient suffering from prostate cancer in 1993 (Pretlow et al, 2003). These cells naturally express XMRV and XMRV is found integrated into the DNA of these cells at about ten copies per genome (Knouff et al, 2009).
    • The fact that the sequences of XMRV in these cell lines is ancestral to XMRV isolated some 17 years later is actually clear evidence of XMRV replicating and naturally changing over time as a result of reverse transcriptase and provides direct evidence contradicting the hypothesis that XMRV is a laboratory contaminant.
    • Further evidence belies the hypothesis that XMRV is a contaminant, including studies which have mapped integration of XMRV in prostate cancer DNA into cancer-suppressing or -causing genes (Dong et al, 2007; Kim et al, 2008). The presence of integrated DNA means that it is not a contaminant.
    • XMRV proteins have been detected in prostate cancer patients (Schlaberg et al 2009). These authors demonstrated that IHC increased detection rates by 400% compared to PCR.
    • Arnold et al (2010) demonstrated the presence of antibodies to XMRV using FISH serology in prostate cancer patients who were otherwise healthy. Arnold and others also demonstrated that FISH improved detection rates by over 400% compared to PCR.

    Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al. (2006) Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2:e25.

    Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA, Ganem D, Derisi JL, Chow SA, Silverman RH. (2007) An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proc Natl Acad Sci. 104:1655-1660.

    Knouf et al (2009) http://jvi.asm.org/cgi/content/full/83/14/7353#R14

    Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. (2009) XMRV is present in malignant
    prostatic epithelium and is associated with prostate cancer, especially high-gradetumors. Proc Natl Acad Sci. 106:16351-16356.

    Pretlow, T. G., S. R. Wolman, M. A. Micale, R. J. Pelley, E. D. Kursh, M. I. Resnick, D. R. Bodner, J. W. Jacobberger, C. M. Delmoro, J. M. Giaconia, and T. P. Pretlow. (1993) Xenografts of primary human prostatic carcinoma. J. Natl. Cancer Inst. 85:394-398.

    Kim, S., N. Kim, B. Dong, D. Boren, S. A. Lee, J. Das Gupta, C. Gaughan, E. A. Klein, C. Lee, R. H. Silverman, and S. A. Chow. (2008) Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J. Virol. 82:9964-9977.

    Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA, Johnson NA, Bhosle SM, Liotta D, Hunter E, Marshall FF, et al. (2010) XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. Urology. 75:755-761.

  2. The BMJ have gone too far. They too are now spreading this lie. Then again, they have never wanted biomedical research into this disease to discover anything.

  3. The BMJ should be getting quotes from those finding the retrovirus, not from spokes people at patient charities who are not able to place the counter argument that these four papers cannot show the previous positive studies were a contaminant.

    All they show is that these researchers (of the four papers) managed to contaminate their own lab.

    It’s a disgraceful and disgusting attempt to halt research.

  4. Well done Garcia, an impressive response.
    What you have written should be read by a wider audience than is available on this website. Have you e-mailed Prof Racinello?
    You could try the BMJ but will it get published?
    Don’t let this good work go to waste. It merits a response from those able to evaluate it.
    All the best, Currer.

  5. Well said Currer, it is excellent.

    When is the Welcome Trust going to retract the statement? or do they think they are above science?

  6. This news broke on Monday, with many similar articles to the one above being published.

    Dr Raciniello of Virology uses the same headline as here (I guess it is from a press release??) but has changed his article substantially after comments by, for one, Eric Stein of the Cleveland Clinic showed his story to be factually incorrect.

    For instance, the journal Retrovirology where the papers were published is not peer reviewed in the classic sense, the submission just needs to be passed by the editor and one other, and accompanied by a payment.

    You can see what I’m talking about here http://www.virology.ws/2010/12/21/is-xmrv-a-laboratory-contaminant/ Do read the comments, you will find the Stein quote and the terms of submission for Retrovirology, among other salient facts.

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