Does a virus cause ME?

The front page of today’s Independent asks whether scientists have found the cause of ME (myalgic encephalitis), also known as chronic fatigue syndrome (CFS). The newspaper reported that researchers have found a “strong link” with a retrovirus called XMRV.

This study compared blood samples from 101 CFS patients with samples from 218 people without it. It found evidence of the XMRV virus in about two-thirds of the people with CFS and less than 4% of people without the disease.

These findings alone do not prove that the virus causes CFS, because they do not show whether the infection occurred before or after CFS developed. The research paper is cautious in its conclusions, saying that XMRV “may” be a contributing factor to CFS, but the opposite may also be true: CFS may make people more susceptible to infection with this virus.

Despite these limitations, these findings will be of interest to the research community, doctors and patients. Larger studies and research that establishes whether the XMRV infection occurs before or after the onset of CFS will be needed before any conclusions can be drawn.

Where did the story come from?

The research was carried out by Dr Vincent C Lombardi and colleagues from the Whittemore Peterson Institute and other research institutes in the US. It was funded by the Whittemore Peterson Institute, the Whittemore Family Foundation, the National Cancer Institute, the National Institutes of Health, the US Department of Defense, the Foundation for Cancer Research, the Charlotte Geyer Foundation and Mal and Lea Bank.

The study was published in the peer-reviewed journal Science.

What kind of scientific study was this?

This research looked for the presence of a retrovirus in the white blood cells of people with chronic fatigue syndrome. It was a case-control study with additional laboratory experiments.

CFS affects several organs in the body, and patients show abnormal immune system function. The cause is not known, but one theory is that certain viruses trigger the disease.

This study investigated whether a retrovirus called xenotropic murine leukaemia virus-related virus (XMRV) might be involved. Previous research into prostate cancer has found this virus in some samples of prostate cancer tissue. Other studies in mice have found that the immune response to some retroviruses is associated with neurological problems.

In the study, blood samples were taken from 101 people with CFS (cases), and from 218 healthy people without CFS (controls). The DNA from white blood cells in these samples was examined to see if it contained any XMRV DNA. People with CFS had been diagnosed using standard criteria (1994 CDC Fukuda criteria and 2003 Canadian Consensus Criteria), and all had severe disability, prolonged disabling fatigue, cognitive defects and immune system abnormalities. They came from areas in the US where there had been reported outbreaks of CFS.

The full genetic sequence of the XMRV from two patients who had the viral DNA was then examined, to determine what strain of the virus it was. This strain was compared to the strain previously identified in prostate cancer patients and to a murine leukaemia virus (MLV), often found in laboratories, to discount the possibility that MLV was contaminating the experiments. Tests that looked for proteins from the XMRV virus in the blood cells were also carried out.

Laboratory tests were carried out to see whether the samples contained infectious XMRV. The tests involved white blood cells containing XMRV from CFS patients being grown and mixed with prostate cancer cells, which are susceptible to infection with XMRV.

The prostate cancer cells were also exposed to fluid from the CFS patient or control blood samples that had been treated by removing the blood cells and concentrating any viruses that might be present. Similar experiments, in which attempts were made to infect T-cells (a type of white blood cell), were also carried out.

The researchers then examined whether CFS patients carrying XMRV DNA or healthy controls had antibodies against a similar virus, which would suggest that they had developed an immune response to XMRV.

What were the results of the study?

The researchers found that blood from 67% of people with CFS contained XMRV DNA compared with 3.7% of controls.

The viral DNA sequences were very similar to those identified in a previous study on prostate cancer. The sequences of these viruses were not similar enough to the MLV virus to suggest that these results were caused by laboratory contamination.

Testing the white blood cells from 30 CFS patients showed that 63% (19 people) of the samples tested showed viral proteins. Tests on samples from five healthy controls did not show any viral proteins.

Overall, samples from people with CFS were 54 times as likely to contain viral sequences as samples from healthy controls.

The researchers found that XMRV found in the white blood cells of CFS patients could be transmitted to prostate cancer cells when grown together in the laboratory. In 10 out of 12 people with CFS (83%), fluid taken from their blood samples could also infect the prostate cancer cells in the laboratory. Similar results were found when uninfected white blood cells were exposed to this fluid. Fluid from the blood samples of 12 healthy controls did not infect the prostate cancer cells.

The researchers found that half (nine out of 18) of CFS patients carrying XMRV DNA had antibodies against a similar virus, while none of the seven healthy controls tested showed an antibody response. This suggested that half of the CFS patients had had an immune response to the XMRV.

What interpretations did the researchers draw from these results?

The researchers conclude that their findings suggest that XMRV may be a contributing factor in the development of CFS. They suggest that infection with the XMRV virus could be responsible for some of the abnormal immune response and neurological problems seen in CFS.

What does the NHS Knowledge Service make of this study?

This research has identified an association between the presence of XMRV viral DNA and chronic fatigue syndrome (CFS).

However, it is not yet possible to say for certain whether the virus causes CFS, a fact that is acknowledged by the authors of the research. This is because the presence of the virus was assessed in people who already had CFS, and so it is not clear if the infection happened before they developed the disease.

An alternative possibility is that people who already have CFS have altered immune systems that make them more susceptible to these viruses.

The study has some limitations to note, some of which are raised in an accompanying editorial in Science :

• A relatively small number of people were tested, particularly in some of the experiments.
• The CFS samples all came from patients who had severe disability, prolonged disabling fatigue, cognitive defects and immune system abnormalities, and who were from regions where there were “outbreaks” of CFS. It is possible these patients are not representative of the full spectrum of patients with CFS, which can range in severity. The selection of cases that were clustered together in “outbreaks” could mean that these cases have a different cause or trigger from more isolated cases.
• The characteristics of the healthy people whose blood samples were used were not reported, and there may have been more differences from the CFS cases than simply the disease itself that contributed to the differing rate of XMRV infection.
• Although the researchers attempted to rule out contamination of their samples, the molecular biologist who co-discovered the XMRV virus suggests in the accompanying editorial that they did not do enough to completely rule out contamination. He also points out that confirmation of the results by an independent group blinded to whether the samples came from cases or controls is “vital”.
• Although the study suggested that the virus could spread to other cells in the laboratory from white blood cells or fluid from blood, this does not mean that the virus would necessarily be able to spread from person to person.

Despite these limitations, the causes of CFS are not yet known and available treatments are limited, so these findings will be of much interest to the research community, doctors and patients. Further research is needed to confirm these findings in more samples, and to establish whether the XMRV infection occurs before or after the onset of CFS.