Retraction Watch

Tracking retractions as a window into the scientific process

New study “puts…speculation to rest” about link between XMRV and chronic fatigue syndrome

with 26 comments

Could this really — and finally — be the end for the alleged link between XMRV, also known as xenotropic murine leukemia-related virus, to chronic fatigue syndrome (CFS)?

The title of the press release announcing a long-awaited study of the subject in mBio is blunt: “Viruses not to blame for chronic fatigue syndrome after all.” A quote in the release from Ian Lipkin, who led the study, is even more direct:

Lipkin says the National Institutes of Health wanted conclusive answers about the possible link. “We went ahead and set up a study to test this thing once and for all and determine whether we could find footprints of these viruses in people with chronic fatigue syndrome or in healthy controls,” says Lipkin. The study in mBio® puts the speculation to rest, he says. Scientists were wrong about a potential link between chronic fatigue syndrome and these viruses.

Retraction Watch readers may recall the XMRV-CFS story, which we started covering in May of last year when Science issued an Expression of Concern about one of the central studies supporting the alleged link. Controversy had swirled around the findings, along with sometimes bitter fights among scientists and activists, for some time by then. Jon Cohen and Martin Enserink wrote a great narrative of all this for Science in September 2011.

The Science study was eventually partially, and then completely, retracted, as was a study in PNAS of the same subect.

Meanwhile, one of the main supporters of the link, Judy Mikovits, ended up in a nasty fight with her former employer — and briefly in jail. The charges were later dropped.

As the release for the new study, which included 147 people with chronic fatigue syndrome and 146 healthy subjects, notes:

The authors of this study include many of the authors of the original papers that reported finding XMRV and pMLV in the blood of CFS/ME patients. This is an important point, says Lipkin, as their participation should lend credibility to the pre-eminence of these newer results over the flawed earlier studies, which offered a certain amount of false hope to the CFS/ME community.

Indeed, Mikovits is second author of the paper.

Science, it would seem, has spoken, and found the XMRV hypothesis wanting, Lipkin notes in the release. But other lines of research will continue:

“[W]e are not abandoning the patients. We are not abandoning the science. The controversy brought a new focus that will drive efforts to understand CFS/ME and lead to improvements in diagnosis, prevention and treatment of this syndrome.”

In a statement sent earlier today to Retraction Watch, the CFIDS Association of America — CFIDS stands for chronic fatigue and immune dysfunction syndrome — sounded similar notes:

Over the past three years, more than 70 publications have followed the original report linking CFS to XMRV. This well-designed, expertly executed study from Alter, et al addresses weaknesses of past efforts, provides a conclusive answer and offers closure. The totality of published evidence indicates clearly that there should be no lingering concerns about XMRV/pMLVs infecting individuals with CFS, the general population or blood donors.

We are grateful to the scientists, physicians, patients and federal agencies that participated in this effort as well as more than 30 studies of CFS and XMRV that preceded it. The intense effort dedicated to exploring XMRV as a possible pathogen in CFS demonstrates that academic researchers and government labs around the world can rapidly mobilize resources when provided a promising lead. The CFIDS Association of America is dedicated to the relentless pursuit of science that translates to meaningful diagnostic and treatment advances for people living with CFS. It is disappointing that XMRV did not illuminate that path, but we will translate the heightened awareness and scientific engagement to hope for better care and ultimately a cure for CFS.

Written by Ivan Oransky

September 18th, 2012 at 12:00 am

  • Angela Kennedy September 18, 2012 at 2:46 am

    So XMRV and pMLV have not been found. But what about other HGRVs? What about other, as yet undiscovered retroviruses? What about other viruses per se? These have NOT been ruled out at all, by this study or elsewhere. What will be interesting is how that simple scientific fact will be treated. Embargo breaking headlines, and the press release itself (!) has already sown confusion by saying just ‘viruses’ have been ruled out! Patient confidence in scientists in this field and the media reporting them has understandably been reduced, when the language used so often does not accurately represent the actual findings, or indeed even the scientific process! The whole field needs clarity and linguistic accuracy more than ever, from the scientists themselves. But so far, this has not been forthcoming, and ideological attachment to prevailing but fundamentally unsafe psychogenic explanations for ME/CFS cannot be ruled out as a reason for this. But, this needs rectifying. Scientists in this field need to develop clear, unambiguous, more scientific language in how they discuss the whole issue.

  • RRM (@RegumM) September 18, 2012 at 3:03 am

    The link to the study is now dead.Perhaps this is because mBio hasn’t published the paper themselves yet:

    • Jack September 18, 2012 at 3:12 am

      Methinks there is a mouse in the machine :)

      Well it’s been a long long time coming. I am very pleased it has finally come out. Also pleased to hear Mikovits endorsing the study wholeheartedly.

      Will try and listen in to the press debrief later today:

      • Ke September 18, 2012 at 1:21 pm

        Of course she endorsed nothing found in a symptom cohort. LOL

  • Tony Mach September 18, 2012 at 5:24 am

    What hasn’t been put to rest is how Mikovits and Ruscetti made their lab-results.

