BioEd Online

A study on chronic fatigue syndrome (CFS) has linked the mysterious and controversial disease to a recently discovered retrovirus. Just last month researchers found the same virus to be associated with aggressive prostate tumours.

CFS is marked by debilitating exhaustion and often an array of other symptoms, including memory and concentration problems and painful muscles and joints. The underlying cause of the disease is unknown; it is diagnosed only when other physical and psychiatric diseases have been excluded. Though the disease's nebulous nature originally drew scepticism from both doctors and the general public, most of the medical community now perceives it as a serious — if poorly defined — disease.

Now Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada, and her colleagues think they have discovered a potential pathogenic link to CFS. In patients with the disease from different parts of the United States, 67% were infected with a retrovirus known as XMRV. Less than 4% of controls carried the virus.

"I can't wait to be able to tell my patients," says Mikovits, who is also the vice president of drug development for Genyous Biomed in Henderson, Nevada. "It's going to knock their socks off. They've had such a stigma. People have just assumed they were just complainers who didn't handle stress well."

Prostate puzzle

CFS researchers have long had their eyes on retroviruses. A number of the symptoms, including fatigue and cognitive dysfunction, can occur when the immune system is dealing with a viral infection, and the disease is often preceded by a flu-like illness. Although a number of retroviruses have been hypothesized to play a role in CFS, none has ever been confirmed.

About three years ago Robert Silverman, a biologist at the Cleveland Clinic Foundation in Ohio and a coauthor of the new study, discovered a previously unknown retrovirus, XMRV, while searching for a pathogen that might contribute to prostate cancer. The retrovirus was very similar to MLV, a group of viruses that can cause cancer and neurological and immunological diseases in mice. Silverman found XMRV in a subset of prostate tumours, and more recent research found a stronger correlation between XMRV and aggressive prostate tumours¹_,².

Mikovits asked Silverman to analyze the blood samples of 101 CFS patients and 218 healthy controls. The authors detected XMRV DNA in the immune cells of 67% of the CFS patients but in only 3.7% of healthy controls. The authors also showed that the virus was able to spread from infected immune cells to cultured prostate cancer cells and that the virus's DNA sequence was more than 99% similar to the sequence of the virus associated with prostate cancer. The findings were published in Science³.

"It's scary," says Mikovits. "But it's cool. Hopefully this will finally make people change their attitudes to this disease."

Mikovits believes the association may be even stronger than the present work indicates. DNA sequencing only picks up active infections, she says, so she wants to study CFS exposure to the virus more broadly. In an unpublished investigation, she and her colleagues analyzed blood cells in about 330 CFS patients and found that more than 95% expressed antibodies to XMRV, whereas about 4% of healthy controls did.

Controversial connection

Although Mikovits acknowledges that it's premature to suggest a causal link between XMRV and CFS, she thinks it makes sense. Chronic XMRV infection in immune cells could cause them to churn out inflammatory cytokines, which are observed in some CFS patients, she says. Mikovits also points out that the MLV coat protein can disrupt red blood cells in mice, leading to low blood oxygen levels.

William Reeves, principal investigator for the Centers for Disease Control and Prevention (CDC)'s CFS public health research programme, says the findings are "unexpected and surprising" and that it is "almost unheard of to find an association of this magnitude between an infectious agent and a well-defined chronic disease, much less an illness like CFS".

But Reeves is cautious. "Until the work is independently verified, the report represents a single pilot study," he says. According to Reeves, the CDC is already trying to replicate these findings. He also notes that CFS is a heterogeneous disease and likely arises from a combination of many factors.

XMRV presents its own puzzle. John Coffin, a virologist at Tufts University in Boston who has studied MLV, points out that the virus's prevalence in healthy controls "is, in some ways, an equally striking result".

"It's highly preliminary, but if it's in fact representative, then there are 10 million Americans with this infection, which is very similar to MLV and is now linked to two important diseases," says Coffin. "There's a lot we don't know, including whether XMRV causes disease, but that's always the case when the first paper, like this one, comes out."