People who suffer from chronic fatigue syndrome (CFS) were dealt another blow this week when it became clear that researchers still fail to understand the genesis of this disease. Perhaps most importantly, these patients are being advised to stop taking antiretroviral medications.

Two new papers published this week in Science cast additional doubt on a two-year-old study that had linked chronic fatigue syndrome to the xenotropic murine leukemia virus-related virus, or XMRV. Many researchers will view the publications as the end to a contentious debate. But in the chronic fatigue patient community, responses to the new findings will likely be more personal.

The approximately one million CFS patients in the U.S. have long faced skepticism from the public and medical community alike, and, for many of them, the 2009 study had served as scientific validation of the malady. Although most experts now agree that CFS is a real condition, patients have endured dismissive nicknames such as "yuppie disease," and the lack of a known cause has made it difficult to the shed the notion that patients' symptoms—which include headaches, pain, and severe fatigue not relieved by bed rest—are all in their heads. Tying CFS to a specific virus not only offered the possibility of new treatments, but also a physical marker for a disease that is traditionally defined not by what it is, but by what it is not: for example, depression or cancer.

There are few treatment options for CFS, and after the 2009 study was published, some patients began asking their doctors to prescribe antiretrovirals—the drugs clinicians use to combat another retrovirus, HIV. Researchers said this would have been premature even if there had been a more strongly supported relationship between XMRV and chronic fatigue. "You really need to be certain before starting that kind of treatment because no drug is safe," says Jay Levy, a medical researcher at the University of California, San Francisco, and a co-author of one of the new Science studies. Side effects of antiretrovirals include nausea, rash and liver damage. In light of the new studies, he says, "those patients should stop taking antiretrovirals immediately."

It makes intuitive sense that chronic fatigue syndrome would be caused by a bacterium or virus. Numerous studies (pdf) of patients with the disorder have found increased levels of cytokines and other factors associated with heightened immune response. The 2009 study was not the first to link CFS to a virus. Previous studies proposed that human herpes virus 6, Epstein-Barr and other viruses might be to blame for the disease, but none of these hypotheses have panned out.

What seemed to intrigue clinicians and patients most about the 2009 study was that it involved a mouse virus that wasn't thought to infect humans. The virus had only been discovered in 2007, when researchers at the U.C. San Francisco (not connected to Levy) claimed to find a previously unidentified version of the mouse virus, which they dubbed XMRV, in cells from prostate cancer patients. The 2009 study, which linked the same XMRV genetic sequence to chronic fatigue syndrome, seemed to lend credence to the idea that the virus could cause human disease.

Several follow-up studies failed to find XMRV in chronic fatigue patients, however. The new study by Levy and his co-authors represents the first attempt to replicate the 2009 study using the same methodology and the same patient population. They also found no trace of the virus. "This is definitive," Levy says of the results.

Meanwhile, the other new paper, by microbiologist John Coffin and his colleagues at Tufts University, the National Cancer Institute, and the University of California, Davis, puts the whole notion of human-contracted XMRV into question. Coffin's paper presents strong evidence that XMRV was created in the laboratory—the result of mouse virus that contaminated a prostate cancer cell line in the 1990s. There's still a possibility that a virus genetically related to XMRV could be involved with CFS, Coffin says. A paper published last year in Proceedings of the National Academy of Sciences suggested just that. But, he says, "it's getting more and more remote, I have to admit."

Levy goes a step further, calling for all research on chronic fatigue syndrome and XMRV to come to a halt. But Ian Lipkin, a virologist at Columbia University who is leading a $1.3 million National Institutes of Health study on the subject, thinks that would be premature. Lipkin concedes that Levy's and Coffin's papers cast doubt on the specific findings of the 2009 paper, but he maintains that there are still unanswered questions regarding XMRV-related viruses and CFS that are worth addressing. "We discussed the recent papers, and we're still full speed ahead [with the study]," he says.

In the meantime, researchers continue to search for new ways to treat chronic fatigue symptoms. For example, a clinical trial published in The Lancet earlier this year found that a combination of cognitive behavioral therapy and gradual exercise appeared to improve patient outcomes. The important message for chronic fatigue sufferers, Levy says, is that the new studies are not a knock against them or their condition. "There's no way we wrote this paper to tell CFS patients that we don't take them seriously," he says. "It's a very real disease."