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Chronic fatigue syndrome virus doubt

“A new study has cast further doubt on the idea that a virus called XMRV causes chronic fatigue syndrome,” BBC News has reported.

In 2009 the condition, also known as myalgic encephalomyelitis (ME), was linked to a virus similar to one found in mice after a study discovered it was present in blood samples from people with the condition.

This well-conducted laboratory research examined the debated link by assessing the purity and ancestry of viral samples isolated from human cells. Based on their findings, the researchers conclude it is very likely that the human cells in the previous study had been contaminated with DNA from mice cells or by cells that contained a virus very similar to XMRV. On this basis they call for more rigorous detection methods during testing.

The authors did not directly analyse the samples from the original study that suggested a causal link. As a result, they cannot prove that the samples were contaminated, but their conclusion that contamination is highly likely sheds doubt on the theory that XMRV causes ME. The cause of the condition is still unknown, and this research does not completely rule out XMRV or exclude another as yet unidentified virus from having some role.

Where did the story come from?

The study was carried out by researchers from University College London, the Wellcome Trust Sanger Institute in Cambridge and the University of Oxford. The study was funded by the European Community’s Seventh Framework Programme, the UK National Institute for Health Research, the Wellcome Trust, the Medical Research Council and The Royal Society.

The study was published in the peer-reviewed medical journal Retrovirology.

The newspapers have reported the findings of this study accurately, placing emphasis on the researchers’ conclusion that ME is not likely to be caused by this virus.

What kind of research was this?

The cause of myalgic encephalomyelitis (ME), now more commonly termed chronic fatigue syndrome (CFS), is largely unknown, but one theory has suggested that a virus called XMRV (xenotropic murine leukaemia virus-related virus) may be involved.

This virus has been linked with other diseases, but not all studies on its potential role in ME have found an association. The 2009 study that first linked XMRV to ME involved examination of blood cells from ME patients, finding that most samples contained DNA from the virus.

The XMRV virus circulates among mice, although in the laboratory it has been found to infect cells from a variety of animal species. The researchers say that the link between the virus and human disease is controversial, and that studies in this area have not produced consistent results. The virus is also found in up to 6% of healthy humans. In this study the researchers undertook a laboratory study to demonstrate that viruses from mice can contaminate human samples.

What did the research involve?

Researchers examined the DNA from different types of mice to see whether they could detect the presence of the virus. All of them were positive. They also investigated how frequently several lines of human cells (samples of extracted human cells cultured for experimentation) were contaminated with the XMRV virus. They tested contamination among nine different human cell lines, including tumour cells. They then investigated the presence of the XMRV virus using complex methods of detection, and also set out to see whether the human cells included viruses that could be mistaken for XMRV.

The researchers then undertook an evolutionary analysis of how the viral DNA comes to be in certain human cells lines. It is reported that XMRV is regularly found in prostate cancer cells, so the researchers cloned these cells and purified the viral DNA from them. They then used complex statistical methods to examine the evolutionary relationships between the sequences they had isolated from these cells.

What were the basic results?

DNA in human cells was frequently contaminated with DNA from different viruses, some of which originated from XMRV but some of which could be mistaken for having an XMRV origin. When cloning pure XMRV from the prostate cancer cells for testing purposes the researchers found that the viral DNA thought to be from XMRV was actually a mix of DNA from two different viruses. They say that this strongly suggests that contamination is the source.

Further analysis showed that viral sequences reported to be coming from unlinked patients actually seemed to be derived from the same original cell line, also suggesting that contamination was a likely reason for detection of this virus in human samples. Finally, the researchers found that the type of XMRV that is derived from human samples is less diverse than that from mouse cells. This is unexpected for a virus thought to cause an infectious disease.

How did the researchers interpret the results?

The researchers have concluded that the XMRV found in patient samples is likely to be derived from contamination either by mouse DNA or by other cells infected with viruses that originate in mouse DNA. They conclude that XMRV is unlikely to be a human pathogen.

They acknowledge that without testing original samples it is difficult to establish whether human samples in previous studies have definitely been contaminated.

