ME/CFS & XMRV virus -Q&A Dr Judy Mikovits

[Guest guest]

Shan's Note: Last question/answer is about Lyme

Disease..............................

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The Q & A below is taken from the most recent IACFS/ME newsletter by

Rosamund Vallings under the 'Correspondance' section, which states:

 

 

" ...Judy Mikovits kindly offered to answer some questions sent in by

members to help clarify some issues. "

 

``````````````

Attachment to IACFS/ME Newsletter Volume 3, Issue 1 • April 2010

pdf file of below Question and Answer Session

_http://www.iacfsme.org/Portals/0/pdf/IACFS-Attachment4-April2010.pdf_

(http://www.iacfsme.org/Portals/0/pdf/IACFS-Attachment4-April2010.pdf)

 

 

 

 

 

Questions and Answer Session with: Dr. Judy Mikovits: Principal

Investigator, Whittemore- Peterson Institute.

 

 

Q:

From what I read, XMRV is infecting immune cells. If patients take

nutriceuticals that have been shown to increase natural killer cell count,

could

some of this increase in NK cells come from dividing infected cells, thus

risking a heavier load of XMRV?

 

Andrew Bokelman

A:

Because XMRV research is in its infancy, little is known about the tissue

reservoirs of the virus, while many cell types can be infected (because the

XPR1 entry molecule/receptor is on every cell in the body), few cells

support high levels of replication of XMRV.

 

You could potentially increase the viral load by increasing the NK cell

count. However, we have done studies with compounds that increase NK cell

Killing without increasing NK replication or XMRV viral loads so NK cells kill

better and can therefore be efficacious in killing XMRV infected cell.

 

An extremely minor species of HIV becomes a dominant species when a large

mixture of the viruses (quasispecies) from the blood of AIDS patients is

cultured in the laboratory.

 

As much as 18% of our human genome (3 billion genetic codes) are made of

retrovirus sequences. The sequence of XMRV is 95% homologous to the human

endogenous retrovirus (HERV) sequence in our human genome.

 

Is the 5% genetic sequence variation enough to call XMRV a new virus? Is

XMRV a minor quasispecies that is selected out and predominantly amplified

from the tissue cultures?

 

The 6 full length XMRV clones: 3 from prostate cancer tissue biopsies from

men in Cleveland and 3 from leukocytes from female CFS patients in the

Western United States drawn in 2006-2008..were 99% similar.

 

We did not despite repeated attempts isolate ANY other variants from those

individuals suggesting that the virus is very low replicating and unlike

HIV does not have quasi species.

 

 

As much at 18% of the human genome is retroviral elements or endogenous

retroviruses.

 

THESE ARE QUITE DISTINCT FROM EXOGENOUS VIRUSES!

 

PRIOR TO THE SCIENCE PAPER THERE were ONLY 2 EXOGENOUS human retrovirus

families, HTLV (1,2) and HIV (1,2).

 

HERVS are not infectious exogenous retroviruses…

 

 

The main point of the science paper was the demonstration that XMRV was

the third human exogenous retrovirus and that it was blood borne and

transmissable (can isolate it and do primary and secondary infections of

primary

human cells).

 

Moreover, the full sequence of XMRV was blasted against the entire human

and mouse genome and NEITHER the mouse genome or the HUMAN genome contained

XMRV.. proving it was NOT a mouse virus.

 

XMRV was on the basis of our data proven to be a NEW HUMAN Blood borne

infectious and transmissable retrovirus.

 

Finally the proof of an immune response in CFS patients from whom the

virus had been isolated and sequenced showed that the XMRV in CFS patient was

not a mouse contaminant or a human lab contaminant.

 

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Q:

It has been said in the new paper article that XMRV is transmitted by

blood, sex and body fluid.

 

The author may have meant that this is what happens in mice but is not yet

defined for human.

 

Sexual transmission (men who have sex with men) and transmission through

blood

(hemophiliacs) were long suspected based on epidemiologic data before HIV

was found to be cause of AIDS in 1984.

 

ME/CFS does not have typical pattern of sexual transmission although there

are rare mentions of transmission between couples.

 

Most of my patients have developed ME/CFS after flu-like illness with

respiratory and/or gastrointestinal symptoms, which would speak against sexual

and blood transmission.

 

Furthermore, why are children developing this illness and why clusters of

cases occurred in Incline village and other areas, if the transmission is

as stated. Please clarify this issue.

 

Thank you,

John K. Chia M.D.

 

 

A:

Newspapers are notorious for extrapolating data and drawing conclusions.

We and Dr. Stuart Legrice attempted several times in writing to correct the

mis-statements in the Wall Street journal and the NY Times.

 

The Science paper showed that XMRV was blood borne, infectious and

transmissable SUGGESTING blood and body fluid transmission although NO studies

have proven transmission of any kind.

 

The authors meant this is the mode of transmission for the other two human

