Tuesday December 21 2010
The link to XMRV may have been based on contaminated samples
“A new study has cast further doubt on the idea that a virus called XMRV causes chronic fatigue syndrome,” BBC News has reported.
In 2009 the condition, also known as myalgic encephalomyelitis (ME), was linked to a virus similar to one found in mice after a study discovered it was present in blood samples from people with the condition.
This well-conducted laboratory research examined the debated link by assessing the purity and ancestry of viral samples isolated from human cells. Based on their findings, the researchers conclude it is very likely that the human cells in the previous study had been contaminated with DNA from mice cells or by cells that contained a virus very similar to XMRV. On this basis they call for more rigorous detection methods during testing.
The authors did not directly analyse the samples from the original study that suggested a causal link. As a result, they cannot prove that the samples were contaminated, but their conclusion that contamination is highly likely casts doubt on the theory that XMRV causes ME. The cause of the condition is still unknown, and this research does not completely rule out XMRV or exclude another as yet unidentified virus from having some role.
Where did the story come from?
The study was carried out by researchers from University College London, the Wellcome Trust Sanger Institute in Cambridge and the University of Oxford. The study was funded by the European Community’s Seventh Framework Programme, the UK National Institute for Health Research, the Wellcome Trust, the Medical Research Council and The Royal Society.
The study was published in the peer-reviewed medical journal Retrovirology.
The newspapers have reported the findings of this study accurately, placing emphasis on the researchers’ conclusion that ME is not likely to be caused by this virus.
What kind of research was this?
The cause of myalgic encephalomyelitis (ME), now more commonly termed chronic fatigue syndrome (CFS), is largely unknown, but one theory has suggested that a virus called XMRV (xenotropic murine leukaemia virus-related virus) may be involved.
This virus has been linked with other diseases, but not all studies on its potential role in ME have found an association. The 2009 study that first linked XMRV to ME involved examination of blood cells from ME patients, finding that most samples contained DNA from the virus.
The XMRV virus circulates among mice, although in the laboratory it has been found to infect cells from a variety of animal species. The researchers say that the link between the virus and human disease is controversial, and that studies in this area have not produced consistent results. The virus is also found in up to 6% of healthy humans. In this study the researchers undertook a laboratory study to demonstrate that viruses from mice can contaminate human samples.
What did the research involve?
Researchers examined the DNA from different types of mice to see whether they could detect the presence of the virus. All of them were positive. They also investigated how frequently several lines of human cells (samples of extracted human cells cultured for experimentation) were contaminated with the XMRV virus. They tested contamination among nine different human cell lines, including tumour cells. They then investigated the presence of the XMRV virus using complex methods of detection, and also set out to see whether the human cells included viruses that could be mistaken for XMRV.
The researchers then undertook an evolutionary analysis of how the viral DNA comes to be in certain human cells lines. It is reported that XMRV is regularly found in prostate cancer cells, so the researchers cloned these cells and purified the viral DNA from them. They then used complex statistical methods to examine the evolutionary relationships between the sequences they had isolated from these cells.
What were the basic results?
DNA in human cells was frequently contaminated with DNA from different viruses, some of which originated from XMRV but some of which could be mistaken for having an XMRV origin. When cloning pure XMRV from the prostate cancer cells for testing purposes the researchers found that the viral DNA thought to be from XMRV was actually a mix of DNA from two different viruses. They say that this strongly suggests that contamination is the source.
Further analysis showed that viral sequences reported to be coming from unlinked patients actually seemed to be derived from the same original cell line, also suggesting that contamination was a likely reason for detection of this virus in human samples. Finally, the researchers found that the type of XMRV that is derived from human samples is less diverse than that from mouse cells. This is unexpected for a virus thought to cause an infectious disease.
How did the researchers interpret the results?
The researchers have concluded that the XMRV found in patient samples is likely to be derived from contamination either by mouse DNA or by other cells infected with viruses that originate in mouse DNA. They conclude that XMRV is unlikely to be a human pathogen.
They acknowledge that without testing original samples it is difficult to establish whether human samples in previous studies have definitely been contaminated.
This well-described laboratory study has used complex methods to analyse DNA and to determine the evolutionary history of retroviruses found in the DNA of mouse and human samples. The researchers conclude that it is possible, and likely, that samples in previous studies which found that XMRV has a causal link with ME, were contaminated with material including DNA from mice cells or from other cells containing a closely related virus.
They note that while it is not possible to prove that previous samples have been contaminated they are confident of their conclusions. One of the lead researchers has been quoted as saying;: "Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome. Our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome samples”. They say that rigorous methods should be used when screening for the virus in future.
The causes of ME are unknown, and while this research provides evidence that XMRV may not be the cause, this does not completely rule out XMRV or exclude another as yet unidentified virus from having some role. Other possible contributing factors include genetic, environmental, lifestyle and psychosocial factors.
Article amended: January 6 2011