Wednesday, September 29, 2010

Cheney's notes on XMRV

From MEActionUK Yahoo group- "Rich Van Konynenburg has posted this to
a few groups tonight. Permission to re-post as long as Dr Cheney is


From Dr Cheney

I attended and was a poster presenter at the recently completed XMRV
conference at the NIH.  It was fascinating and I took perhaps 30 pages
of notes.  The bio-political undertones were also intense
but I have
to say that the presentations of XMRV association with CFS (4
presentations) were much stronger than the presentations of negative
XMRV associations with CFS (4 presentations).  They were stronger
specifically because of the multiple methods they employed and not
just PCR.

Very interesting in this regard were comments by the head of the blood
working group at the NIH who is trying to determine the cause of the
discrepancy.  He hinted strongly that it is the way blood is collected
and processed for nucleic acids and not the detection methods for XMRV
itself that divides the two groups.

In an NIH blood group sponsored study, a group comparison study with
both camps represented detect successfully, in a blinded fashion, XMRV
spiked buffer in varying concentrations but they nevertheless divide
into two camps when clinical blood samples are taken and processed for
XMRV nucleic acids.  Using only PCR, one camp sees ~80% positive in
CFS and one camp sees 0% positive in CFS

There is no one in between and no middle ground between the two groups
which was striking and noted by Joe B. who was also in attendance.
There is no evidence by mouse mitochondrial DNA probes, that any of
the positive associations were
contaminated.  However, one of the negative association speakers found
non-human mouse virus MLV contamination perhaps localized to heparin
tubes used for blood collection.  Heparin is often produced in China
where mice are common as pets.
When the contamination was cleared, she found no association of XMRV with CFS.

I also wanted to share some other highlights of the conference  Among
them, a very interesting presentation was made by a group connected to
Abbott Labs that infected male and female Macaques (monkeys closely
related to man) with human XMRV to see what happens and where the
virus ends up or concentrates itself.

Within a few weeks, the virus was largely cleared from blood where it
was initially injected in high concentration.  Even antibody response
was lost over time (months) as the infection was largely removed from
the blood and virus did not appear to persist in the blood.
Apparently, there was not enough viral antigen to keep antibody levels
high or persistent.

However, the virus was found more or less in every organ, at least
initially, and thought to be carried around the body in T-cells and
B-cells during the active phase of infection.  This is consistent with
the ubiquitous nature of the Xpr1 receptor used by the virus to gain
access to almost all cells of the body. Organs where the virus was
initially most concentrated appeared to be lymphoid organs such as the
spleen, liver and mesenteric nodes of the GI track and in sex organs
and in particular the epithelium of the prostate gland where it was
highly concentrated at first and then the infected cells later
apoptosed and infection disappeared from the epithelium and then the
virus was more likely to be seen in the interstitial cells in the
stroma or matrix of the prostate, especially the fibroblasts which may
be one reservoir in all the various organs that are initially
infected.  The virus was also found in the epithelium of the cervix in
the female macaque.

Over time, the infections of various organs tended to be cleared by
either immune mechanisms but especially by restriction enzyme systems
present in almost all human cells that hypermutate the virus so it
cannot persist as a competent infectious agent. Indeed, mutated viral
strains are almost always found in CFS cases by both Judy Mikovits at
WPI and Frank Ruscetti at NCI.  Sometimes this makes the virus
incompetent as an infectious agent and sometimes has no effect on

Very interesting is that another cell that appears to be a reservoir
of XMRV other then fibroblasts within tissue stroma are tissue
macrophages  The pulmonary alveolar macrophages were absolutely loaded
with XMRV virus and other tissue macrophages could also be a potential
reservoir in other tissues as well, especially in the GI tract, sex
organs and sinuses.  Tissue macrophage reservoirs would be analogous
with HIV as well.

It would seem that bronchial secretions, nasal secretions and sex
organ secretions as well as feces and urine are well positioned to
help the virus to spread itself to other macaques, especially if

As for activation of more or less low level or quiescent but
persistent infectious virus, there seem to be several mechanisms.  The
virus has both a glucocorticoid response element (GRE) and an androgen
response element (ARE) in its promotor region.  It also has binding
regions for NK Kappa B proteins in its response elements.  In any
organ with high levels of local androgenic
stimulation such as the prostate and perhaps during puberty, the virus
could activate. No mention was made of the effect of the predominant
female sex hormones but estrogen is the equivalent androgen-like
hormone in females.

As for the GRE in the promotor region, severe stress will activate the
virus or the use of glucocortocoid hormones and perhaps any precursor
steroid hormone such as pregnenolone.  As for the NF Kappa B sites,
any strong immune response with an associated cytokine storm would
also be a strong stimulant and such stimulation certainly occurs in
the bronchial tree which is frequently stimulated with antigen,
especially during allergy season.

Perhaps most interesting of all was what happened with the injection
of a bolus of foreign peptides into macaques that had apparently
completely cleared the virus from blood.  There was a huge
reactivation of infectious virus in the blood proving that latent but
persistent virus is just below the surface and that XMRV infection
cannot be completely cleared from all reservoir sites. The peptide
injection mimics an acute infection (? borrelia or the flu), an
immunization or even acute mold exposure.

The effect of XMRV infection over time was not studied in the macaque
but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has
been well studied in cats for decades.  I will in another post
describe a most interesting talk at this conference by a veterinarian
on the life history of infection by a gammaretrovirus in cats.

Paul Cheney, M.D.

No comments: