Saturday, October 17, 2009

More Vindication!

  Bron: ME Research UK (Merge)
Datum: 16 oktober 2009
Ref: Eerder op het ME-NET,

XMRV and ME/CFS - A stunning find

The discovery of a potential retroviral link to ME/CFS, which is
estimated to affect some 17 million people worldwide, has certainly
caught the world's attention - no bad thing for an under-researched
and often-overlooked illness!
The scientific report, entitled
'Detection of infectious retrovirus, XMRV, in the blood cells of
CFS patients', appeared online in Science, one of the most prestigious
scientific journals in the world, on 8th October 2009 and described
the findings of a consortium of researchers from the Whittemore
Peterson Institute (WPI, located at the University of Nevada, Reno),
the National Cancer Institute (part of the National Institutes of
Health) and the Cleveland Clinic, Ohio.

The findings

The headline finding of the research paper was that DNA from a human
gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV),
could be detected in the peripheral blood mononuclear cells of 68 out
of 101 ME/CFS patients (67%) compared with only 8 out of 218 healthy
controls (3.7%). The extent of this difference in proportions is
as it is the norm for scientific researchers to find
relatively small yet significant differences between patients and
closely matched control groups; in the modern world, novel associations
of such magnitude are rarely found between long-standing chronic
illnesses and infectious agents. In addition to the headline finding,
the researchers determined that XMRV proteins were being expressed in
blood cells from ME/CFS patients at very high levels compared with
controls, and through cell culture experiments they showed that
patient-derived XMRV was infectious and transmissible. So, as well as
being the first to show infection with this novel virus in ME/CFS
patients, the researchers appear to have been the first to be able to
isolate XMRV particles from the blood, and to show direct transmission
of this virus between blood cells - dramatic observations indeed.

What has caught the attention of the scientific world is that these observations seem to fit neatly, at least at a first glance, with what is already known about ME/CFS as a chronic illness. For example,
viruses related to XMRV have been reported to be involved in damage to
blood vessels and nerves, and natural killer cells (historically low
in ME/CFS) are said to be susceptible to infection by XMRV. Also, the
fact that retroviruses like XMRV are known to be able to activate some
other (latent) viruses might explain why ME/CFS has been associated
with a range of different viral triggers, such as herpesviruses like
Epstein-Barr, over the years. Again, as Dr Judy Mikovits and colleagues
point out in their paper, some of the most commonly reported features
of ME/CFS include neurological symptoms and immune dysfunction with
inflammatory cytokine and chemokine upregulation, and some of these
observations could be accounted for by infectious XMRV in lymphocytes.
The fact that such pieces seem to fit so well together is suggestive
only at this stage, however, and a virologist at Tufts University was
surely wise to say in New Scientist that while it's not impossible
that infection with this agent might cause a disease with neurological
and immunological consequences, we don't know for sure as yet.

The background

The scientific journey towards this discovery is an extremely
interesting one, and includes several strands: prostate cancer, the
RNAse L immune pathway, the discovery of the novel virus XMRV, and
ME/CFS. XMRV is a human retrovirus similar to HIV, HTLV-1 and a group
of endogenous murine leukaemia viruses found in the genomes of wild
mice (see the informative presentation on retroviruses by Dr Jones
of SAIC-Frederick/NCI-Frederick), and was first identified only in
2006 by Prof. Robert H. Silverman of the Cleveland Clinic, a co-author
on the 2009 ME/CFS study. Prof. Silverman initially showed the
presence of XMRV in prostate cancer tissue samples (PLoS Pathog,
2006), and subsequent work has confirmed XMRV protein expression in
23% of 334 prostate cancer biopsies (Proc Natl Acad Sci USA, 2009).
Importantly, the men with prostate cancer initially studied by Prof.
Silverman all had a specific genetic defect in their antiviral
defences, the RNase L antiviral pathway which Prof. Silverman had
been studying for 30 years, a lifetime's work of scientific
progression described in his fascinating essay, 'Journey through
the 2-5A/RNase L System'.

RNase L is the terminal enzyme in the 2,5A synthetase/RNase L
antiviral pathway, and plays an essential role in the elimination
of viral mRNAs. The enzyme has been the focus of research interest
in ME/CFS patients for nearly 20 years, and deregulation of this
pathway in subsets of ME/CFS patients has been reported extensively
in the scientific literature
(reviewed by Nijs and Fremont, 2008).
In ME/CFS, a wide spectrum of 'cleavage' of RNase L can be observed
(a phenomenon also seen in multiple sclerosis patients), and such
altered RNase L activity profoundly affects cellular physiology,
including apoptosis. Overall, an upregulated RNase L pathway in
ME/CFS is consistent with an activated immune state and a role for
persistent viral infection in the pathogenesis of the disorder -
and it is because of these and other findings that many researchers
have come to view ME/CFS as primarily a disorder of the innate
immune system
(see Klimas and Kineru, 2008). It was thanks to the
insight of Dr Judy Mikovits and her team at WPI that the potential
connection between RNase L dysfunction in XMRV-infected prostrate
cancer and in ME/CFS was recognised, and an exploration undertaken
to test for the presence of the virus in the banked blood samples
in the WPI tissue repository, the largest ME/CFS sample repository
in the world.

