There is no evidence that the XMRV mouse virus plays a role in the development of chronic fatigue syndrome (CFS), as suggested in a study published in 2009, and the more likely explanation is lab contamination, say two new reports in Science this week, one where researchers say they re-tested patient blood samples and the other where researchers show how XMRV probably arose from proviruses present in host mice used to develop cancer cell lines.
The news will come as a blow to many people who suffer from CFS, also known as ME (short for myalgic encephalomyelitis), a disorder characterized by long-term persistent fatigue that is not caused by exertion and does not go away with sleep or rest.
XMRV is a close relative of a group of retroviruses called murine leukema viruses (MLVs), which are known to cause cancer in mice. It was first discovered in 2006 in samples taken from men with prostate cancer.
In October 2009, Science published a study by Vincent C Lombardi and colleagues that “raised the possibility” XMRV may be a “contributing factor” in the development of CFS because they found it in the blood of 67% of patients with the disorder compared to 3.7% of healthy controls.
There are reports that on the basis of that study, some patients with CFS tried to get hold of antiretroviral drugs used in the treatment of HIV, because they had been shown to stop XMRV from multiplying.
However, since Lombardi and colleagues published their findings, studies published in other journals have not been able to repeat them.
Now, this week, Science has posted online two new reports that strongly support the growing idea that a more likely explanation for the link between XMRV and CFS is “contamination of laboratories and research reagents with the virus”, as phrased by an accompanying Editorial Expression of Concern about the original study.
In the first report, Jay Levy of the University of California, San Francisco, and colleagues, describe how they found no evidence of XMRV or related viruses (MLVs) when they evaluated blood samples of 61 patients with CFS, 43 of whom had previously tested positive for the virus.
They also found that these viruses were strongly or partially “susceptible to inactivation by sera from CFS patients and healthy controls”, which they say shows it would be very difficult for MLVs to establish themselves successfully in humans.
Also, consistent with previous studies, they found sequences of MLVs in commercial laboratory reagents, or chemical compounds used in lab tests. So they concluded that:
“Our results indicate that previous evidence linking XMRV and MLVs to CFS is likely attributable to laboratory contamination.”
In the second report, Vinay K Pathak of the National Cancer Institute, and colleagues, said they decided to investigate when and how XMRV first arose, to try and explain the discrepancies that have arisen.
They studied human prostate cancer cell lines that produce XMRV almost identical to the strain found in patient samples, and they also studied the xenograft those particular cell lines were produced from, which had been grown in lab mice. (Human disease tissue is sometimes transplanted to mice as part of the process of creating cell lines for research).
Pathak and colleagues found XMRV infection in the two cell lines, “and in the later passage xenografts”, but not in early passages. They also found that the host mice contained two proviruses (precursors or latent forms of viruses) that share 99.9% of the genetic material of XMRV.
From these findings, they concluded that XMRV was not present in the original prostate cancer tumor “but was generated by recombination of two proviruses during tumor passaging in mice”.
While recognizing that in theory it is possible that an identical recombinant XMRV was generated independently, the chances of this happening are negligible (they estimated it to be around one in a million million, or 1 followed by 12 zeros).
So they concluded that the mice that had been host to some of the tissue used to create the cell lines used in the lab tests had carried the appropriate proviruses that came together and created XMRV.
“… our results suggest that the association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event” they wrote.
Konstance Knox et al., Science, Published Online 31 May 2011, DOI: 10.1126/science.1204963
Tobias Paprotka et al., Science, Published Online 31 May 2011, DOI: 10.1126/science.1205292
Written by: Catharine Paddock, PhD