exogenous retroviruses HTLV-1 and HIV. XMRV is NOT a Mouse virus and NO

ONE knows how it got into the human population). This author has never worked

with mice.

 

It is important NOT to think only of HIV when considering modes of

transmission. Body fluid means ANY body fluid, blood was proven in the Science

paper, but one can also consider saliva, vomit, urine and feces.

 

XMRV is a gammaretrovirus (simple) and these tend to be much more stable

than HIV and HTLV1 which are complex retroviruses.

 

XMRV has been demonstrated by us in the science paper to be very stable

and easily transmissable CELL Free unlike its cousins HTLV (which is tightly

cell associated) and HIV, which is very labile and not stable in vomit

feces or urine and while it can be shed and theoretically transmitted in saliva

this is rare as it is labile cell free as well..

 

The flu like illness and gastrointestinal issues are consistent with

stability in other body fluids and particularly in acidic environments such as

the gut and urine…

 

We have isolated infectious XMRV from saliva and prostatic secretions to

date and tested its stability.

 

These are unpublished data and we await the development of a quantitative

viral load assay, but when we can quantify the stability, my hypothesis is

that XMRV is the most stable human retrovirus to date and while no human

retrovirus (or animal retrovirus is transmitted airborne) our hypothesis is

that we will find the transmission is in other body fluids and outbreaks

occur because of the stability of XMRV in other body fluids

 

 

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Q:

Do you think that any of the new biotech drugs for MS could be useful for

CFIDS?

 

Thank you.

Pat Turello

 

 

A:

My (limited knowledge of the new MS drug is that they target the

hyperactive immune response and trafficking of white blood cells from lymph

nodes so

if a reservoir of XMRV is the lymph nodes and the hyperactive immune

response (as we suspect) plays a role in disease progression through increased

replication of XMRV or trafficking of white blood cells harboring XMRV to

sites of inflammation, then these drugs could be useful for XMRV associated

CFIDS.

 

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Q:

Are there any official ( or unofficial) records of forested areas near and

around Incline Village being sprayed for 'insect control' prior to the

outbreak of CFS there?

 

 

A:

There is no data or records that I am aware of and no evidence that XMRV

is spread through insects (in fact there is no evidence of how XMRV got into

the human population)

 

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Q:

Is it possible that XMRV is ( or related to) an 'escaped,' genetically-

engineered laboratory research retrovirus?

 

A:

NO laboratory researchers are not smart enough to engineer new human

retroviruses. XMRV has never been detected in ANY other animal in nature except

humans.

 

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Q:

Please explain the significance of " xenotropic " in the transmission or

infectivity of XMRV ?

 

Nancy Allen

 

 

A:

Xenotropic viruses are not able to infect cells derived from laboratory

mice (or the mice themselves but they can infect cell lines from a number of

other species including humans and wild field mice…more proof that this is

not a lab engineered or escape variant.

 

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Q:

Hey guys! miss you! I am keeping things hopping here in Miami, but it is

weird being off the board. I noticed VIP Dx has dropped the PCR part of the

XMRV testing, in favor of culture.

Why?

 

Nancy Klimas

 

 

A:

PCR of genomic DNA was found by the WPI and its NCI collaborators to be

the least sensitive method of detecting XMRV because of the low copy number

of XMRV and the realization by the negative studies that only 1 in 1miiolon

resting white blood cells harbors a copy of the XMRV provirus.

 

Thus VIPDx was getting too many false negatives.. ie the failure to detect

XMRV.

 

The same reason that other companies using sensitive PCR failed to detect

XMRV from a spot of blood or 1 ml of blood.

 

Retroviruses multiply only in dividing cells so VIPDx dropped the first

PCR in favor of biological amplification of XMRV before PCR detection.

 

Not only are the results more reliable but the test is considerably

cheaper. The most important thing is to get the CORRECT answer!

 

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Q:

Do you feel that XMRV is necessary and sufficient or necessary but not

sufficient or not necessary or sufficient to cause chronic illnesses like CFS?

 

 

A:

Our hypothesis is that chronic XMRV infection creates results in an immune

deficiency that is necessary but not necessarily sufficient to result in

chronic illnesses like CFS.

 

As with HIV/AIDS copathogens define AIDS, CMV retinitis, kaposi’s sarcoma

are AIDS defining co-pathogens.

 

That said XMRV is a type C retrovirus and Type C retroviruses are

associated with neurovirulence in a range of host species, including humans,

cats,

rodents and birds with or without concurrent immunological disease

