In XAND Land
Into this bleak landscape last October blazed an unpredictable claim by an obscure researcher from a little-known institute
that the cause of CFS may have been discovered: a human retrovirus called xenotropic murine leukemia virus–related virus (XMRV).
Biochemist Judith Mikovits at the Whittemore Peterson Institute (WPI) in Reno, NV, along with colleagues at the National Cancer
Institute and the Cleveland Clinic, reported in the journal Science that DNA from the mouse-derived retrovirus were found in 67 out of 101 blood samples of CFS patients. Testing of 300 additional
samples was said to hit 98 percent. What's more, 3.7 percent of the 218 control samples also contained XMRV.
The media predictably amplified the remarkable, if preliminary, findings into a "cause-of-CFS" story, and WPI was only too
happy to oblige. "This is the breakthrough that we have been hoping for. Now we have scientific proof that this infectious
agent is a significant factor in CFS," Annette Whittemore, WPI founder and president, proclaimed in the initial press release,
which also announced that WPI had renamed CFS as XMRV-associated neuro-immune disorder (XAND).
WPI did not discover the XMRV virus, however. That distinction goes to scientists at the Cleveland Clinic and the University
of California San Francisco, who in 2005 detected this fourth human retrovirus in the cancerous prostate tissue of 40 percent
of men with a particular defective gene. WPI's Mikovits made the opportune leap from prostate cancer to CFS when she learned
of the high incidence of lymphoma among the original Lake Tahoe cohort. XMRV seemed a possible culprit because it decimates
natural killer blood cells, the immune defense against cells infected by HTLV-I. In addition, some CFS patients carry the
same genetic mutation as men with prostate cancer who tested positive for XMRV. The working hypothesis at WPI is that XMRV
indirectly causes CFS by inflicting so potent an assault on the immune system that it reactivates other viral infections and
a chronic inflammatory response. "XMRV is the sort of agent that could create that effect on the immune system," Daniel Peterson,
WPI's medical director and the co-discoverer of the original Lake Tahoe outbreak, told The New York Times in a piece headlined "A Big Splash by an Upstart Medical Center."
WPI was founded in 2006 by Whittemore and her husband, Harvey, a prominent Nevada couple whose daughter, Andrea, 31, has lived
with a severe case of CFS for 20 years. Frustrated by Andrea's marginalization by doctors and by the lack of leadership, funding,
and research at CDC, Annette Whittemore invested $5 million to launch her own research institute at the University of Nevada
Medical School in Reno.
A flurry of activity followed on the heels of the discovery. Other researchers raced to confirm the WPI study. Patients flocked
to the Internet for more information: Was XMRV fatal? How was it transmitted? Could they get tested for it? The answer to
the last question was yes. A diagnostic test for the virus was already being marketed at $650 a shot by VIP Dx, which just
happens to be owned by Annette and Harvey Whittemore. "Leaving aside the issue of who's right and who's wrong, the original
paper did not establish the virus [causes CFS] and didn't establish it as a viable marker," Tufts University retrovirologist
John Coffin, who wrote the editorial accompanying the original Science study, told the journal. Nevertheless, VIP Dx reported a six-to-eight-week backlog for results.
In general, patients' emotions bordered on the euphoric. Cort Johnson, whose Phoenix Rising Web site is one of the most trusted
sources of information in the CFS community, says, "Patients are starved for good news. A discovery like this excites researchers,
brings in funding, and gives patients hope—something they haven't had for many years." Meanwhile, the nation's handful of
CFS specialists tried to temper patients' expectations with YouTube educational lectures on XMRV and its potential treatment
For public health officials, the most alarming data point was XMRV's 3.7 percent prevalence rate in the control group. Extrapolating
a worst-case scenario led to the prospect that as many as 10 million Americans could be carrying an infectious retrovirus
already linked to two serious diseases. In January, a federal task force was convened to safeguard the nation's blood supply,
an operation that could take a year or more, according to member Suzanne Vernon. Then again, a little public panic has its
upside. "As we saw in the early years of HIV, fear among the general population at least gets the money flowing," says Moore.
A Pharma Screening
XMRV is exactly the kind of bug that hooks Big Pharma. "Two of the world's biggest drug companies contacted us the day our
Science paper appeared," says Judith Mikovits. "By showing that XMRV is an infectious agent, we think we've convinced them to become
interested in this target." Although Mikovits refused to disclose the identity of the two companies—"for fear that patients
might seek out the treatments before studies"—she said that both were already screening HIV antiretroviral compounds in WPI
cell lines for a hit.
Given the similarities among human retroviruses, an HIV drugmaker may already possess an effective anti-XMRV agent—if not
a drug already on the market, then one of the thousands of marginally variant molecules made in the painstaking process of
discovery—and currently gathering dust. Two classes of HIV drugs are in the running.
Both HIV and XMRV replicate by virtue of reverse transcriptase, the enzyme that links their viral RNA to the host cell's DNA.
Reverse-transcriptase blockers were the first victory Big Pharma scored against HIV. Ironically, in the February Virology, Mayo Clinic researchers reported that after testing 10 HIV drugs against XMRV in vitro, the virus was susceptible only to
AZT, a nucleoside reverse-transcriptase inhibitor (NRTI) notorious for its toxicity. "No CFS patient wants to go near AZT,"
Other RTs (or experimental versions) that may show promise include Bristol-Myers Squibb ddI and d4T, GlaxoSmithKline's Ziagen,
and Gilead's Emtriva and Viread. Merck's first-in-class integrase inhibitor, Isentress, may work "because of its broad-spectrum
activity," according to Coffin. In the best case, an already-approved antiretroviral will reveal XMRV-busting prowess, allowing
the drugmaker to bypass safety and other early tests and advance straight into humans. "If one of the drugmakers currently
screening candidates gets lucky, we could start a clinical trial in a month," says Mikovits.
Veteran advocates like Kimberly McCleary do a double-take at the news that two global pharmas are on the trail of CFS. "Now
what we need is a race between them to see which can be first to market," she says.