New UK study casts doubts on the link between XMRV and ME/CFS

Press release issued by the Wellcome Trust Sanger Institute, 20 December 2010

Chronic Fatigue Syndrome is not caused by XMRV
New research shows XMRV virus is a lab contaminant

A virus previously thought to be associated with chronic fatigue syndrome is not the cause of the disease, a detailed study has shown. The research shows that cell samples used in previous research were contaminated with the virus identified as XMRV and that XMRV is present in the mouse genome.

XMRV was first linked to chronic fatigue syndrome – also known as myalgic encephalomyelitis (ME) – in a study published in October 2009, where blood samples from chronic fatigue syndrome patients were found to have traces of the virus. XMRV had also been identified previously in samples from certain prostate cancer patients.

The new study, published in Retrovirology, identifies the source of XMRV in chronic fatigue syndrome samples as being cells or mouse DNA rather than infection by XMRV. The research does not rule out a virus cause of chronic fatigue syndrome – it is simply not this virus.

The research team developed improved methods to detect XMRV against the genetic noise of other sequences and make recommendations for future study of virus causes of human disease.

“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” says Professor Greg Towers, a Wellcome Trust Senior Research Fellow at University College London (UCL). “All our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome and prostate cancer samples.

“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.”

The team, from University College London, Wellcome Trust Sanger Institute and University of Oxford, showed clearly that the experimental design of previous studies would pick up sequences that resembled XMRV; however, in this improved study, they could prove that the signal was from contamination by a laboratory cell line or mouse DNA. The sequences from the contaminated cell line and chronic fatigue patient samples were extremely similar, contrary to the pattern of evolution expected during the infectious spread of a virus in a human population.

They also showed that the existing methods would indicate that one in fifty human cell lines they examined were infected with XMRV-related viruses: they showed that contamination of human tumour cells with XMRV-related viruses is common and that a principal prostate cancer line used is contaminated.

“When we compare viral genomes, we see signs of their history, of how far they have travelled in space or time,” says Dr Stéphane Hué, Post Doctoral Researcher at UCL. “We would expect the samples from patients from around the world, collected at different times, to be more diverse than the samples from within a cell line in a lab, where they are grown under standard conditions. During infection and transmission in people, our immune system would push XMRV into new genetic variants.

“Viral infection is a battle between the virus and the host and XMRV does not have the scars of a virus that transmits between people.”

Together the results demonstrate that XMRV does not cause chronic fatigue syndrome or prostate cancer in these cases. The team’s methods suggest ways to ensure that virus contamination does not confound the search for a cause of disease in future work.

The authors propose that more rigorous methods are used to prevent contamination of cell and DNA samples. They also suggest that consistent and considered standards are needed for identifying viruses and other organisms as cause of a disease.

“Increasingly, we are using DNA-based methods to accelerate our understanding of the role of pathogens in disease,” explains Professor Paul Kellam, Virus Genomics group leader from the Wellcome Trust Sanger Institute. “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.”

ENDS

A number of studies and commentaries on the subject have been published by the current issue of the online journal ‘Retrovirology’. To visit their website, click HERE

Whittemore Peterson Institute statement (text below):

WPI statement on XMRV research and PCR contamination:

The Lombardi et al. and Lo et al. studies were done using four different methods of detection. They were not simply PCR experiments, as were the studies by McClure et al. and others who have recently reported their difficulties with contamination. Experienced researchers such as Mikovits, Lombardi, Lo and their collaborators understand the limitations of PCR technology, especially the possibility of sample contamination. As a result, we and Lo et al. conducted rigorous studies to prevent and rule out any possibility that the results reported were from contamination.

