ME/CFS -Could a Stealth Virus Be Lurking?

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>>>> 12 November 2009 <<<<

Editorship : j.van.roijen

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_http://bit.ly/2xa90H

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NOVEMBER 2009

HOT TOPICS ARCHIVE

 

 

 

Chronic Fatigue Syndrome

Could a " Stealth Virus " Be Lurking?

 

 

From Infectious Disease Alert

 

 

 

 

Abstract & Commentary

 

By John F. Joseph, MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for

Education, Ralph H. Johnson Veterans Administration Medical Center; Professor

of Medicine, Medical University of South Carolina, Charleston, is

Associate Editor for Infectious Disease Alert.

 

 

 

Dr. John is a consultant for Cubist, Genzyme, and bioMerieux, and is on

the speaker's bureau for Cubist, GSK, Merck, Bayer, and Wyeth.

 

Source: Lombardi VC et al. Science. 8 October 2009

(10.1126/science.1179052).

 

 

 

It has been known for years that patients with chronic fatigue syndrome

(CFS) have a defect in a major antiviral pathway, the 2-5A/RNase L pathway.

 

The RNaseL produces non-specific viral cleavage and, thus, protects us

from many viral infections (innate immunity).

 

Defects in this pathway not only lead to susceptibility to viral

infections but may also increase our susceptibility to tumor development.

 

The RNaseL gene, called Human Prostate Cancer 1 (HPC1), has a variant

R462Q related to a potential etiologic agent of prostate cancer, a novel human

retrovirus, xenotropic murine leukemia virus (MuLV), named XMRV.

 

 

So, it was by a bit of serendipity that a group of workers headed by

several from the Whittemore Peterson Institute in Reno, Nevada, asked if XMRV

could be associated with CFS.

 

What led to any rationale connection between prostate cancer and CFS is

not clear, but the question led to a series of experiments that culminated in

a very recent publication showing an association between the presence of

this retrovirus in the peripheral blood mononuclear cells (PBMCs) of

patients with CFS.

 

 

 

We are dealing here with intricate science that surely took these 13

scientists and a host of technicians years to produce. Yet the paper contains

astounding findings that I'll try to summarize succinctly, for

besides the eight primary article pages from Science Express, there are 18

additional pages of " supporting " materials that also contain fascinating

data.

 

 

Here is what the paper reports.

 

In 101 banked samples of PBMCs, 67% (68) were positive for a XMRV gag

sequence. Next, seven of 11 PBMC CFS samples held at the Cleveland Clinic were

shown to have XMRV gag plus env. Only 3.7% of PBMC DNA from healthy controls

had XMRV gag when tested by PCR.

 

Amazingly, those gag and env sequences were nearly identical to those from

XMRV from prostate cancer-associated strains (PLoS Pathol. 2006;2:211).

 

Full-length SMRV from two patients differed from prostate cancer strain

VP62 by only six nucleotides, showing again a > 99% identity between the CFS

and prostate cancer XMRV.

 

 

 

A phylogenetic comparison of six isolates from CFS/Prostate cancer showed

them to be significantly different from other murine leukemic viruses.

 

In all, 50 other isolates of MLV were used to make the neighbor-joining

trees. The suspected closest relatives were other xenotropic murine viruses

(Xmv 15-19 and Xmv 10, 13, 16) and polytropic (Pmv) plus modified polytropic

(Mmpv) viruses, which were in fact very removed genetically from XMRV.

 

 

 

Next, it was shown that several antibodies with " novel viral

specificities " all reacted with VP62 XMRV proteins when grown in several cell

lines,

including a line called LNCaP of prostate cells that are known to permit

infection with MXRV. Flow cytometry of activated lymphocytes also showed that

19

of 30 PBMC CFS samples reacted with antibodies to MLV P30 Gag and other

MLV proteins whereas PBMCs from normal patients were negative, for an odds

ratio of 54.1. (confidence intervals of 23.8-122).

