Wednesday, September 29, 2010

No Meeting of Minds on XMRV’s Role in Chronic Fatigue, Cancer

No Meeting of Minds on XMRV's Role in Chronic Fatigue, Cancer
17 SEPTEMBER 2010 VOL 329 SCIENCE
www.sciencemag.org


BETHESDA, MARYLAND - For the past few years, researchers have been
tantalized by reports linking a new retrovirus to some cases of
prostate cancer and, more recently-and more controversially-the
mysterious illness chronic fatigue syndrome (CFS). With the excitement
over discovering a possible new cause for these diseases, however, has
come skepticism, as some groups have found scarcely a trace of the
novel virus, called XMRV. Many hoped a 1.5-day workshop* here last
week would help resolve the controversy. Instead, the field remains
mired in "a zone of chaos," concluded co-organizer and retrovirologist
John Coffin of Tufts University in Boston and the National Cancer
Institute (NCI) in Frederick, Maryland. "We don't have agreement on
almost anything."

Still, in spirited discussions, sometimes frustrated-sounding
researchers had a chance to air their findings and discuss ways to
move forward. At the meeting Francis Collins, director of the National
Institutes of Health, announced that NIH is funding a new study that
could help resolve whether the presence of XMRV varies with geography
or whether differences in how labs prepare and test samples explain
the varying results.

XMRV, which resembles a mouse retrovirus, was discovered in 2006 in a
group of men with a hereditary form of prostate cancer. Some groups
have since confirmed the finding, but others, particularly in Europe,
have not. Then a year ago, a report in Science linked XMRV to CFS, a
disease in volving fatigue and muscle pain mostly in middle-age women
(Science, 9 October 2009, p. 215). Although patient groups were
ecstatic to finally have a potential cause for what some people
consider not a true disease, the study, led by Judy Mikovits of the
Whittemore Peterson Institute (WPI) in Reno, Nevada, met with doubts
as other groups failed to confirm it (Science, 15 January, p. 254).

This summer, scientists at the U.S. Centers for Disease Control and
Prevention (CDC) found no XMRV in blood from CFS patients, while a
team at the Food and Drug Administration (FDA) and NIH reported
finding genes from a group of viruses closely related to XMRV, dubbed
MLV-related viruses, in 87% of 37 blood samples from CFS patients and
in 7% of healthy people (Science, 27 August, p. 1000). Differences in
virus-detection methods or in how patients were diagnosed or recruited
could help explain the discrepancies, the two sets of authors
suggested.

At last week's workshop, 220 scientists and others ran through many of
the published studies, as well as some new unpublished ones. For
example, Mikovits has now found XMRV in patients in England with CFS.
She defended her group's original findings: "We have independent
confirmation from three groups," she said at the workshop. But some
participants raised concerns about possible sources of stray mouse
DNA, from knives for slicing tumors to the heparin sometimes used to
stabilize blood samples. Tufts immunologist Brigitte Huber reported
that her lab initially found almost no XMRV in CFS patient samples,
but when they tested more samples from patients and healthy people
prepared a different way, many were positive. These samples turned out
to contain endogenous mouse retrovirus DNA, probably from a
contaminated reagent, said Huber: "It's a false positive in our
hands."

One underlying issue is that the polymerase chain reaction assay used
to detect XMRV-the assay copies and amplifies pieces of DNA-is so
sensitive that it can detect extremely small traces of viral
sequences, the amount in a milliliter of water from a swimming pool in
which a drop of mouse blood has been mixed, Coffi n said. This makes
it easy to pick up contaminant mouse viral DNA. Even if XMRV is
present in some tumors, the reported levels are so low that it's
unclear how it could contribute to the development of cancer, says
pathologist Angelo De Marzo of Johns Hopkins University in Baltimore,
Maryland. "The data [are] very noncompelling," says De Marzo, whose
lab, working with NCI's Alan Rein, failed to find XMRV in nearly 800
prostate tumor samples.

Some meeting participants said the only way to establish that XMRV
actually causes CFS and isn't simply a "passenger" virus that doesn't
contribute to the illness is to treat CFS patients with antiretroviral
drugs. Coffin cautioned that it would be "premature" to do so without
an assay to monitor the amount of XMRV in a patient's blood, as is now
done with AIDS patients on antiviral therapy. But if such a test is
developed, "I would not be averse to doing very small studies under
tightly controlled clinical conditions," he said.

Hoping to figure out what's going on, a federal working group
involving labs at FDA, CDC, WPI, and elsewhere has compared results
for blood samples to which various amounts of XMRV had been added.
(All six labs detected it.) The group has also tested four WPI samples
from CFS patients but isn't ready to discuss the results because
"we're still confused by them," says Coffin, who is part of the
working group.

More answers could come from the study Collins announced. National
Institute of Allergy and Infectious Diseases Director Anthony Fauci
has asked Columbia University epidemiologist W. Ian Lipkin to collect
blood samples from 100 CFS patients from four parts of the United
States and 100 healthy people and send blinded samples to the FDA,
CDC, and WPI labs for testing. "We're interested in settling a
discrepant observation," Fauci says.

Chaos may still reign, but Coffin thinks order may emerge over the
next year. If nothing else, he says, "people left the meeting talking
to each other when they weren't always before. I hope that will
continue."


–JOCELYN KAISER

*1st International Workshop on XMRV, 7–8 September 2010, Bethesda, Maryland.

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