Text from Live Chat: CFS-Science and Controversy

[Guest guest]

Note: This is the text from Science's Live Chat with Busch and

Jay Levy on XMRV and CFS.

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http://news.sciencemag.org/sciencenow/2011/09/live-chat-chronic-fatigue-syndro.h\

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Live Chat: Chronic Fatigue Syndrome—Science and Controversy

by Enserink on 21 September 2011, 3:36 PM

Today's Topic

Two years ago, Science published a paper suggesting that a mouse

retrovirus called XMRV might be involved in chronic fatigue syndrome

(CFS), a debilitating disease with no known cause. The study raised

worries that XMRV might be spreading via blood donations. Since then,

many other studies have failed to find XMRV in CFS patients, and some

have suggested that the 2009 paper was the result of lab

contamination.

Where does the science stand today? And how has the long and sometimes

bitter debate affected the scientific field and CFS patients? Join us

for a live chat on this page at 3 p.m. EDT on Thursday, 22 September,

to discuss these and other questions with Busch, a transfusion

medicine scientist involved in XMRV research, and retrovirologist Jay

Levy. You can leave your questions in the comment box below before the

chat starts.

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3:02 Enserink: Hello everybody and welcome to this chat, where

we will talk about chronic fatigue syndrome, or CFS. There are new

data to discuss: Today, Science published the long-awaited study by

the Blood XMRV Scientific Research Working Group. This collaboration

of nine labs set out to find if XMRV, or a broader group of viruses

called Murine Leukemia Viruses (MLV's), can be reliably detected in

CFS patients and healthy people. They also wanted to know whether XMRV

or MLV's pose a danger to the blood supply. Their paper is here:

http://www.sciencemag.org/content/early/2011/09/21/science.1213841.abstract

3:03 Enserink: Today, Science also runs a partial retraction

of the 2009 paper, (often called Lombardi et al.) that first reported

the link between XMRV and CFS. Two of the authors on that paper,

Silverman and Jaydip Das Gupta, have concluded that their

contribution was caused by contamination, and is wrong.

http://www.sciencemag.org/content/early/2011/09/21/science.1212182.abstract

With us today is Busch, the director of the Blood Systems

Research Institute in San Francisco, who coordinated the study by the

Blood Working Group. (He is the last author on today's paper.) Also

present is Jay Levy, an HIV/AIDS researcher at the University of

California, San Francisco; he was not involved in the current study,

but he published a paper in the 1 July issue of Science that failed to

find XMRV in CFS patients.

http://www.sciencemag.org/content/333/6038/94

Welcome to both of you.

3:03 Dr. Busch: The study involved collection of specimens

from 15 patients who were previously reported as positive for XMRV or

related viruses in the Lombardi et al and Lo et al studies and 15

control donors who had been previosuly confirmed as negative by the

key labs. Multiple panels comprised of coded replicate samples these

30 patients/controls as well as positive controls were distributed to

9 labs. These labs performed multiple assays including PCR, culture

and antibody assays. Only 2 labs reproted positive results, the WPI

lab and the lab of their collaborator Ruscetti at NIH. The

results in these labs were inconsistent within and between the labs

and hence judgeed to represent false positive results. This led the

group to conclude that none of the tests could reliable detect these

viruses.

3:03 Enserink: Before we start, I'll also mention that my

colleague Jon Cohen and I wrote an 8-page news feature about the

entire XMRV saga, which Science is also publishing today. It may be a

useful way to get up to speed on this confusing story. You can find it

here: http://www.sciencemag.org/content/333/6050/1694.summary

Now, first off, , can you explain very briefly and in simple

terms why the Blood Working Group study was set up and what it has

shown?

3:04 Dr. Busch: See my response above

3:05 Enserink: Okay thanks - does that mean the link between

CFS and XMRV is now offcially dead?

3:06 Dr. Busch: Although our findings failed to corroborate

the previous publications and strongly suggest that the previous

results may have been false positive results, there is another larger

study funded by NIH in progress that is examining the relationship

between XMRV and CFS. Those results are expected in early 2012.

3:07 Enserink: Right. Let's start with our readers' questions;

we have tons of them.

3:08 Enserink: asked: How can a disease such as CFS or

really ME occur in outbreaks and within families so often? I would

think some infectious agent must be involved HGRV or Not. My whole

family has ME and we got it suddenly after an infection all at once. I

am adopeted and my parents obviously are not genetically related. So

how can science explain these apperrent infectious outbreaks of ME? 26

years latter my Mom , Sister, Brother and I are still very ill with

what feels like an infection. What are scientists doing to help figure

this apperrant contagiousness of CFS and ME out?

