A report finding an association between chronic fatigue syndrome (CFS) and a mouse virus — xenotropic murine leukemia virus-related virus (XMRV) — drew a cacophony of skepticism from neurologists and infectious disease experts when it first appeared in Science in 2009. Subsequent papers — as recently as this past May — failed to replicate the original findings in patients with CFS and went further with claims that the virus found in the patients in the original were likely due to laboratory contamination from mouse DNA.
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Now, in another paper that has resulted in a partial retraction of the original 2009 data, a new multi-laboratory study reports finding no association between CFS and a mouse virus and suggests that the 2009 findings were the result of laboratory contamination. The new study was published in the Sept. 22 edition of Science.
The lead study author Michael P. Busch, MD, PhD, director of the Blood Systems Research Institute in San Francisco, told Neurology Today that nine laboratories performed multiple assays on samples drawn from 15 subjects who had been participants in the original 2009 study — 14 of whom are patients with CFS — and 15 healthy subjects. Additionally, researchers also prepared stocks of XMRV-infected human cell lines to create a set of low-level positive controls.
These samples were distributed in a blinded fashion to nine laboratories which performed assays designed to detect XMRV/MLV nucleic acid, virus replication, and antibody.
DR. MICHAEL P. BUSCH...Image Tools
Six of seven laboratories that performed nucleic acid amplification testing on three sample types (plasma, peripheral blood mononuclear cells and white blood cells) reported no positive result for coded clinical samples, whereas these laboratories detected XMRV in 100 percent of the spiked controls.
Two laboratories that did detect the virus in the patient cohort on some of the assays also reported it at the same rates among the healthy control samples, and replications of the tests found discrepant results, indicating a false positive finding, said Dr. Busch, adjunct professor in the department of laboratory medicine at the University of California, San Francisco.
“It is very strong evidence that the previous data using the same assays is almost certainly invalid,” he said in an interview. “Our main conclusion is that using a highly selective sample, including patients with CFS who were previously reported as XMRV positive, we were unable to accurately detect the virus in any of these people.”
In the “partial retraction” that accompanied the new study, authors of the original 2009 report in Science that found the positive association between XMRV and CFS, stated that a re-examination of samples used in the previous study “shows that some of the CFS peripheral blood mononuclear cell DNA preparations are contaminated with XMRV plasmid DNA.”
On the basis of that contamination, the authors retracted selected data reported in specific graphs and tables of the original 2009 report, but appeared to stop short of fully disowning their findings.
The study by Dr. Busch and colleagues in Science is not the first to refute the 2009 association between XMRV and CFS, but it is one of the most definitive and would appear to put to rest permanently a subject that has been fraught with controversy from the beginning.
For many patients, the original finding was welcome news because it seemed to establish a viral cause for symptoms that have been viewed in some quarters as psychosomatic. But as reported by Neurology Today, two other studies appeared in May this year in Science failing to replicate the XMRV-CFS association; at the time, the editors of Science took the unusual step of publishing an “Expression of Editorial Concern” from its editor-in-chief Bruce Alberts, PhD, about the 2009 study.
And in the wake of the new report refuting the connection, the Whittemore Peterson Institute announced that Judy Mikovits, PhD — the lead author of the 2009 report — was terminated from her position as research director. Institute President Annette Whittemore, in a statement, said that Dr. Mikovits has “publicly confirmed that her employment was terminated.”
Whittemore's statement also drew oblique reference to allegations that data in the original report may have been manipulated. “The Whittemore Peterson Institute has recently been made aware of these allegations about Dr. Mikovits' presentation, and [we] are investigating accordingly,” Whittemore said. “…It is our understanding that some patient ID numbers may have been changed to a new set of coded numbers during the research to protect their privacy before publication. We will work with Science in hopes of addressing their concerns and to gain a full understanding of the cause of any potential discrepancies.”
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Experts who reviewed the new report in Science and the accompanying partial retraction say this along with previous published papers all but conclusively put to rest the association between XMRV and CFS.
“I think the new study provides compelling evidence that there is no evidence for a link between XMRV and CFS,” said Kenneth L. Tyler, MD, Reuler-Lewin Family Professor and chair of the department of neurology at the University of Colorado-Denver. “There is now no compelling evidence whatsoever that links CFS with either the presence of XMRV or the detection of antibodies against XMRV.”
“In light of other data now available the original results were likely due to laboratory and reagent contamination,” Dr. Tyler told Neurology Today, for which he serves as associate editor.
He added that he believes the problems with the original Science publication of a positive finding merited a full, rather than a partial retraction. “The retracted material casts into doubt the entire thesis of the paper linking XMRV and CFS and a partial retraction only creates confusion for readers,” Dr. Tyler said.
Joseph Berger, MD, voicing the skepticism of many neuroimmunologists, said the study and retraction “speak for themselves” and lay the matter to rest. “The XMRV [found in the earlier publication] was clearly a contaminant,” he said.
“I personally fall into the camp of neurologists that is very skeptical about the entire entity of chronic fatigue syndrome,” said Dr. Berger, professor and chairman of neurology at the University of Kentucky College of Medicine in Lexington. “I suspect that for some patients there is an underlying identifiable pathological process, such as multiple sclerosis, or a chronic infection. But I am unconvinced that this is a uniform disorder that will ultimately be proven to be the consequence of a single entity, be it microbial or other.”
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He added, “However, I keep an open mind to this possibility.”
Dr. Tyler emphasized that the new Science publication only addresses the failure to reproduce the original linkage between XMRV and CFS, and does not rule out a potential role for other viruses, related or not. “But the field is essentially back to where it was before this linkage to XMRV was reported,” he said.
However, Dr. Busch expressed a more optimistic take on the controversy saying that it has focused research dollars on unraveling the mystery of CFS. “From a research perspective there is now very elevated interest in trying to understand the cause of CFS, and recognition that it is a complicated and heterogeneous disorder,” he said. “There is a lot of research activity focused on what the disorder means in terms of immune function.”
• Simmons G, Glynn Sa, Busch MP, et al, for the Blood XMRV Scientific Research Working Group. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: A multi-laboratory study. Science 2011; E-pub 2011 Sept. 22.
• Lombardi VC, Ruscetti FW, Gupta JD, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science
• Coffin JM, Stoye JP. A new virus for old diseases? Science 2009;326:530-531. Knox K, Carrigan D, Levy JA, et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science 2011; E-pub 2011 May 31.
• Paprotka T, Frankenberry-Delviks KA, Pathak VK, et al. Recombinant origin of the retrovirus XMRV. Science 2011; E-pub 2011 May 31.
• Alberts B. Editorial expression of concern. Science 2011; E-pub 2011 May 31.
• Hurley D. Neurologists intrigued, but not convinced, by study linking retrovirus to chronic fatigue syndrome. Neurology Today, Dec. 3, 2009; http://bit.ly/k9wsjN