More Chinks in XMRV-Chronic Fatigue Link

More Chinks in XMRV-Chronic Fatigue Link

By John Gever, Senior Editor, MedPage Today
Published: September 23, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine.


Action Points
Note that this study suggests that the lab tests used in a previous study to detect XMRV, a mouse retrovirus, in the blood of patients with chronic fatigue syndrome (CFS) are unreliable, casting serious doubt on a purported link between the infection and the syndrome.

Point out that, however, the leader of the team that conducted the original study still stands by most of the data and feels that the possibility that mouse retroviruses infect people with CFS has not been ruled out.

The mouse retrovirus XMRV could not be found consistently in the blood of patients with chronic fatigue syndrome (CFS), according to a multicenter study that included the first researchers to link the virus to CFS.

But those researchers, led by Judy Mikovits, PhD, of the Whittemore Peterson Institute in Reno, Nev., refused to concede that the link was spurious -- even as they were forced to retract a portion of their initial research paper on XMRV and CFS.

Both the new study and the retraction were published this week online in Science, which will likely persuade most clinicians and researchers that the XMRV theory of CFS was a dead end.
The new study was conducted under the auspices of the Blood XMRV Scientific Research Working Group, an ad hoc collaboration of the field's major players intended to bring a measure of consensus.

Led by Michael P. Busch, MD, PhD, of the University of California San Francisco, it sent blood samples from 15 patients with CFS and 15 healthy controls to nine laboratories, including that of Mikovits.

The CFS patients were among those in whose blood Mikovits and colleagues had previously found the virus, leading to their 2009 paper in Science that ignited the current debate.
Unlike that initial study, though, lab personnel running the tests did not know which samples came from patients versus controls.

Seven of the nine labs failed to detect XMRV in any of the samples. One of them was that of Shyh-Ching Lo, MD, at the FDA, who in 2010 had published the only independent confirmation of the 2009 report.

Two did find the virus in patient samples -- Mikovits' and Francis Ruscetti's at the National Cancer Institute, which was part of the original 2009 team -- but they also found it in controls.
In addition, when these labs performed their tests on divided samples, the results were discordant.

"Based on these findings, we conclude that currently available XMRV/P-MLV [polytropic murine leukemia virus] assays, including the assays employed by the three participating laboratories that previously reported positive results on samples from CFS patients and controls, cannot reproducibly detect direct virus markers (RNA, DNA, or culture) or specific antibodies in blood samples," according to the Science report.

The researchers also agreed that the study was proof that XMRV poses little or no hazard to the blood supply.

Another blow to the XMRV-CFS theory came from two co-authors of the 2009 paper, Robert H. Silverman, PhD, and Jaydip Das Gupta, PhD, both of the Cleveland Clinic. They found that some of their reagents had been contaminated with XMRV, leading to false-positive results from certain of the assays reported in the paper.

The retraction was limited to two figures and one table in the 2009 report. According to a statement issued by Science, "the authors feel the [study's] conclusions do not stand on these figures and table alone and can be supported by the remaining evidence in the study."
However, several previous studies had indicated that contamination was a widespread problem in labs working with XMRV. One had concluded that the virus had arisen in the laboratory and had never circulated in the wild.

Last May, the growing doubts about XMRV and the 2009 paper in particular had led Science's editor to publish a "letter of concern" about the paper. It fell short of a full retraction but news reports, confirmed by Mikovits, indicated that the journal had asked the paper's authors to retract it voluntarily.

This week, the journal hinted that it was still pressing for more than the partial retraction. "The editors will be discussing next steps with the authors, in light of the new findings," it said in a statement.

In comments published in a separate Science news story, Mikovits continued to strike a defiant tone, insisting that XMRV had not been ruled out as a potential cause of CFS.
"Anyone who says this is a lab contaminant has drawn the wrong conclusion and has done a disservice to the public," she told the journal.

"The conclusion of the Blood Working Group was that we don't have a reproducible assay to detect XMRVs in the blood -- not that they weren't in the patients at all."
She vowed to continue working to prove that XMRV is a genuine virus and is present in CFS patients. "The virus is real," she told Science. "I have isolated it from patients. I know it's there."
Ruscetti, too, indicated that he was not ready to give up on XMRV. "As long as there are scientific reasons to continue, I think it's incumbent upon me to do it," he told Science.
But most researchers believe the last chance for the XMRV-CFS theory is an ongoing study sponsored by the National Institutes of Health. It is testing 150 blood samples from patients, with results expected early in 2012.

No specific funding for the study was provided, but individual researchers were supported by a variety of government grants or were government employees.
Some co-authors reported relationships with Gen-Probe, Novartis, Cerus, and Abbott, all of which have commercial interests in blood testing or pathogen inactivation. The Whittemore Peterson Institute holds patents on XMRV testing methods.

Primary source:
ScienceSource reference:
Simmons G, et al "Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: A multi-laboratory study" Science 2011; DOI:10.1126/science.1213841.

Additional source:
ScienceSource reference:
Silverman R, et al "Partial retraction" Science 2011; DOI:10.1126/science.1212182.

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