3:09 Jay Levy:

It is very possible that and that you and the family got exposed to an

infectious agent like the cold virus and had an immune response

against that virus. In most people such exposure to an infectious

agent leads to an activation or stimulation of the immune system. This

leads to all of the symptoms one gets with CFS and related to

conditions since the symptoms come from the outpouring of products

from the immune system. In most people the immune system is later

quieted down by other cells of the immune system and the symptoms will

go away. It is our impression that in people with CFS the stimulation

of the immune system is not dampened or suppressed by the response of

other immune cells to bring immune system back into balance. Thus CFS

reflects a chronic immune activation condition.

3:11 [Comment From mary : ]

question.. Does this debate ever end? One science group publishes

contamination...another opens clinics for testing and treatment for

xmrv + people..do the groups ever reconcile?

3:13 Dr. Busch: This is why it was important for our current

study that we included the scientists at WPI, NCI and FDA who

previously reported positive findings, along with 6 other very

experienced labs. The findings strongly suggest that the tests that

were previously reported as positive are false positives. Our hope is

that this study plus the pending study led by Likpn will resolve the

issue for good.

3:14 [Comment From Bob : ]

Why has no one, including Dr. Levy, attempted to do an exact

replication of Lombardi et al?

3:14 Jay Levy: Bob,

In our studies we did repeat the experiments described by Lombardi et

al. The approaches to detect nucleic acids in CFS blood samples

followed both the techniques of Lombardi as well as those of Alter.

The virus isolation was conducted under very similar conditions and

actually by a very sensitive method my laboratory developed when we

discovered these mouse viruses 40 years ago. The serology was done by

the Abbot lab which has a very sensitive procedure for looking at

antibodies. You will note in the paper in Science today that that

technique by Lombardi using flow cytometry is the only one that has

given a positive result which can be explained by the lack of

specificity of this approach to detect antiviral antibodies.

3:15 [Comment From : ]

If it's not XMRV which is behind CFS, will you look for other

retroviruses? And more importantly, will you try to take blood from

CFS patients, inject it into animals (such as monkeys) and see if they

get CFS? That would give strong indications as to wheather it (CFS) is

blood bourne or not.

3:18 Jay Levy: ,

You're absolutely correct that more work must be done in looking for

the cause of CFS. Those studies would involve animal experiments if

needed and certainly cell culture and antibody studies. The fact that

XMRV is not the cause should certainly stimulate scientists to look

further into a condition that I believe results from exposure to many

different viruses but in which the person with CFS does not have the

correct countering response of the immune system to quiet down after

the initial state of stimulation against the agent has occurred.

3:18 [Comment From Phil : ]

Can't they just send blinded and mixed bloodsamples (of CFS patients

and healthy people) to the WPI and see if they are able to make the

distinction? Seems the easiest way to know wether XMRV is related to

CFS or not.

3:18 Dr. Busch: Our study published today did involve sending

blinded panels of different blood sample types (plasma, PBMC, whole

blood) derived from CFS patients previously reported as XMTV/P-MLV

infected to the WPI laboratory. The results inidcated their assays

were inconsistent and, based on ther overall study, were false

positive results.

3:19 Enserink: In other words, Phil, the Blood Working Group

did what you suggested.

3:20 [Comment From Milo Paradiso : ]

Could it be possible that XMRV tested in known positive was not

present at moment of second testing?

3:21 Dr. Busch: As we noted in the paper it is possible that

the specimens from previously positive patients we studied, which were

collected 1-3 years after the previous tests had been performed, could

have been negative for the virus if the infection waned or was

cleared. However the absence of antibodies and virus in all of these

patients, who have been previously positive on multiple time points by

all assays, is inconsistent with fluctuating viremia. Antibodies do

not disappear in this time frame.

3:22 [Comment From Joe : ]

Is it possible that XMRV is more likely to be found in organ tissue

than in the circulating blood, or that the current tests are just not

accurate enough to find it?

3:22 Jay Levy: Joe,

The techniques for detecting an XMRV infection would certainly pick up

the virus in organs since this virus is reported to infect B cells

which circulate through the body. Importantly as our group showed in a

previous Science paper in June, human blood has a natural mechanism

for destroying XMRV so it would not have the capability of even

infecting a human.