 

So, there is a non-random association of CFS PBMCs with XMRV. Both

activated T and B cells from CFS were infected with XMRV.

 

 

 

The next experiment was quite ingenious. PBMCs from CFS patients were

co-cultured with LNCaP cells, the ones defective in RNaseL pathways.

 

The LNCaP cells became infected, as shown by presence of XMRV gag and env

proteins and by the presence of whole virus, as seen by electron

microscope both at the time of infection and upon release. The electron

micrographs are quite stunning.

 

The same type of infectivity was also seen when only plasma from CFS

patients was applied to LNCaP cells. Thus, cell-associated and cell-free virus

seems to be infectious, at least to some cell lines.

 

Finally, it was shown that 50% of plasma samples from patients with CFS

have a humoral response to XMRV, demonstrated by presence in flow cytometry

assays of antibodies to a viral env closely related to XMRV env.

 

 

 

 

Commentary

 

 

It was courageous of Science to publish this paper because there are

obvious epidemiologic data missing from the report.

 

Still, patients with CFS can clearly see from this article the

sophistication and dedication of scientists studying CFS, giving them hope that

there

will be some etiologies discovered in the near future.

 

Indeed, when Robert Suhadolnik and colleagues at Temple University School

of Medicine described the defects in RNaseL in the mid 1990s, the newer

methods in retrovirology were just emerging so, in a sense, these new studies

had to await the sophistication that has come with laboratory advances in

the HIV/AIDS era. Good science

(methodology) begets better science.

 

 

 

Esteemed Professors John M. Coffin and Jonathan P. Stoye of Tufts

University wrote an accompanying editorial in the issue of Science Express.

 

They emphasize that the gammaretroviruses of mice, including endogenous

MLVs, have given us much understanding of cancer pathogenesis; no such

association has been made in humans until XMRV was discovered in prostate

cancer tissue only three years ago.

 

 

 

This work will have its critics. One concern is laboratory contamination

with MLV.

 

It is very unlikely that laboratory contamination freed the XMRV into

human cell lines. CFS PBMCs and prostate cancer patients come from very

disparate backgrounds.

 

Indeed, the patients at the Whittemore Peterson Institute also come from

diverse geographies and, except for their common diagnosis of CFS, have

little in common.

 

That fact makes it even more remarkable that out of

nearly 8000 nucleotides in XMRV-a retrovirus — only

about 30 show variation.

 

That lack of genetic variation for XMRV lies in great contrast to the huge

variation we are used to seeing in HIV, suggesting that XMRV has recently

descended from a common ancestor.

 

 

Drs. Coffin and Stoye in their editorial also focus on the 3.7% of XMRV

positivity in normal PBMCs and non-cancerous prostate tissue. If this rate

were to hold up in studies from other geographic regions of the world, that

would suggest that at least 10 million people worldwide harbor the virus and

perhaps are more susceptible to a wide variety of full expression of the

retroviral infection.

 

 

 

As one of a group of physicians who has recognized and managed patients

with CFS for many years, my bias is to believe the validity of these current

data.

 

Yet, many theories about the cause of CFS have come and gone. CFS patients

are always looking for new hope.

 

Indeed, an article in the New York Times of October 13 by Denise Grady

speaks to thousands of patients already clamoring to be tested for the new

virus.

 

Of note also is that the Whittemore Peterson Institute was founded by

parents of a young woman with CFS, so the data from Whittemore need to be

verified in additional cohorts of CFS patients.

 

Nevertheless, the passion of physicians like Dan Peterson himself, and

others in that kindred, has driven the science of CFS.

 

Steadfast organizations like our national CFS foundation, CFIDS

(_www.cfids.org_ (http://www.cfids.org/) ), and many state CFS organizations

continue

to sponsor patients and programs that demand a balanced scientific playing

field which in part has led to the quality of work demonstrated in the paper

by Lombardi et al.

 

 

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>>>> 12 November 2009 <<<<

Editorship : j.van.roijen

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