XMRV and ME/CFS -A stunning find

[Guest guest]

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

— 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 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 —

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 of SAIC-

Frederick/NCI-Frederick), and was first identified only

in 2006 by Prof. 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. Coffin, and colleague

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 — 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 , 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 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 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