3:23 [Comment From : ]

So you, Jay Levy, say there is no virus in CFS/ME patients anymore,

only a viral response? How can you be sure there is no virus anymore

in any tissue?

3:24 Jay Levy: ,

It is very good that you understood my response. Yes I think the agent

causing the symptoms of ME and CFS has gone but the immune system

remains stimulated against it. What needs to be done is to find a way

of quieting down the immune system as is done by most people who are

infected by such an agent and do not have a chronic immune activated

condition.

3:25 [Comment From Inger : ]

I am positive for HGRV with a serology test, but you are telling me I

can now safely donate blood again? And are you also saying that I dont

have to worry about sexually transmitting ME?

3:26 Dr. Busch: Hello Inger,

If you have CFS/ME you should not donate blood, both for your own

health and since it is still possible that there is an infectious

cause of yoru disease. There is a lot of current research, stimulated

over the past 2 years, searching for additional viruses in samples

from CFS/ME patients. These studies invoved very sensitive " deep

seqiencing " and " metagenomics " techniques. Until the results of these

studies are available I expect there will be continued deferral of

patients from blood donations. The risk of sexual transmission is

unknow.

3:27 [Comment From : ]

Hi - I have been diagnosed with Fibromyalgia, but was originally

diagnosed with CFS. I am a biomedical researcher, myself. I am

wondering, aside from possible sample contamination on the part of the

lab(s) that found XMRV, what could other conclusions be from these

discrepancies? Is it possible that there are subsets of patients that

are positive for XMRV that manifest CFS symptoms, while others may

develop CFS from other viral triggers? Also, is it known what XMRV

does in humans and how it would cause a CFS-like syndrome? Thank you!

3:27 Jay Levy: ,

It is possible that people with CFS are infected by different viruses

but their immune system, activated against that virus, does not quiet

down. However there is no evidence nor any possibility that XMRV could

infect humans. As is shown in our Science paper in June, human blood

inactivates XMRV very effectively so an infection by that virus would

not be possible.

3:28 [Comment From Lizzy : ]

If CFS is indeed a chronic immune activation condition, as Jay Levy

says, what kinds of treatments might be worth trying?

3:30 Jay Levy: Lizzy,

You are correct that it would be very good if we could find a

treatment against a chronic immune activated state. However it would

have to be very selective because we would not want to completely

suppress the immune system. My hope is that the needed further

research in CFS/ME will lead to the development of a therapy that can

respond to this chronic immune activation and cure this condition.

3:30 [Comment From Tamara : ]

If the positive results initially found by WPI were the result of

contamination, how does one explain the negative results for samples

provided by healthy controls?

3:32 Dr. Busch: The WPI lab reported similar rates of

positive results on the coded samples from previously " positive " CFS

patients and previously " negative " healthy controls. Also the results

of indetical replicate samples snet to that lab were inconsistent.

These results indicate that their assays cannot reliable identify

samples from CFS patients as positive, including those from patients

theyt previously tested as positive. The false postie results could be

due to either assay non-specificity or contamination. This is eratic

so detected in a similar oportion of samples from both cases and

controls.

3:33 [Comment From rivka : ]

Why are some people doing better on anti-retrovirals?

3:33 Jay Levy: Rivka,

There is some evidence that antiretroviral drugs quiet the immune

system. So some relief could be expected since many people with CFS

show evidence of a chronically stimulated immune system. However these

antiretroviral drugs are not free of toxic effects and so one would

not recommend them for CFS. We need to find other drugs that can quiet

the immune system in a selective and beneficial way

3:33 [Comment From Diane : ]

Regarding the blood working group study - why only 15 patients? With

such a small group, and given the fact that XMRV is very hard to

detect in blood, wouldn't there be the possibility of a large margin

of error? Especially if XMRV levels vary in patients from week to week

depending on their state of health - we all know that exercise, for

example, can exacerbate symptoms and affect the immune system. In the

Rhesus macacque studies, for example, XMRV left the bloodstream

quickly and settled into organs. Any thoughts on perhaps studying

tissues in the future?

3:36 Dr. Busch: The clinical collabrorators were asked to

recruit as many previously positive patients as possible, but were

only succesfull at recalling the 15 patients. But these patients were

highly selected based on the revious results by the WPI and Lo/Alter

groups, so " enriched " for probable positive subjects. Yet none of

these had positive results based on the current study. In terms of the

virus going latent into organs, we cannot rule that out, but it would

be very surprising that antibody tests are negative. Plus the original

positive findings were based on blood sample results.