What we don't know

A plethora of unanswered questions arise from this discovery. Chief
among these concerns cause and effect: the researchers' work has
shown a suggestive, significant association between the presence of
XMRV and a diagnosis of ME/CFS, but this is far from proof that the
virus has a direct or even indirect role in the development or
maintenance of the illness. This and other points have been well-put
in a fine 'perspective' in Science by National Academy of Sciences
member and expert retrovirologist, Prof. John Coffin, and colleague
Jonathan Stoye, who say, 'There is still much that we do not
understand. Whether the virus plays a causative role in either
chronic fatigue syndrome or prostate cancer is unknown.'
They go on
to point out that XMRV infection might be higher, by co-incidence,
in the same locations as clusters of patients; that patients with
ME/CFS or prostate cancer might be more readily infected due to
immune activation; that XMRV might prefer to proliferate in cells
that are dividing rapidly, and that the presence of these cells in
these illnesses might simply make it easier to detect infection; and
that the mechanism of viral transmission remains unknown, as does
the prevalence or distribution XMRV in human or animal populations.
In the aftermath of all initial scientific reports of a potentially
major find, the unknown wildly exceeds the known - an exciting place
for ME/CFS research to find itself.

The next steps

The researchers say that since publication they have continued to
refine their test for XMRV, finding that 95% of 330 ME/CFS samples
have tested positive for XMRV antibodies in the plasma (showing
that these patients have at least been in contact with the virus
at some time). They plan to continue their in-depth studies of XMRV
to clarify its effects on the human immune system, and are
clinically validating a blood test for the detection of XMRV in
ME/CFS and other human diseases. And they will shortly begin the
work of determining if any currently approved drugs, such as AZT,
might be useful for suppressing XMRV. If these efforts are
successful, human clinical trials to determine the most effective
patient treatments in a clinical setting would surely be close

At the same time, other independent laboratories across the world
will be attempting to replicate the findings in their own local
populations of ME/CFS patients. Since the WPI researchers used
samples selected from several regions in the US where 'outbreaks
of CFS' had been documented (using patients diagnosed on CDC-1994
and 2003 Canadian Clinical criteria ), blood samples from patients
in other countries (possibly diagnosed with less stringent
criteria) might throw up very different results. Furthermore, it
will be particularly important for independent laboratories to
conduct double-blind studies to search for XMRV in ME/CFS patients
and healthy matched controls, to strengthen the evidence base as a

The long-term

This is a stunning find - like a comet from a cloudless sky to
patients across the world. Yet it is too early to know whether
the discovery will change the ME/CFS landscape or not. At worst,
the discovery will be just one of a number of false dawns that
have arrived over the years -- albeit one that has brought,
suddenly, the world's attention to a neglected field largely
ignored by mainstream biomedical medicine. In this scenario,
XMRV might prove to be simply a passenger virus carried by an
immune-depressed ME/CFS patient population, with little or no
influence on the illness. At best, however, XMRV might be found
to be the casual factor in the development and maintenance of
ME/CFS, and a combination of anti-viral drugs will be found to
eradicate the viral load from patients
. One consequence of this
'jackpot' scenario would be a demolition of the existing
diagnostic criteria for the 'syndrome' CFS (currently a ragbag
of common non-specific symptoms, with many causes, shared with
other illnesses), as well as the older criteria for myalgic
encephalomyelitis. These would be replaced by objective
diagnostic criteria based on state-of-the-art methodology -
surely a welcome liberation for both CFS and ME patients
currently parked in a Diagnostic Terminal. Indeed, the WPI group
has already suggested that a new disease entity - X associated
neuro-immune disease, or XAND - might arise from the rubble,
implying (one assumes) that the one-third of ME/CFS patients
found to be 'negative' for XMRV in the WPI report would also
acquire new, more appropriate diagnoses.

Like Dr Dan Peterson, medical director of the WPI, we are hopeful.
As he says, 'Patients with ME/CFS (XAND) deal with a myriad of
health issues as their quality of life declines. I'm excited
about the possibility of providing patients who are positive for
XMRV a definitive diagnosis, and hopefully very soon, a range
of effective treatment options.'

(c) 2009 ME Research UK (Merge)


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