Chronic Fatigue Syndrome:
New XMRV Paper Looks Good, Skeptics Admit—Yet Doubts Linger
Martin Enserink
The plot thickens. This week, a long-awaited paper by U.S. government labs about the link between a virus and chronic fatigue syndrome (CFS) finally saw the light of day. The study confirms a controversial 2009 paper that reported CFS patients are often infected with the virus, called XMRV. Since then, four other studies have failed to duplicate those findings. Even skeptics are impressed by how much care the authors of the new study took to ensure accuracy. But that makes it even more baffling why some labs easily detect the virus while others can't find a trace of it in any patient.
The new paper, published on Monday by the Proceedings of the National Academy of Sciences (PNAS), also adds a confusing twist: Rather than XMRV itself, the team found a broader and more diverse group of closely related viruses. That leads some critics to say the paper is a new finding, not confirmation of the first one. "Let's be clear. This is another virus," says retrovirologist Myra McClure of Imperial College London, a co-author of one of the four negative studies.
The controversy began in October 2009, when a team led by Judy Mikovits of the Whittemore Peterson Institute (WPI) in Reno, Nevada, reported in Science (23 October 2009, p. 585) that 67% of CFS patients were infected with XMRV, compared to just 3.4% of healthy controls. The study caused huge excitement among patients and raised hopes of a cure. But when four other groups were unable to repeat the results, some suspected that WPI, a privately funded lab many researchers had never even heard of, might be wrong.
U.S. government labs soon found themselves on opposite sides of the debate. Researchers at the Centers for Disease Control and Prevention (CDC) failed to find the virus, whereas the new study—by scientists at the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and Harvard Medical School—says that Mikovits was right. Both groups temporarily put their papers on hold to check their results and try to understand what was going on (Science, 2 July, p. 18). Both eventually felt confident enough to publish, and the negative CDC paper appeared in Retrovirology in July.
(Under a picture of Alter is the caption: "No doubt. NIH's Harvey Alter says he's sure the findings are not the result of mistakes or contamination.")
For the PNAS paper, researchers looked for traces of XMRV's so-called gag gene in samples taken from 37 CFS patients collected in the mid-1990s. They found evidence for the virus in 32 (87%) of the patients, but in only 3 out of 44 healthy controls (6.8%). The group went to great lengths to avoid errors, says senior author Harvey Alter of the NIH Clinical Center. XMRV is closely related to an endogenous mouse retrovirus, so the team tested every sample positive for XMRV for traces of mouse mitochondrial DNA, which would have been a telltale sign of lab contamination. They found none. They also took fresh samples from eight of the patients and found that, 15 years on, they were still infected, and that the virus had evolved, "just as we would expect from a retrovirus," says Alter.
The data do seem solid, admits Steve Monroe, director of CDC's Division of High-Consequence Pathogens and Pathology. "It's simply a good paper," adds virologist Reinhard Kurth, former director of the Robert Koch Institute in Berlin. Alter, a widely respected virologist and winner of the Albert Lasker Award for Clinical Medical Research, "clearly knows what he is doing." But Kurth nonetheless remains skeptical. So does Robin Weiss of Imperial College London, who says he's seen too many instances of proposed new human retroviruses that fell apart on closer inspection—including one he reported in 1999. "You can have a very good reputation and be very careful, and still get it wrong," Weiss says.
Part of the problem, skeptics say, is that the researchers didn't exactly replicate the Science paper. XMRV is a so-called xenotropic murine virus, which means it can no longer enter mouse cells but can infect cells of other species. The PNAS authors say the viral sequences they find are quite diverse and more closely resemble the so-called polytropic mouse viruses, which is why they adopted the term MLV-related virus, for murine leukemia virus. But Alter says that XMRV is a subset of MLVs, and that his work does support the earlier study. Mikovits—who is "delighted" by the results—says that in the meantime, her group has found more diversity in the virus as well.
A working group coordinated by the National Heart, Lung, and Blood Institute (NHLBI) is already trying to find out why careful studies by veteran scientists can have such opposing results. Patient selection could play a role: Different studies have used different diagnostic and recruitment criteria. But even so, it's hard to explain why four studies wouldn't have included a single infected patient.
Subtle differences in sample collection and handling, or in the way tests are performed, could also have led the four labs to miss the virus. But CDC's Monroe says he's confident that his lab can identify XMRV correctly. As part of the NHLBI program, researchers at FDA, CDC, WPI, and other labs have all blindly tested a panel of samples, some of them "spiked" with different amounts of the virus; all of them performed well. Further exchange of samples and reagents is now under way. "They should be able to clear this up by Christmas," says Kurth.