3:36 [Comment From Raj : ]

For how long has CFS been described in the medical literature? Is it

something that physicians have seen for centuries or has it cropped up

in more recent times?

3:36 Jay Levy: Raj,

This disease syndrome has been around for at least 100 years. It was

called neurasthenia at the turn of the last century and has returned a

different periods of time over the years.

3:37 [Comment From Robin : ]

So, it seems that XMRV as a theory is dead. What about the results of

the Alter/Lo FDA-NIH study that found related virus in both fresh and

stored patient blood. Was that a contamination too?

3:39 Dr. Busch: We did include 5 patients who had been

positive in the Lo/Alter study in our current study, and Lo's lab

found them to all be negative, as did most of the other labs. Hence

the results of the Lo/Alter study could nbot be confirmed. It is

unclear if the original results were due to contmanation by mouse DNA

but that is certainly a resonable explanation.

3:39 [Comment From Tamara : ]

I am concerned that with this latest study's results, the general

public opinion of CFS/ME will regress to " all in your head. " In your

opinion, is there any danger of this happening in the scientific

community, as well?

3:41 Jay Levy: Tamara,

That should not happen since in many cases one can find evidence of a

chronic immune activated state. That means that CFS patients have been

exposed to some agent but their immune system has not quieted down.

Attention should be given to identifying the defect in the immune

system that's not bringing it back to balance after the infectious

agent has been eliminated.

3:42 Enserink: Mike: Judy Mikovits, who first reported the

link between CFS and these viruses is a co-author on the Blood Working

Group paper. Yet in the story that Jon and I wrote, she says she still

stands behind her original findings, and wants to continue her work on

MLV's . What's your reaction?

3:45 Enserink: (Actually, I should have said: she wants to

continue working on gamma retroviruses.)

3:45 Dr. Busch: I respect Judy, who I have met numerous

times, for participating in the design and conduct of the SRWG studies

including the blinded panel study just reported. She agreed with the

findings and conclusions, but has argued that there are other

interpretations, such as clearance of the virus or latency in tissues.

This does not explain the results from her lab showing similar or

higher rates of positive results in pedigreed controls vs previously

positive patients replicate samples. Judy shoudl certainly continue

her work on CFS/ME as well as gamma retroviruses.

3:45 [Comment From Jim : ]

Is it possible that CFS arises from a viral infection that generalizes

to the host tissue (ie cross reactivity) and then becomes a low level

autoimmune condition. If so could it be detected by any tests showing

an overactive immune system, or an unusual reaction such as a pure

delayed hypersensitivity?

3:45 Jay Levy: Jim

You are correct that CFS does resemble an autoimmune condition. In the

past our laboratory has shown evidence of an overactive immune system

by measuring markers on white cells in the blood that are associated

with a stimulated immune system. These type approaches could be

helpful in seeing if the blood will indicate evidence of chronic

immune activation.

3:47 [Comment From jemal : ]

Will there be a Phase 4 in the Blood Working Group study? Or is the

group going to be disbanded now?

3:48 Dr. Busch: The BWG decided not to pursue the previously

planned phase IV study for 2 reasons. First the results of the phase

III study incated a lack of reliable assays for detection of XMRV and

related viruses in clinical samples. Second the American Red Cross has

completed a much larger study than the planed phase IV study involved

>10,000 blood donors as well as linked donation and hghly transfused

recipient samples. That study, which was negative, has been submitted

for publication.

3:48 [Comment From Milo Paradiso : ]

Can you make a parallel between the early days of HIV and the early

days of XMRV (for those who were old enough to live through it)?

3:53 Dr. Busch: There have been two studies that injected

high concentrations of XMRV into rhesus monkeys, which led to

dissemiated infection and seroconversion. This finding establishes

that this new virus, created indvertently in a research lab by

recombination of endogenous mouse viruses to yield a virus that could

grow in human and monkey cells, may be able to infect humans. However

the extensive studies over the past few years have faile to confirm

widespread or in fact any human infecitons. We are lucky!

3:53 Jay Levy: Milo,

In the early days of AIDS, again much effort was made towards

identifying the causative agent. When it was found that information

was confirmed by many groups, Antibodies that detected the virus could

be readily found in standard assays. With XMRV, only one group

actually found evidence of this virus and that has not been confirmed

in many studies. It does now indicate that that original report

reflected contamination with XMRV in the laboratory. In the case of

the Alter paper, different mouse viruses were detected and that

finding has never been confirmed. In this case contamination with

mouse material in the reagents used to detect the mouse virus was the

cause of the false positives.