Conclusion

This well-described laboratory study has used complex methods to analyse DNA and to determine the evolutionary history of retroviruses found in the DNA of mouse and human samples. The researchers conclude that it is possible, and likely, that samples in previous studies which found that XMRV has a causal link with ME, were contaminated with material including DNA from mice cells or from other cells containing a closely related virus.

They note that while it is not possible to prove that previous samples have been contaminated they are confident of their conclusions. One of the lead researchers has been quoted as saying;: “Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome. Our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome samples”. They say that rigorous methods should be used when screening for the virus in future.

The causes of ME are unknown, and while this research provides evidence that XMRV may not be the cause, this does not completely rule out XMRV or exclude another as yet unidentified virus from having some role. Other possible contributing factors include genetic, environmental, lifestyle and psychosocial factors.

Article amended: January 6 2011

Links to the headlines

ME ‘virus’ was actually a lab mistake, study says. The Independent, December 21 2010

Scientists conclude mouse virus does not cause ME. The Guardian, December 21 2010

ME ‘not caused by the XMRV virus’. BBC News, December 21 2010

Links to the science

Hue S, Gray ER, Gall A et al.Disease-associated XMRV sequences are consistent with laboratory contamination. Retrovirology, 2010, 7:111

Readers' comments (3)

  • What a pity you didn't go to the source instead of picking up part way through and only reporting on one side of the controversy. From WPI

    Turning Today’s Discoveries Into Tomorrow’s Cures
    January 1, 2011
    XMRV: A Human Retrovirus with Unknown Pathogenic Potential, Not a Lab Contaminant
    The recent proclamation that “XMRV is not the cause of CFS,” came from an individual who did
    laboratory experiments to show how PCR experiments can become contaminated. These results
    have nothing to do with the reality of a disease or the methods used by those who have detected
    XMRV in the blood and tissue of patients found to be infected. The positive studies, which
    cannot be explained away by PCR experiments, are those which have used multiple methods to
    show that XMRV is a live replicating gamma retrovirus in human blood and tissue samples using
    the gold standard methods of viral isolation and antibody testing, in addition to PCR.
    Unsupported conclusions, such as the one offered by the Wellcome Trust spokesman, often
    create sensational headlines but do little to move science forward. Authors of the positive
    XMRV studies have been extremely careful not to claim causality, realizing that more scientific
    research is required to make such a statement. However, one fact still remains clear. Not one of
    the negative studies changes the results of the scientific research done by Lombardi et al., Lo et
    al., Urisman et al., and Schlaberg et al.
    The WPI-led scientific study, which rigorously ruled out contamination, revealed high
    associations of gamma retroviruses with physician-diagnosed CFS patients, using four different
    methods of detection. Recent commentary associated with the negative research papers on
    XMRV, which used only one testing method, claimed that these studies proved that XMRV was
    not the cause of human disease. On the contrary, what the authors of the “contamination studies”
    confirmed is something that most experienced scientists already know; there are risks associated
    with using PCR if one does not properly control for contamination. They cannot conclude that
    other research groups had the same problems or that “XMRV is not the cause of CFS”.
    Most significantly, the recent Retrovirology publications failed to address the most
    important pieces of scientific evidence of human infection in the previous XMRV studies,
    including the fact that XMRV positive patients produce human antibodies to gamma
    retroviruses, XMRV integrates into human tissues, and infectious virus has been cultured
    from the blood of hundreds of patients with a diagnosis of Chronic Fatigue Syndrome and
    M.E. Humans do not make antibody responses to mouse DNA sequences from
    contaminated lab experiments. The Retrovirology studies only point out that XMRV
    research cannot be done in a mouse laboratory without extreme caution and should not
    rely solely on PCR methods.
    Many researchers realize that the question of gamma retroviruses and human disease cannot and
    should not be dismissed lightly. Retroviruses integrate into their host’s DNA causing life long
    infection. Human retroviruses, such as HIV and HTLV-1, are causative for immune
    deficiencies, neurological disease and cancer. Animal studies involving XMRV demonstrate that
    the virus moves quickly away from the blood to various organs within the body, such as the
    spleen, lymph nodes, GI tract, and reproductive organs. This helps to explain why the virus is
    difficult to detect in blood even as it replicates in the tissues of those infected. Other studies
    using mouse models of Murine Leukemia Virus infection, a close relative of XMRV, have
    shown significant tissue involvement soon after infection, resulting in many physical symptoms
    of disease including cognitive deficits and immune deficiencies, symptoms which are well
    documented in patients with XMRV associated diseases.
    Many anxious patients have asked, “Where do we go from here?” and “Is this the end of XMRV
    research?” The answer to the second question is an unequivocal “no.” As to the first question, a
    quick check of the status of ongoing research in various labs confirms that the research groups
    who have been working on XMRV over the past year are still hard at work developing better
    assays to check the world’s blood supply for the new retrovirus, finding correlates of immune
    dysfunction, engaging in animal studies, extending their findings to other groups of patients, and
    in general, enthusiastically continuing their research. They understand that novel scientific
    discoveries, which threaten current dogma, will continue to be challenged until the evidence can
    no longer be denied. For instance, there are still those few who question the fact that HIV is the
    cause of AIDS. It took Nobel Prize winner, Dr. Barry Marshall, 17 years and three trials in
    which he infected and then cured himself of H-Pylori associated ulcers, before the medical world
    would accept the fact that the bacterium causes the disease. Today we are engaged in a new
    battle to prove that human gamma retroviral infections, such as XMRV, are underlying
    pathogens in neuro-immune diseases and untold cancers.
    It is clear that more research must be done to clarify the role of gamma retroviruses in human
    disease. However, when a pathogen such as XMRV is found in over 80% of those tested with
    the same diagnosis, causality is clearly a reasonable hypothesis that begs further scientific and
    medical research. It is a known fact that important questions of causality can often be answered
    through well designed clinical trials. For those who have suffered for years from these
    debilitating diseases, novel drug trials cannot begin soon enough.
    WPI’s collaborative research projects are revealing the infectious and inflammatory nature of
    neuro-immune diseases, providing strong evidence against the use of CBT and exercise therapy
    as rational “treatments” for those who are ill. Such knowledge underscores the urgent need for
    much more private and federal funding of biological research to provide diagnostic tests and
    effective drug therapies for the millions who are ill, stop the spread of infectious retrovirus(es),
    and end the devastating cycle of disease.
    .
    Annette Whittemore
    President
    Whittemore Peterson Institute