suggesting XMRV can be necessary and sufficient to cause CFS.

 

--------------

 

Q:

What are your current % positives in CFS? In controls?

 

 

A:

In CFS disease satisfying the Canadian consensus criteria, we have

isolated virus from more than 300 patients of ~400 tested but we have

serological

evidence in another ~10% of CFS patients fulfilling CDC criteria, from whom

we have not isolated virus, clear evidence of infection but the

significance of which is not known.

 

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Q:

Is there an indication that the virus is active and being transcribed in

CFS? What percentage of positives are being transcribed?

 

 

A:

The Science paper clearly showed active transcription of XMRV in >75% of

the patients tested and similar suggestion of latent infection or evidence

of infection without isolation of virus in 10-15%.

 

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Q:

With the known % of CFS patients positive for Mycoplasma species (~60% in

multiple studies), Chlamydia pneumoniae

(~10% in multiple studies), HHV-6 (~30% in some studies) and other

infections, is there any concordance with XMRV positivity?

 

 

A:

We have only done those analyses on the 101 in the original study, HHV6A

was 10%, EBV ~14% and nothing else more than 10%. We are working with

several groups at Lyme and those numbers may approach 30%-40 of those tested.

 

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Q:

Do you feel that XMRV could act to cause dysfunction of the immune system,

allowing opportunistic infections (such as in 4, above), similar to HIV-1

in AIDS?

 

 

A:

Absolutely that is our working hypothesis

 

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Q:

Do you think that treatment of XMRV might be useful or possibly too late

in CFS to restore patients to preinfection health status?

 

 

A:

I am extremely optimistic that treatment of XMRV or its immune target(s)

will restore CFS patients to at least 85% of the original health status even

in the sickest of the sick.

 

I base this optimism solely on the level of health that was achieved in

HIV AIDS patients with the advent of highly active antiretroviral therapy

(HAART) and XMRV is much less cytopathic than HIV, its effects on the immune

system are more subtle.

 

I think the evidence is that some recover with out ever treating the XMRV

or maintain relative health for years between “crashesâ€.

 

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Q:

When you assess signs/symptoms of patients with positive XMRV, are there

any that track or don't track well with XMRV positivity compared to CFS

patients as a group?

 

 

A:

I am not a clinician and right now we don’t have sensitive quantitative

assays to monitor viral load so we have not actually tracked symptom severity

and XMRV positivity.

 

For Science paper we did correlation analyses on every clinical marker of

immune status, that we had available to us including RNAase L, NK (number

and function, co-infections, cytokines and chemokines and NOTING

significantly correlated with a CFS diagnosis

 

(the referees and editors felt these data were not important for the paper

as they were all negative data.

 

The only one they published was the R462Q RNaseLvariant as this was the

original hypothesis under which XMRV was discovered.

 

The ONLY immune marker which correlated with XMRV infection 100% was

decreased Interferon alpha.)

 

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Q:

In families with more than one CFS (or other chronic illness), is there

any indication that XMRV was transmitted to immediate family members?

 

Prof. Garth Nicolson The Institute for Molecular Medicine

 

 

A:

YES… lots of them and I have not looked at everyone but my knowledge of

the 101 in the Science paper is that more than 2/3 of them have family member

who are infected and MOST are ill perhaps with another overlapping chronic

illness..

 

For instance FM and CFS or CFS mom and autistic kids and the cancer in

some of the families is frightening.

 

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Q:

current research findings about XMRV. I have been looking, but unable

include this.

 

Q:

I read where 75 top researches met on 16 Dec. 2009 to discuss the to find

any information about what they had found. Hope you will.

 

William Hays

 

 

A:

I am not aware of that meeting nor am I aware that on December 16th of

2009 there were 75 top researchers working on xmrv!

 

On November 10 the cleveland clinic sponsored a meeting where ~15

scientists presented their data including the WPI) on xmrv in cancer and cfs.

There

were 75 people in attendance and it was an interesting meeting but

honestly I would be surprised is there are yet 75 top researchers in the world

working on xmrv.

 

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Q:

how do you see hhv-6 and xmrv interacting?

 

 

A:

there are no data to suggest that hhv6 and xmrv directly interact in any

way.

 

Xmrv is a simple retrovirus so it encodes only structural proteins and not

transacting factors like hiv and htlv.

 

We are testing the hypothesis that like hiv, the transmission of xmrv and