3:54 Enserink: Mike just answered a question we hadn't posted

yet. I will do so now:

3:54 [Comment From Guest : ]

You say that XMRV cannot infect humans. Yet it has been proven that it

can infect rhesus maquaces. How do you explain this?

3:55 Enserink: Guest was referring to this study:

http://www.ncbi.nlm.nih.gov/pubmed/21325416

3:56 [Comment From Ralph : ]

If CFS is " chronic immune activation " without a pathogen, then would

not taking e.g. glucocorticoids eliminate all symptoms?

3:56 Jay Levy: Ralph,

Unfortunately glucocorticoids would suppress the immune system and not

be specific. That could lead to infections and other conditions

occurring without the function of other parts of the immune system.

I will take this opportunity to say that with the chronic activated

immune state, contact with other allergens could exacerbate the

condition and that may be why CFS is maintained for many years

3:57 [Comment From Guest : ]

If you were sick for 20 years and tested postive for hhv-6a,

mycoplasma, EBV, CMV, aspergillis, Subclass IgG deficiency, low t3 and

are always ill- progressed to having severe neuro systems where you

could not even walk- and were saved by Immuogloblin- why would

Immunoglobin help if the immune system is over active since it boosts

the immune system. I am very upset how bad patients are treated. I

almost died many times already and if not for a few doctors and my

husband being a doctor from another country I would not be here. Yet-

doctors do not take this illness serious, I do not care what you call

it- Lyme, CFS, ME, Fibro- gulf war. Many scientists have linked to our

illness to vaccines and that these are stealth pathogens- when if the

US Gov going to stop the cover up? We are a tuskegee experiment-

nothing else makes sense. So far Dr., Judy Mikovits is the only doctor

willing to speak out about how ill patients are. When will other

doctors speak out and care about patients and not the AMA, FDA, pharm,

and insurance companies? Do you not care that people are dying? I lost

4 friends - I know I do not have long and without treatments I would

die. Sometimes I want to die - for the suffering is so intense. What

would you do if you lost your life and lived in bed and homebound-

after making 300k a year and having a successful career and had a

wonderful life... WE NEED TREATMENTS NOW- NOT IN 10 years- those ill

20+ years will not make it another 20. I am tired of the lies-

3:59 Jay Levy: That is why we need more funding for research on CFS

and education in our medical institutions on this disease so that it

is seriously considered.

4:00 Dr. Busch: I have worked closely with Judy for the past

2 years, and secured funding to support her lab in the previous and

future studies. But Judy needs to acknowledge that the current data

fail to confirm her previous findings. I am eager and willing to

continue to work with her, but only if we can objectively design

experiments and interprest results with scientific rigor and without

emotion or influence from her institute sponsors or patient groups.

4:00 [Comment From Will : ]

Question for Jay Levy: are you saying that you believe that there is

no existing agent?

4:01 Jay Levy: Will,

My point is that in most cases the causative agent has already gone

but the immune system continues to be activated against it. During

that immune activation there may be other viruses that are stimulated

to replicate like EBV. Importantly, we need more research looking at

how the immune system can be quieted down to resolve symptoms of

CFS/ME.

4:02 Enserink: Okay, we have time for one more question.

4:02 [Comment From mohamad : ]

What about future studies?

4:03 Dr. Busch: The silver lining of the past 2 years is that

there are now a number of sample sets and research labs studying CFS.

Large scale studies are in progress to attempt to identify infectious

agents that may precipitate or persist in this disease, as well as

studies to elucidate other immune or genetic factors that cause this

disease. Hopefully this expanded work will lead to effective therapies

and even a cure.

4:04 Jay Levy: Mohammed,

As I've mentioned in other notes, future research should be aimed at

looking at ways of quieting down a chronic activated immune system.

There is a natural balance after infection in which some white cells

are activated to attack the infecting agent. Later other immune cells

are present to quiet down the immune system. Studies of this interplay

and balance need to be encouraged.

4:05 Enserink: Alright, on that note, we have to end it. We

still have lots of questions pouring in, but time is up. Obviously

this is a story that will continue to be debated for a long time.

Many thanks to Jay Levy and Busch for their insights -- and to

our readers for their smart questions. There will be a new live chat

next week.