journal Science, has the potential to be a great advance, and a short
overview essay can be seen here
http://www.meresearch.org.uk/information/publications/xmrvfind.html. The
text is given below.=20
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.
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
[www.sciencemag.org/cgi/content/abstract/1179052], one of the most
prestigious scientific journals in the world, on 8th October 2009 and
described the findings of a consortium of researchers from Whittemore
Peterson Institute (WPI) [http://www.wpinstitute.org] (located at the
University of Nevada, Reno), the National Cancer Institute (NCI), part
of the National Institutes of Health [http://www.cancer.gov]; and the
Cleveland Clinic, Ohio [http://www.clevelandclinic.org].
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 68/101
ME/CFS patients (67%) compared with only 8/218 (3.7%) healthy controls.
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 - 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
[http://www.wpinstitute.org/xmrv/xmrv_team.html] 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 to
New Scientist
[http://www.newscientist.com/article/dn17947-chronic-fatigue-syndrome-li
nked-to-cancer-virus.html] 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.=20
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 leukemia viruses found in the genomes of wild mice
(see the informative presentation on retroviruses by Dr Jones of
SAIC-Frederick/NCI-Frederick from the WPI link
[http://www.wpinstitute.org/xmrv/index.html]) and was first identified
only in 2006 by Dr. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075094/?tool=3Dpubmed]
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
[http://informahealthcare.com/doi/abs/10.1517/14728222.12.3.281?cookieSe
t=3D1&journalCode=3Dett]). In ME/CFS, a wide spectrum of "cleavage" of =
RNase
L can be observed (a phenomenon also seen in MS 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://www.ncbi.nlm.nih.gov/pubmed/18177602]). 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://www.wpinstitute.org/research/research_biobank.html], 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" [http://www.sciencemag.org/cgi/content/abstract/1181349]
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.=20
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 these 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://www.annals.org/cgi/content/full/121/12/953] and Canadian
Clinical criteria 2003 [http://www.cfids-cab.org/MESA/ccpc.html] ),
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 - 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, and their replacement with 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 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 treatments
options."
The Whittemore Peterson Institute has a very useful page of "Questions
and Answers" [http://www.wpinstitute.org/xmrv/xmrv_qa.html] on this
topic, including items on clinical and treatment aspects.
Links to scientific coverage of the story
* Whittemore Peterson Institute Press Release
http://www.wpinstitute.org/news/news_current.html=20
* Science News: Retrovirus might be culprit in chronic fatigue
syndrome
http://sciencenews.org/view/generic/id/48157/title/Retrovirus_might_be_c
ulprit_in_chronic_fatigue_syndrome
* New Scientist: Chronic fatigue syndrome linked to 'cancer virus'
http://www.newscientist.com/article/dn17947-chronic-fatigue-syndrome-lin
ked-to-cancer-virus.html?full=3Dtrue&print=3Dtrue
* Scientific American: Retrovirus Linked to Chronic Fatigue
Syndrome, Could Aid in Diagnosis
*
http://www.scientificamerican.com/article.cfm?id=3Dchronic-fatigue-syndro=
m
e-retrovirus&print=3Dtrue
* Nature: Virus linked to chronic fatigue syndrome
http://www.nature.com/news/2009/091008/full/news.2009.983.html
* NIH News: Consortium of Researchers Discover Retroviral Link to
Chronic Fatigue Syndrome
http://www.nih.gov/news/health/oct2009/nci-08.htm
Dr Neil Abbot
Operations Director
ME Research UK
The Gateway
North Methven St
Perth PH1 5PP, UK
ME Research UK is a registered charity (SC 036942). Our principal aim is
to commission and fund high-quality scientific (biomedical)
investigation into the causes, consequences and treatment of ME/CFS, but
we also have a mission to "Energise ME Research"
http://www.meresearch.org.uk/=20
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