In addition to the use of PCR methodology, the Lombardi team used two other scientific techniques to determine whether, in fact, we had found new retroviruses in human blood samples. We identified a human antibody response to a gamma retroviral infection and we demonstrated that live gamma retrovirus isolated from human blood could infect human cells in culture. These scientific findings cannot be explained by contamination with mouse cells, mouse DNA or XMRV-related virus-contaminated human tumor cells. No mouse cell lines and none of the human cell lines reported today by Hue et al. to contain XMRV were ever cultured in the WPI lab where our PCR experiments were performed. Humans cannot make antibodies to viruses related to murine leukemia viruses unless they have been exposed to virus proteins. Therefore, recent publications regarding PCR contamination do not change the conclusions of the Lombardi et al. and Lo et al. studies that concluded that patients with ME/CFS are infected with human gammaretroviruses. We have never claimed that CFS was caused by XMRV,only that CFS patients possess antibodies to XMRV related proteins and harbor infectious XMRV, which integrates into human chromosomes and thus is a human infection of as yet unknown pathogenic potential.

“The coauthors stand by the conclusions of Lombardi et al. Nothing that has been published to date refutes our data.” Judy A. Mikovits

Here’s a selection of newspaper and web coverage so far:

A number of studies and commentaries on the subject have been published by the current issue of the online journal ‘Retrovirology’. To visit their website, click HERE

Today’s BBC News story – contains additional comment from Professor Tim Peto, consultant in infectious diseases at Oxford University.

“Scientists conclude mouse virus does not cause ME” – The Guardian.co.uk

Reuters News Agency

“ME ‘virus’ was actually a lab mistake” – The Independent

Bloomberg

NPR Blog, US

Web MD Health News

Wall Street Journal health blog (Amy Marcus Dockser, who has been following the story closely)

Commentary on the NHS Choices website

15 thoughts on “New UK study casts doubts on the link between XMRV and ME/CFS”

  1. The papers that came out today mean nothing of the sort! This article is complete misrepresentation.

    1. If HMRV was contamination, there would not consistently be significantly different numbers of positives in patients and controls.

    2. If HMRV was a contaminant, there would not be an antibody response.

    3. If HMRV was a contaminant, there would not be viral mutation detected in the 15 years between the stored samples that Alter and Lo tested and the fresh ones. A contaminant would remain consistent.

    4. NONE of the positive papers were produced by labs that use mice.

    Speculation is not proof. Claiming that it is is disingenuous, and is bad science.

  2. This research does not show that XMRV, or more importantly MLV related retroviruses, are not the cause of ME. It does indicate that those researchers (from the Wellcombe Trust) contaminated their samples with a mouse retrovirus. Only further research will answer the question that the Wellcombe Trust Sanger Institute seems to believe is over. In short, they are exaggerating their studies results and abilities.

    This study does not explain why those finding the virus in patients get such largely differing results to controls. It also does not explain the immune response that the other researchers are finding. It does not explain why the labs finding the retrovirus in ME patients are unable to detect a mouse contaminant, nor why the CDC could not detect a mouse contaminant from the 20 WPI samples they tested. Nor why the CDC could find XMRV in the Phase IIa of the blood working group study, or why the WPI and NCI have the same results for serology in Phase IIb.

  3. I am surprised that you have been so hasty in accepting this research as being definitive.

    A lack of sequence diversity and other circumstantial evidence presented in a “pay to publish” journal like “Retrovirology”, is insufficient proof to disprove the case in favour of the XMRV connection, which has been subject to much more careful scrutiny over a prolonged period.

    What about the serology studies, the antibodies to virus that have been discovered in infected patients and the picture of the budding retrovirus ?

    Your judgement is in stark contrast with that of Graham Simmonds, who is leading the Blood Working Group investigation in the U.S. and who specifically ruled out concerns about contamination when he talked on the subject last friday, during the CFIDS Association webinar.

    The ME Association does the patient community a disservice by rushing to judgement in this way and patients will be justifiably unforgiving in the future when the science is eventually allowed to win out over politics.

  4. You can bet that the Wellcombe Trust won’t put money into finding the virus that they think might cause ME. Don’t want the truth to come out.

  5. Dionysius – We haven’t rushed to judgement – far from it. We are simply reporting what emerged today in the press release from the Sanger Institute and pointing people towards the newly published studies and commentary in “Retrovirology”.

    1. You had a choice about whether to give this “research” the oxygen of publicity and chose to do so very quickly, without presenting the counterbalancing evidence and arguments.

      People will draw their own conclusions.

  6. tonybritton – …. while trying to pass off these speculations as definitive.

    This is disingenuous behaviour. No paper that claims contamination should be reported on without any analysis of all of the accumulating evidence to the contrary.

  7. Awol is right about reporting the accumulating evidence to the contrary. It could be a few days before responses to this are in, and then it’s Christmas. People should be aloud to see the errors, and erroneous conclusions, that these people are drawing.

    The BBC is also badly reporting this research. They actually say XMRV is a mouse virus. But it has not been shown to be a mouse virus. They also quote a Professor Tim Peto who says that XMRV is is unlikely to be found in ME patients. What about prostate cancer? Which disease association are these people truly trying to kill? Can we have balanced reporting please. The BBC is not the BBC of old. It’s a hatchet job. We only want the truth, not propaganda.

  8. Interestingly, Retrovirology published five studies today, all purporting to uphold the contamination theory, all with consecutive URL’s

    http://www.retrovirology.com/content/7/1/112

    http://www.retrovirology.com/content/7/1/111

    http://www.retrovirology.com/content/7/1/110

    http://www.retrovirology.com/content/7/1/109

    http://www.retrovirology.com/content/7/1/108

    As Dr Harvey Alter said, in the BWG last Tuesday,

    “…/ But I still want to counter by saying that the current evidence for disease association is very strong, that XMRV or MLV is strongly associated with CFS.

    In those labs who do find the agent, it’s very reproducible. Year after year, same patients test positive.

    Confirmed by sequencing, reproducible over time.

    Dr. Hanson has demonstrated how critical the assays are. When they tweaked the assays, they are getting findings identical to the Lo lab.

    Diversity of XMRV/MLV being confirmed in WPI lab, so XMRV is not the only agent being confirmed there now.

    Using 100s of neg controls in same lab (Lo’s), all results for contamination were negative. Lo has done what Coffin recommended to test for contamination, and results were also negative. Always negative for contam. It isn’t logical to suggest otherwise.

    Stoye used single-case, anecdotal information to try to make a case. Simply because it has happened in the past isn’t a valid basis to negate reproducible data from 4 diff laboratories.”

  9. The research also does not correspond with this study:

    Knouf et al.
    ‘Multiple Integrated Copies and High-Level Production of the Human Retrovirus XMRV (Xenotropic Murine Leukemia Virus-Related Virus) from 22Rv1 Prostate Carcinoma Cells.’

    “Here we show that 22Rv1 prostate carcinoma cells produce high-titer virus that is nearly identical in properties and sequence to XMRV isolated by others and consist primarily of a single clone of cells with at least 10 integrated copies of XMRV, warranting further study of a possible role for XMRV integration in carcinogenesis.”

  10. ‘In a statement, professor Greg Towers, a Wellcome Trust senior research fellow at University College London, says: “Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome.

    “All our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome and prostate cancer samples.”

    However, he stresses: “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.”
    http://www.webmd.com/chronic-fatigue-syndrome/news/20101219/chronic-fatigue-syndrome-not-caused-by-xmrv?src=RSS_PUBLIC

  11. Obviously this study does not support what the Wellcome Trust want it to.

    Here are some quotes:

    Ian Lipkin http://merutt.wordpress.com/
    “These papers emphasize the pitfalls of molecular assays and raise concerns. Nonetheless, it is premature to rule out XMRV or related viruses as factors in prostate cancer or CFS. Links have also been made based on serology and the presence of viral proteins as well as of viral sequences. Thus, we still need appropriately powered, rigorous blinded studies of well characterized patients and controls. One such study is underway under the auspices of the National Institutes Health.”

    John Coffin http://blogs.wsj.com/health/2010/12/20/xmrv-raising-the-issue-of-contamination/
    “while his group’s study demonstrated that mouse DNA is everywhere in labs, none of today’s published papers ”definitively show that any prior study is wrong.””

    Yep, XMRV is still not disproven

  12. NHS choice have now changed the title of their article from ”Chronic fatigue syndrome ‘not virus’ to ‘Chronic fatigue syndrome virus doubt’

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