    (Wink, wink, table 4 in the 2010 “Mikovits/Ruscetti Addendum”)

    • Tony Mach September 18, 2012 at 5:47 am

      And one more thing: The parallels between the reported behavior of Judy Mikovits (passing of XMRV as the cause ME/CFS, among other actions by her), and John Crewdson’s account of Robert Gallo’s behavior (passing of the HTLV family of viruses as the cause of AIDS, among other actions by him) seem to me more than coincidental. Either Judy Mikovits has used Crewdson’s book as an manual, or she aquired Gallo’s methods from some other place (hmmm, why do I have think of Ruscetti’s lab?)

      (And just for the record: It was Luc Montagnier in his sane days, who found HIV, then called “LAV”, as the cause of AIDS – Gallo’s only contribution to AIDS was spreading of misinformation).

      • Ke September 18, 2012 at 6:19 am

        Dr Mikovits has been one of the few scientists who has approached this appropriately. The next step is next generation sequencing. PCR cannot detect MLVs in wild mice. So why keep using PCR on humans after another study proved there are people with an immune response to MLVs?

      • JudyH September 18, 2012 at 9:52 am

        Um, make that Françoise Barré-Sinoussi and Jean-Claude Chermann who discovered the cause of AIDS.

    • Ke September 18, 2012 at 6:15 am

      Excuse me Tony, but others confirmed their results. Lo et al., Lee et al., Paolucci et al., and Grossberg et al.

      You are selecting you data, rather than looking at the entire field.

      • Marco September 18, 2012 at 12:00 pm

        Ke, can you explain how the retracted Lo et al paper supports the Mikovits finding? Or how Paolucci’s 2 out of 12 with detectable MLV/XMRV (note, MLV is not XMRV) fits with the >60% XMRV Mikovits found? Or how Grossberg et al finding a completely different retrovirus confirms the original finding?

        In my world those results contradict(!) those of Mikovits & Ruscetti.

      • Ke September 18, 2012 at 1:18 pm

        Paolucci found xmrv and mlv. Please read the paper.

        “The finding of two related, but different, virus sequences (polytropic MLV and XMRV) in two CFS patients,”

        Grossberg’s virus is designated as XMRV in the Genbank.

        In my world I look at the data.

      • Marco September 18, 2012 at 3:06 pm

        Yes, Ke, Paolucci found XMRV in *one* patient out of 12. Quite a difference from >60% (wasn’t it 67% or so?).

        Regarding Grossberg et al:
        “The NCBI taxonomy database is not an authoritative source for nomenclature or classification – please consult the relevant scientific literature for the most reliable information” – Grossberg et al describe it as distinctly different from XMRV, so I’d like to keep with the original source.

      • Ke September 22, 2012 at 9:24 am

        Paolucci tested a fatigue cohort, the Lombardi paper was required PEM. So 1 in 12 is expected for when a test will only find one sequence and when there will be multiple sequences. The other 1 was another sequence. So that is 2/12. What about sequences they have not yet looked for? They also found no evidence of contamination just as in all the other studies.

        The Grossberg virus is an MLV-related virus and is under XMRV. Now that Coffin changed xmrv to mean only the VP62 strain alone, well yes lets not call it XMRV. It should along with all the other ME retroviruses be called a gamma retrovirus.

        Added to that is the fact that the designations xenotropic, polytropic, modified polytropic and ecotropic are all subjective anyway. They have no meaning. And gamma’s infect in familes.

  • Ke September 18, 2012 at 6:13 am

    The study reports finding serology positives in a cohort of patients selected with an unrecognised criteria.

    The serology test only reacts to MLVs, not contaminants or endogneous retroviruses.

    This is evidence that further research is required and that another study this time using an accurate criteria is now required.

    • SG September 18, 2012 at 9:44 am

      I am not sure what you are getting at but the mBIO study used serology and found 9 positives (out of 147) amongst the CFS patients and 9 positives (out of 146) normal controls. So, the serology does NOT correlate with the disease. Whatever the positives are (and to say that serology only reacts to MLVs makes me doubt how much you know about serology and immunology ) they have NOTHING to do with CFS.

      • Ke September 18, 2012 at 1:20 pm

        The serology shows people are infected. The cohorts were not shown to all have the cardinal feature of ME. CFS is a label and not the disease ME.

      • SG September 18, 2012 at 1:41 pm

        Again, I question your knowledge of what serology can and cannot tell you. The serology shows that those 18 folks have antibodies that can bind to a mouse virus. Maybe the mouse virus happens to have an epitope that is similar to some other virus or bacteria and it was that infection that gave rise to the cross reacting sera. The answer is pointless though since there is NO correlation between being serology positive and having the disease. Further work on a XMRV-CFS link would be a monumental waste of time and money. Spend the money on CFS research that at least has a chance of telling us something about the disease. Mikovits’ work is a dead end.

      • Ke September 22, 2012 at 9:30 am

        Again I do question you knowledge of serology, I know it to be wrong.

        The serology is evidence those people, none who were shown to have ME, are producing an immune response to a MLV. There is nothing else that has ever in history cross reacted with that antibody but an MLV.

