Tuesday, March 15, 2011

XMRV and deficiencies in a virus-defence pathway in ME/CFS

When Judy Mikovits found links between chronic fatigue syndrome and a virus, the world took notice. Now, she's caught between the patients who believe her work and the researchers who don't.

Ewen Callaway, Published online 14 March 2011 | Nature 471, 282-285 (2011):

On a sunny January afternoon in Santa Rosa, California, a small crowd waits patiently for Judy Mikovits to arrive. She is scheduled to deliver a talk on a mysterious virus called XMRV, which she believes underlies chronic fatigue syndrome. Although she's two hours late — held up by fog at San Francisco International Airport — not a single person has left. And when she arrives, they burst into applause.

To a rapt audience, she gives a chaotic and wide-ranging talk that explores viral sequences, cell-culture techniques and some of the criticisms that have been thrown at her since she published evidence1 of a link between XMRV and chronic fatigue in 2009. Afterwards, Mikovits is swarmed by attendees. A middle-aged woman who spent most of the talk in a motorized scooter stands up to snap pictures of her with a digital camera. Ann Cavanagh, who has chronic fatigue and has tested positive for XMRV, says that she came in part for information and in part to show her support for Mikovits. "I just wish there were a hundred of her," Cavanagh says.

The event was "surreal", says Mikovits, a viral immunologist at the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Reno, Nevada. She is discomfited by the attention from patients, which at times borders on adulation. But her reception among scientists has been markedly cooler. Numerous follow-up studies have found no link between the virus and the disease; no group has published a replication of her findings; and some scientists argue that XMRV is an artefact of laboratory contamination. Now, even some of Mikovits's former collaborators are having second thoughts.

Mikovits has dug in, however, attacking her critics' methods and motives. She says that their distrust of her science stems from doubts about the legitimacy of chronic fatigue syndrome itself. Chronic fatigue, also known as myalgic encephalomyelitis, affects an estimated 17 million people worldwide, but it is extremely difficult to diagnose. Many with the disorder are told that their symptoms — which include exhaustion, joint and muscle pain, cognitive issues, and heart and respiratory problems — are psychosomatic. "I had no idea there was that much bias against this disease," Mikovits says.

The stakes are high and many are taking the risks seriously. Several countries have barred people with chronic fatigue from donating blood in case the virus spreads (see 'Something in the blood'). And the US government has launched a US$1.3-million study to investigate the link. Patients are already being tested for XMRV, and some are taking antiviral drugs on the assumption that the virus causes chronic fatigue by attacking their immune defences. Many say that such action is premature, but Mikovits is steadfast. "We're not changing our course," she says.

First findings

In October 2007, Mikovits attended a prostate-cancer meeting near Lake Tahoe, Nevada, where she met Robert Silverman, a virologist at the Cleveland Clinic in Ohio. Silverman co-discovered XMRV, which stands for xenotropic murine leukaemia virus-related virus2. While examining human prostate tumours, he and his collaborators found genetic sequences that resemble retroviruses found in the mouse genome. Like all retroviruses, XMRV rewrites its RNA genome into DNA on infection, then slips the DNA into the genomes of host cells. Ancient remnants of such viruses litter animal genomes. But the only active retroviruses conclusively linked to human disease are HTLV-1, which causes leukaemia, and HIV.

At the meeting, Silverman was presenting research linking XMRV to deficiencies in a virus-defence pathway. Mikovits recalled that the same pathway was weakened in some patients with chronic fatigue. She wondered whether the prostate-tumour virus could also be behind chronic fatigue. After the meeting, Silverman sent Mikovits reagents to test for XMRV.

The idea excited Mikovits, but she had other priorities. After stints in industry and at the US National Cancer Institute (NCI) in Maryland, she had recently joined the WPI to lead its research programme. The WPI was founded in 2006 by physician Daniel Peterson, an expert on chronic fatigue, and by Annette Whittemore, the wife of a well-connected Nevada businessman, whose daughter Andrea has had chronic fatigue for more than 20 years. The Whittemores spent $5 million establishing the WPI, and several million more to support Mikovits's research, which has attracted few other grants.

At the WPI, Mikovits established a sample collection from Peterson's patients and began screening it for signs of an infection. A litany of pathogens has been linked to chronic fatigue over the years, including Epstein-Barr virus, Borna disease virus, human herpes virus 6 and HTLV-2. None panned out. Still, the disorder bears some hallmarks of an infection. Many patients report acute illness before chronic symptoms appear, and their bodies often show signs of an immune system at war. The disease can also crop up in apparent outbreaks, including one characterized by Peterson near Lake Tahoe in the 1980s.

Just before Christmas 2008, Mikovits turned her attention to Silverman's reagents. She and her postdoc, Vincent Lombardi, known as Vinny, asked a graduate student to test for XMRV DNA in white blood cells from some of the most seriously ill people being studied at the WPI.

The first try turned up just two positives out of 20. But by tweaking the conditions of the test, Mikovits says her team found XMRV in all 20. "Vinny and I looked at each other and said, 'Well, that's interesting'," she says. They spent the next few weeks convincing themselves that they were onto something, and soon conscripted Silverman and Mikovits's former mentor at the NCI, Frank Ruscetti, to help prove that XMRV infection was behind chronic fatigue.

"We really retooled our entire programme and did nothing but focus on that," she says. They kept the effort under wraps, dubbing it 'Project X'. Even Peterson and the Whittemores weren't clued in. Mikovits says that the secrecy was necessary because her team also found XMRV in the blood of some healthy people, raising concerns about blood products. She hoped to build an airtight case because she worried that sceptical public-health officials would undermine her work. Read more>>

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