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>>>> 27 November 2009 <<<<
Editorship : j.van.roijen@chello.nl
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http://www.meresearch.org.uk/information/publications/xmrvfind.html
ME Research UK
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
=97 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 [ http://bit.ly/6F4MJe ],
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.
``````````
ME Research UK welcomes good-quality
outline applications from Research Units
anywhere in the world for funding to
replicate and/or extend the work on the
possible links between XMRV and ME/CFS.
Applications will be processed rapidly, and
the peer-review process expedited, for
such applications.
``````````
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
unusual, 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 =97
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
[ http://bit.ly/8iZQkl ] 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".
[ http://bit.ly/8PLRXZ ]
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:
http://bit.ly/72Kbct ).
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 [ http://bit.ly/8px8PT ], 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 [ http://bit.ly/8iZQkl ]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 behind.
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 [ http://bit.ly/7WjaNF] and
2003 Canadian Clinical criteria [http://bit.ly/13FRXv],
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 whole.
The long-term
This is a stunning find =97 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
causal 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."
``````````````
The Whittemore Peterson Institute has a
very useful page of "Questions and
Answers" on this topic
[http://bit.ly/6xkHqn], including items on
clinical and treatment aspects. Also, the
National Cancer Institute in the USA has a
responsible page called "XMRV: Questions
and Answers" [http://bit.ly/52xsZ8]
``````````````````````````
Links to scientific coverage of the story
* Whittemore Peterson Institute Press Release:
http://bit.ly/7XrUBp
* Science News: Retrovirus might be culprit in chronic
fatigue syndrome: http://bit.ly/61WFyd
* New Scientist: Chronic fatigue syndrome linked to
'cancer virus': http://bit.ly/8epvAc
* Scientific American: Retrovirus Linked to Chronic
Fatigue Syndrome, Could Aid in Diagnosis:
http://bit.ly/4m33Eg
* Nature: Virus linked to chronic fatigue syndrome:
http://bit.ly/50c8sH
* NIH News: Consortium of Researchers Discover
Retroviral Link to Chronic Fatigue Syndrome:
http://bit.ly/5Bcvw8
~~~~=20
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