        CFS is a label not a disease, so I also question your knowledge about ME.

        The more than 6 PCR positive results in the multi lab study are also evidence that gamma retroviruses are infecting people. Something that almost every negative study failed to find.

        So the link is MRVs to ME, not xmrv to cfs. And it backed with PCR and serology results.

        Mikovits work is only the begining. The cohort is the major problem. You can’t say something isn’t associated when you pretty much let anyone into the study under the cfs label.

  • Jack September 18, 2012 at 2:32 pm

    “…To avoid drawing incorrect conclusions about the presence of virus based on the antibody reaction alone, it is imperative to use appropriate control experiments in parallel.

    In the 2009 study and this multicenter study, a monoclonal antibody produced from a rat (7C10 rat monoclonal antibody) was used in the tests. However, this particular antibody has been shown to cross-react with a number of other different viruses when it was originally produced in the early 1980s.[6]

    As the authors indicate in the mBio paper, the fact that the positive antibody signal was found in equal numbers of CFS case and healthy control subjects’ serum is strong evidence that it is a sign of nonspecific cross reactivity with no clinical relevance. It is also worth noting that study authors agreed in advance that the only “subjects with two positive results in the same sample type were considered positive for XMRV/pMLV.”

    The 18 samples that tested positive by this method did not meet the stated standard for a “positive” result as agreed to by all the authors…”

    • Ke September 18, 2012 at 2:54 pm

      The serology assay is based on the monoclonal antibody SU protein of the SFFV. It does not react with anything but MLVs.

      The CAA are talking about something else.

      • SG September 22, 2012 at 10:37 am

        Let me quote Dr. Ian Lipkin who knows more than both of us and agrees with me.

        “The one wrinkle is that there were patients who were found to be XMRV-positive in serological tests by Francis Ruscetti, [an immunologist at the NIH in Frederick, Maryland,] in 9 cases and 9 controls. Some might say that this is evidence that there are people who are infected with XMRV, even if it isn’t associated with CFS. But I have concerns about that interpretation. If you consider this in the context of the work that shows that XMRV originates in the laboratory then I think we can probably close the door on this once and for all.”

        “As far as we know, there is no human being that is infected with XMRV.”

        Follow his advice and close the door. Monoclonal antibodies can cross react, monospecific sera can cross react, polyclonal sera always cross reacts.

  • Kate September 18, 2012 at 7:27 pm

    Another paper refuting the link between XMRV and prostate cancer. More retractions to come?

  • Grant Jacobs September 18, 2012 at 10:30 pm

    Looks like the PLoS Pathogens paper “Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant” has just been retracted today:

    “In light of the findings from a recent study “In-Depth Investigation of Archival and Prospectively Collected Samples Reveals No Evidence for XMRV Infection in Prostate Cancer” (…) and others in the field, the editors of PLOS Pathogens have issued a retraction of this study. The association of XMRV with prostate cancer has now been thoroughly refuted. Although the original finding of a novel gammaretrovirus, XMRV, with the use of a pan-viral detection microarray is valid, and sequencing and phylogenetic characterization of the virus still stands, the editors agree that it is clear that XMRV found in this study is laboratory-derived and there is no association of XMRV with prostate cancer. As a result the paper was retracted from PLOS Pathogens on September 18th, 2012. (comment on this retraction)”

    • Ke September 22, 2012 at 9:31 am

      Since when does IHC and FISH produce a result from contamination?

  • David September 20, 2012 at 5:54 pm

    About CFS called ME in UK from the DAILY MAIL ONLINE writen by
    Sonia Poulton

    ME is no more ‘in the mind’ than Multiple Sclerosis. When is the world going to get that?

  • sylvia franklin September 17, 2013 at 1:08 am

    Articles always sound good but never a many using big articulating words to described an express the symptoms and pain of chronic fatigue, I don’t know how this is possible if you’ve never lived with this illness as a patient or a family member who suffers just as much with constant care..Drs. and researcher have degrees and have labored to remedy this illness. The problem is your education and thinking outside the box will be the only way you will be able to find the answer with the help of the Lord first. I’ve had this illness since 1982.. younger age BMI wasn’t a problem was a size 5. 9..12..16.22.24. now 20/22.. you want use people who has been in this from the very begining because of age and BMI.I have my history blood work statement from drs..specialist mayo clinic.. mobile sleep hospital..Hippocrates health institute..UAB birmingham and more. This illness has blown me up then I get skinny to blow back up..I’ve been on :medication beyond..but you only want little skinny young people for research..there’s not much I’ve not studied or tried with this illness u see I’m not depressed that is be to my Lord Jesus Christ..You will continue to make money on article of hope that will never be fruitful for us who are suffering. Another area in Birmingham had application to be considered for the study..they turned me down because of age and weight but if I lose weight they may can’t put this illness in a box based on age and weight..I ve been on both ends can explain important elements they are missing. I’m not blaming the profession its what you’ve been taught..I know I can help with a real true understanding of this disease and what I’ve tried and results if any. Well hope you can understand tired of reading what they think chronic fatigue is its me..thanks be blessed!

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