the progression of xmrv disease are accompanied by de novo infection by

other microbes or by activation of microbes that were present in the host in

homeostatic equilibrium before xmrv infection.

 

In recent years, data have accumulated on the interactions of these

coinfecting microbes & shy;viruses in particular & shy;with hiv.

 

Coinfecting viruses generate negative and positive signals that suppress

or upregulate hiv-1, suggesting that the signals generated by these viruses

may largely affect xmrv transmission and pathogenesis as they do with hiv

transmission and pathogenesis.

 

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Q:

the brits have commented that both m.e., And the u.s. Cluster outbreaks of

the

1980s, seem to spread like an enterovirus (a polio-like virus), not like

a herpes virus.

 

 

A:

xmrv is a retrovirus not a herpesvirus so I don’t understand the comment.

Hiv causes leaky gut and disruption of the gut microbiome and an open blood

brain barrier allowing pathogens access to areas of the body that these

pathogens normally would not have access…

 

The same could happen with xmrv… I guess I cannot answer this because more

than 75 of the 101 patients in our study were not involved in cluster

outbreaks.

 

Whether that criticism holds, it certainly seems the outbreaks did not

follow the pattern set by hiv.

 

While our knowledge of hiv disease is useful in developing hypotheses and

studying potential mechanisms of hiv pathogenesis, xmrv is totally unlike

hiv and htlv-1 in that it is a simple retrovirus; the first ever identified

human exogenous simple retrovirus and the family of viruses most closely

related to xmrv causes neurological diseases and cancer very by mechanisms

distinct in many aspects from hiv and htlv.

 

We discussed earlier xmrv may be much more stable in body fluids other

than blood and cell free and would completely explain clusters and sporadic

transmission as seen in cfs both in the us and uk

 

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Q:

how would teachers in the same school, for example (who were not

misbehaving), contract the disease from each other?

 

 

A:

see above but what if xmrv is more stable in body fluids such as saliva,

urine, vomit such that exchange of body fluids less directly than sexual

contact and blood borne direct infection were the mode of transmission.

 

This hypotheses would satisfy the familial and close contact such as a

school particularly if a co-pathogen enhanced transmission and progression as

was the case of hiv and hsv in africa.

 

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Q:

what does this mean for young women who wish to become pregnant, but who

might have xmrv?

 

 

A:

gammaretroviruses can be transmitted vertically and are transmitted in

breast milk.

 

The hormone responsiveness of the virus suggests that lactating moms

express more xmrv in breast milk.

 

Htlv 1 was endemic in japan so simply preventing breast feeding reduced

htlv-1 associated neuro- immune disease and cancer by 40% on one generation.

 

Vertical transmission is more difficult but even if infected, the key is

to keep the reservoirs of virus low.. stop the xmrv from being expressed and

spread to healthy cells keep the xmrv provirus from integrating into long

lived cells ….

 

The variation was so small and the lack of quasi species and high levels

of replication suggest that vaccine development will be easier with this

retrovirus that with the complex retroviruses, hiv and htlv.

 

The most important thing to do is identify everyone infected and stop the

spread and replication of the virus in every individual prevent disease in

those who are well and stop the progression and restore the immune system

in those who are ill.

 

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Q:

given the association of xmrv with patients whose blood was stored at WPI,

how many other docs have sent samples that are positive?

 

 

A:

contrary to the assumptions and misinformation about the samples in the

WPI repository. These samples were not solely from the incline village

outbreak.

 

All samples were drawn from patients coming to sierra internal medicine

between 2006 and 2008.

 

Fewer that 20 of the 101 were from the original outbreak and more than 75

were sporadic cases of cfs from patients who came to dr. Peterson from 12

states and canada.

 

The 101 were representative of patients satisfying CDC and Fukuda criteria

throughout the us.

 

At least 5 doctors from across the us including Dr Klimas and Dr Cheney

had patients in the repository and in the study.

 

The 101 patients were selected at random from the hundreds in the

repository. The main consideration was that we had samples that could be

cultured

(retroviruses cannot multiply unless a cell divides and several samples

from a given patient.

 

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Q:

are your “hit rates†different in the samples sent to you since the

science paper?

 

 

A:

not as long as the physicians sending the samples are diagnosing as dr

peterson does on CDC criteria. In fact the hit rates from overlapping diseases