    Unsuitable or offensive?

  • The study you are quoting is an interpretation by Temple et al for the Wellcome Trust which has been presented as a firm assertion: ‘XMRV is not the cause of CFS’.

    A more accurate presentation of what the Hue study actually concluded would be that anyone using PCR as a method of looking for retroviruses such as XMRV needs to be careful to avoid contamination affecting their results.

    As PCR was only one of four methods used by the Whittemore Peterson Institute in identifying XMRV, even if contamination in PCR was proven, it still would not affect the other findings of that study.

    In addition, Lombardi is far from the only study which has concluded that a biological cause for this disease is likely. Three other studies have confirmed the presence of XMRV in ME/CFS patients.

    You may wish to ask yourself – since Wellcome is a major sponsor of the forthcoming but deeply-flawed PACE Trial, which aims to prove that the cause of ME/CFS is psychological – what their aim in making this statement really was?

    Unsuitable or offensive?

  • The study you are quoting is an interpretation by Temple et al for the Wellcome Trust which has been presented as a firm assertion: ‘XMRV is not the cause of CFS’.

    A more accurate presentation of what the Hue study actually concluded would be that anyone using PCR as a method of looking for retroviruses such as XMRV needs to be careful to avoid contamination affecting their results.

    As PCR was only one of four methods used by the Whittemore Peterson Institute in identifying XMRV, even if contamination in PCR was proven, it still would not affect the other findings of that study.

    In addition, Lombardi is far from the only study which has concluded that a biological cause for this disease is likely. Three other studies have confirmed the presence of XMRV in ME/CFS patients.

    You may wish to ask yourself – since Wellcome is a major sponsor of the forthcoming but deeply-flawed PACE Trial, which aims to prove that the cause of ME/CFS is psychological – what their aim in making this statement really was?

    Unsuitable or offensive?

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