‘Hurricane force’ debate about XMRV findings – ‘Science’ magazine, 7 January 2010

From ‘Science’ magazine (“News of the Week”), 7 January 2010. Story by Jocelyn Kaiser with additional reporting by Martin Enserink.

Studies Point to Possible Contamination in XMRV Findings

The stormy debate over a potential cause of chronic fatigue syndrome (CFS) is nearing hurricane force. Last month, it prompted headlines suggesting that researchers have reached a dead end, scores of blog posts from disappointed patients, and accusations that scientists had gone beyond their data. The 14-month-old row intensified when four papers appeared in Retrovirology suggesting that reports linking the virus XMRV to CFS were based on false positives.

The debate began in 2009 with a report in Science that XMRV, a retrovirus recently reported to have been found in prostate tumors, had been detected in 67% of a set of CFS patients but in only 4% of controls (Science, 9 October 2009, p. 215). Since then, one other group has found XMRV- like viruses in CFS patients’ blood. But sev- eral teams have failed to detect the virus in CFS or cancer patients or in healthy peo- ple. Researchers have struggled to explain the discrepancies (Science, 17 September 2010, p. 1454).

The potential link to CFS has had important consequences: Some CFS patients have begun taking antiviral drugs, which can have side effects. Last month, after being briefed on the original XMRV studies, advisers to the U.S. Food and Drug Administration recommended that CFS patients be barred from donating blood.

The Retrovirology papers point to contamination as a possible source of positive results in previous studies. The polymerase chain reaction (PCR) test used to detect XMRV (a mouse retrovirus adapted to infect humans) could actually be picking up minute amounts of mouse DNA or similar mouse viruses.

Two of the four studies in Retrovirology used highly sensitive assays for mouse DNA and found that samples positive for XMRV-like viruses also tested positive for mouse DNA. Another study found mouse viral RNA in a commercial PCR kit. And the fourth study argues that XMRV sequences previously reported in patient samples don’t show the diversity expected if the virus were spreading through the human population. Instead, these authors report, the sequences are similar to those found in a popular pros- tate cancer cell line, 22Rv1. This cell line, used in lab experiments, was already known to contain an XMRV-like sequence.

Greg Towers of University College London (UCL), who led the study of XMRV diversity, says the evidence linking this virus and human disease “is really looking pretty shaky now.” The Wellcome Trust, which cosponsored the research, and UCL issued a press release last week declaring flatly that the Towers study showed that “chronic fatigue syndrome is not caused by XMRV,” a message some newspapers repeated. Towers says he was “comfortable” with the release. But John Coffin of the U.S. National Cancer Institute (NCI) and Tufts University Sackler School of Graduate Biomedical Sciences in Boston, who co-authored two of the contamination papers, is wary.

He says these studies “just point out how careful one must be.”

Virologists who have found a virus-disease link disagree with coverage of the Towers paper. “The data shown … do not justify some of the sweeping statements made,” says Ila Singh of the University of Utah, Salt Lake City, who has reported XMRV in prostate cancer samples. Moreover, the lead author of the Science paper on CFS and XMRV, Judy Mikovits of the Whittemore Peterson Institute (WPI) in Reno, Nevada, points out that PCR wasn’t the only test her studies used: For example, Mikovits’s team also showed that XMRV-positive patients make antibodies to the virus and that XMRV isolated from their blood can infect cultured human cells. Mikovits said in a statement, “Nothing that has been published to date refutes our data.”

One outspoken scientist wavered on the significance of the Retrovirology papers. Columbia University virologist Vincent Racaniello, who runs a popular virology blog and podcast, initially e-mailed a Chicago Tribune reporter to say that they were “prob- ably the beginning of the end of XMRV and CFS.” But he retracted that statement (and a similar comment to Science) after reviewing the studies more closely. “It’s pretty complicated,” Racaniello concludes.

Some had hoped that a project in which several U.S. labs are testing for XMRV in the same samples would clear up the picture. But so far this effort has been incon clusive. Four CFS patients’ blood initially tested positive for XMRV at WPI and the U.S. Centers for Disease Control and Pre- vention but not at an NCI lab. When all three labs tested new samples from the same patients, none found XMRV—for reasons that aren’t yet clear, says Coffin. The group now plans to test blood from several dozen CFS patients and controls.

A bigger study is now under way. Funded by the U.S. National Institute of Allergy and Infectious Diseases, virologist W. Ian Lipkin of Columbia University is lead- ing a project that will collect blood from 150 CFS patients and 150 controls from six U.S. clinical sites. The samples will be tested blindly by several labs. Because all the clinicians have agreed on standard methods, the study should help resolve concerns that differences in how CFS patients are selected or how samples are handled could explain clashing conclusions, Lipkin says: “Results will be definitive.”

As the new study gets started, some wonder whether it’s worth the $1.3 million it will cost. Jonathan Stoye of the MRC National Institute for Medical Research in London concedes that the Towers study was “over- hyped.” But he says “it’s pointing people in a certain direction,” away from chasing an elusive link to XMRV. Still, he says, a larger study may be the only way to satisfy patients.