more than we expected now ~35%.

 

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Q:

Given that a number of physicians who send you XMRV samples are also

collecting HLA DR data, can we sort the positives and negatives by HLA DR

haplotype, i.e., is there evidence of an increased relative risk for carriage

of

XMRV and presence of illness by HLA DR?

 

 

A:

We established the original WPI research program to look at the underlying

genetics from the exact same population from which we were looking for

novel viruses and correlating immune profiles and gene expression patterns.

 

Therefore our collaborators Mary Carrington and Michael Dean of the NCI’s

genomic diversity program and the geneticists who identified the HLA and

KIR susceptibility and resistance loci in HIV/AIDS have all of these studies

well underway…

 

Some of these data were presented at last year’s IACFS meeting. At that

time we did not know XMRV status of those patients. Those data are currently

being analyzed.

 

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Q:

Do we know of any patients with acute acquisition of XMRV? How can you

confirm a new case versus reactivation of transcription of intercalated viral

material in DNA? What happens to their symptom with acquisition? What

happens to their measures of innate immune responses?

 

 

A:

No. None of these studies can be done yet.

 

We are working on cases of suspected “transfusion acquired†CFS which

could establish an acute infection.

 

These studies will require quantitative assays. The requirement that a

diagnosis of CFS require an individual to be ill for 6months has precluded

anyone from having such data.

 

Hopefully at least one archaic practice will soon be gone.. the worst

predictor of HIV disease progression is the viral set point and reservoir viral

load.

 

Set the reservoirs as low as possible! That is identify the infection as

soon as possible. This is the best chance to prevent disease development and

progression.

 

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Q:

Do we know if genes carried by XMRV are being transcribed? If so would

genomic data from samples collected by other labs be useful in a pooled

analysis?

 

 

A:

XMRV is a simple retrovirus and encodes and expresses only the gag pol and

env genes. ALL are expressed and proven to make functional proteins.

 

This was clearly demonstrated in our Science paper. Gamma retroviruses do

not cart or pick up cellular genes? Hope I answered the question because I

don’t understand the second part.

 

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Q:

What regulatory mechanisms are felt to be present that would affect

transcription of XMRV genetic material?

 

 

A:

Expression of XMRV and all simple retroviruses are controlled only by cis

acting elements in the upstream untranslated region.

 

In XMRV 3 transcriptional control elements have been identified - two

gluccocorticoid response elements ( a strong one responding to androgens and

estrogens, a weaker one responding to the stress hormone cortisol and an NfKB

site). All turn on XMRV.

 

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Q:

If XMRV is actively being transcribed, is there a difference in lab

parameters and symptoms compared to those who carry XMRV but are without

transcription?

 

 

A:

We don’t have these data yet but that is a testable hypothesis.

 

--------------

 

Q:

If XMRV is present but inactive, are there any suggestions as to what

could be a trigger for (re)-activation?

 

 

A:

Estrogens, Androgens, Cortisol (stress) and inflammation.

 

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Q:

Given the problems with antigen presentation seen routinely in so many

patients with chronic fatiguing illnesses, we would expect to see some

patients with culture (+) XMRV who are antibody negative?

 

 

A:

Yes! We see lots of those… these data are very interesting and suggest

immune therapy including antibody therapy may be most useful in this disease.

 

-----------------

 

Q:

I heard that there may be another study in the U.K. that came to a

different conclusion about a possible link between CFS and XMRV. Can you

comment

on the differing results, and whether the results of the two studies can be

reconciled?

 

Thank you.

 

 

A:

The negative studies were technically flawed in that their methods were

demonstrated NOT to be capable of detecting XMRV.

 

Their patient populations likely did not satisfy CDC criteria and they

looked only by PCR on genomic DNA the least sensitive way of detecting XMRV.

 

To date none one has attempted to replicate our study.

 

It is very clear that the prevalence of XMRV in UK is NOT ZERO and that

XMRV has been detected in CFS patients in the UK.

 

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Q:

How might the finding of the XMRV virus relate to Lyme Disease?

 

 

A:

We are seeing XMRV in Chronic Lyme patients sent to us from several

including Lyme physicians. The hypothesis that chronic XMRV infection creates

an

underlying immune deficiency is consistent with many co-pathogens.

 

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