‘Science asks researchers to withdraw paper on chronic fatigue syndrome and infectious retrovirus’, British Medical Journal, 6 June 2011

From the British Medical Journal, 6 June 2011 (news story by Matthew Limb)

Researchers are facing calls to retract published findings that link chronic fatigue syndrome to a retrovirus called xenotropic murine leukemia virus related virus (XMRV) after new scientific criticism of their validity.

Editors of the journal, Science, have issued an “editorial expression of concern” over a research paper it published in October 2009, saying the report is “now seriously in question.”

The study, “Detection of an infectious retrovirus, XMRV, in blood cell of patients with chronic fatigue syndrome,” was led by Vincent Lombardi and Judy Mikovits of the Whittemore Peterson Institute, Reno, Nevada (Science 2009;326:585).

It purported to show that a retrovirus XMRV was present in the blood of 67% of patients with chronic fatigue syndrome (CFS) compared with 3.7% of healthy controls.

The study caused a stir when it appeared and led to some CFS patients, believing XMRV to be a possible contributor to their condition, seeking antiretroviral treatments marketed to combat HIV.

But Science, which is the weekly journal of the American Association for the Advancement of Science, has now highlighted “flaws” in the paper.

Since 2009, it says, at least 10 studies conducted by other investigators and published elsewhere have failed to detect XMRV in independent populations of CFS patients.

Furthermore, Science has published two new reports that “strongly support the growing view that the association between XMRV and CFS described by Lombardi and colleagues likely reflects contamination of laboratories and research reagents with the virus.”

One report provides evidence that the virus originated when two mouse leukaemia viruses underwent recombination during experimental passage of a human prostate tumour xenograft in mice in the 1990s.

In their analysis, Paprotka and colleagues conclude that laboratory contamination with XMRV produced by a cell line (22Rv1) derived from these early xenograft experiments is the most likely explanation for detection of the virus in patient samples. (Science 2011 doi:10.1126/science.1205292)

“Our results suggest that the association with XMRV with human disease is due to contamination of human samples with virus originating from this recombination event,” the authors write.

In the second report, K Knox and colleagues examined blood samples from 61 CFS patients from the same medical practice that had provided patient samples to Lombardi and colleagues.

Comprehensive assays by Knox and colleagues for viral nucleic acids, infectious virus, and virus-specific antibodies showed no evidence of XMRV in any of the samples (Science 2011 doi:10.1126/science.1204963).

In February 2010, a Dutch study refuting the original US study reporting the link was published in the BMJ (2010;341:c1018; doi:10.1136/bmj.c1018).

It has emerged that editors of Science, before publishing their “editorial expression of concern,” privately requested that the authors of the original study retract it themselves.

Dr Judy Mikovits has written to the editors warning that Science’s action could be “disastrous” for future research in this field while insisting the study is accurate.

She wrote that she and her co-authors shared the “deep concern” over the number of studies that had not been able to replicate their findings.

She said other scientists had not replicated their work faithfully and there were no data to support claims of laboratory contamination.

Since the study was published there have been calls in the US for people with CFS to be barred from donating blood in case blood supplies might be contaminated by the “contagious” retrovirus.

The US National Institutes of Health is sponsoring new studies to ascertain whether the association between XMRV and CFS can be confirmed.

Editor in chief of Science, Bruce Alberts, writing in the journal, said, “Science eagerly awaits the outcomes of these further studies and will take appropriate action when their results are known.”

Jonathan Stoye, a retrovirologist at the UK Medical Research Council National Institute for Medical Research, has joined in criticism of the paper by Lombardi and colleagues, despite having co-written an editorial in Science in 2009 in support of it.

He told the BMJ that there was strong evidence that contamination explained the findings and therefore the suggested the link between XMRV and CFS was “wrong.”

He said, “Nobody has reproduced the original results and that is very unsatisfactory.” I don’t see any reasons for the scientific community to spend any more time and effort on this.”

He told the BMJ he had no plans to do further research himself in this area, adding, “I believe the scientific argument is done, but the political argument may not be.”

He said although requests to withdraw a published research paper were “unusual, it does happen.

“In football terms, it’s somewhere between a yellow and a red card,” he said.

Dr Stoye said it should not be forgotten that a subset of CFS patients “almost certainly” had disease triggered by a viral infection, and although efforts to explain this should continue, the viral trigger was not XMRV.

Charles Shepherd, medical adviser to the UK based ME Association, a national charity supporting people affected by myalgic encephalopathy (ME), CFS, and post viral fatigue syndrome, said the failure of many leading experts to support the findings of Lombardi and colleagues “must be taken seriously.”

He said the charity was waiting to hear the results of ongoing US research, including a multicentre study of CFS patients by virologist Ian Lipkin, which might provide “definitive” results.

Dr Shepherd told the BMJ, “I am trying to take a balanced view although it will be a tremendous disappointment to many patients if it turns out that XMRV is a red herring.”

He said, given the current uncertainty, it would be “unethical” for doctors to prescribe antiretrovirals for CFS patients, and there was no evidence for this happening in the UK.

Peter Spencer, chief executive of the charity Action for ME, said, “Like many patients, we were excited when the original study was published in 2009, and hoped that further studies would lead to independent and substantive confirmation of a link between XMRV and ME. Unfortunately, it seems that it is now time to move on. But it’s imperative that this very disappointing news does not overshadow the continuing importance of rigorous scientific study into the biology of ME. There is still a long way to go.”


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