XMRV and chronic fatigue syndrome: Questions I have

There has been nothing published connecting XMRV to autism. Nothing. There has been nothing published connecting XMRV to chronic Lyme disease. There has been nothing published connecting XMRV to breast cancer.

Smith, on this issue you have been nothing short of brilliant. Clearly, this is a case of a "virus in search of a disease." These jerks are sub-par scientists trying to give false hope to CFS patients and make some big bucks by patenting a "test" for XMRV antibodies. Next thing, they'll try to convince the American Red Cross to use this "screening" test on the blood supply -- a lotta money to be made with this scam.

You have smoked out these quacks with facts, logic and good science. Well done.

I do not know who you are, I am not a scientist myself, and I get lost in most of your arguments. But for some reason it seems to me you have something personal against WPI and Judy M. which I do not understand why... maybe because you need visits into your blog that will generate traffic, which also will generate add revenues into your pocket? Could be... What I know is that WPI has no economical interest, is a foundation, the mother of a CFS patient is in charge. The benefits of the XMRV test are used for research, and you are wrong assuming that XMRV has not been linked to Autism, Fibromialgia or Rare Multiple Sclerosis. You are wrong because it was detected in 40%, 60% and 100% of the small samples they analyzed but was not published in Science, because in order to publish you need a big study as they did with CFS. But is worth to have a look given the small studies. In my view anybody can understand that...

pochoams, if you read and understood erv's arguments about the handling of the science, you would understand why she's unimpressed.

100% of a small sample of people with autism had two legs. Let's start the amputations right away, shall we?

pochoams - there's one thing I don't understand about your argument (OK, that's a lie) - why do you accuse this blog of having a conflict of interest, and in the same paragraph say that because the Reno group is led by a mother with CFS that is a good thing?

Surely they are both 'conflicts of interest'.

On a side note - as a (somewhat) medically trained person, your blog does a very good job of explaining virology. Keep up the good work.

This was a fantastic post, Abbie. Very clear and emphatic. Too bad at least one person still doesn't get the point...

Which branch of the shadowy international cabal is paying you to weave your web of lies?

Do they have any openings in legal?

Have robe, will travel.

One aspect of this issue confuses me. I've heard that CFS is kind of an umbrella diagnosis, and that people whose symptoms have no confirmed cause often get a CFS diagnosis.

Is it a disease, many diseases, a group of symptoms? I'm not a researcher, so I don't know whether one assumption is more practical than another. Is it best to assume all CFS diagnoses have the same cause until proven otherwise? Are researchers trying to find one identifiable marker (such as XMRV) and eject all non-XMRV-infected, chronically fatigued people from the CFS diagnosis? Was my impression about the umbrella diagnosis all wrong?

Excellent question, Stella. I have heard CFS refered to as a garbage can diagnosis, a receptacle for patients who insist on an answer but the science is not available to supply one. Certainly, once the science does come up with something (perhaps XMRV) to define the disease, patients given an incorrect diagnosis will be shuffled off into the next garbage can diagnosis.

And, erv, as for the connection to other diseases as mentioned in the original post, people with a diagnosis of CFS have scientifically and anecdotaly shown higher incidences of breast cancer, leukemia and other diseases. Families show evidence of being communally infected, and children in those families do have a higher occurance of Autism. Provided the connection between XMRV and CFS holds up, it is a legitimate theory, but, as of know, it is just a theory.

As for a test that looks for XMRV antibodies, that brings up an interesting dilemma. Many of the usual tests for other diseases are not effective on people with damaged immune systems, simply because they do not have the ability to produce antibodies. Now, as of today, I do not have a way to scientificly prove that I have CFS. But tests have proven beyond any doubt that my immune system is lacking several components. Here's another THEORY for you. Patients who become ill with CFS do so because they are unable to produce the antibodies needed to to stop XMRV in its tracks.

Heidi, antibody deficiency is not common in CFS (nor is it common in HIV). That notion would directly contradict the claim of opportunistic infections (EBV, HHV-6, CMV, etc) in CFS patients. Most of those opportunistic infections are detected, after all, via abnormal antibody tests. If your body is not producing antibodies to common pathogens, it would be extremely unlikely that you'd end up with a CFS diagnosis.

Despite the media gaffes, the WPI has made a huge contribution to the sufferers of CFS, their families, and to those yet to become sick with this truly pernicious and misunderstood illness. It's a net positive, no matter how you break it down. More funding, more news, more hope, more research. Obsessively condemning a few speculations that J.M. made during a web seminar strikes me as really, really silly. Yeah, JM is not so savvy in front of the cameras. Are you?

Also, during her lecture, JM went out of her way to advise CFS patients to wait for a better diagnostic test. I.e. an antibody test. She did not once explicitly recommend the VIP XMRV culture test for CFS patients.

I enclose the last XMRV presentation given by WPI in case anybody is interested.
http://www.wpinstitute.org/news/docs/WPI_JAM_012210.pdf

"Yeah, JM is not so savvy in front of the cameras. Are you?"

Yes, she is. ;)

Prometheus, even us lurkers know you're in love with her.

"But, quote Mikovits, 'XMRV doesnt act as a quasispecies.'"

What? Just, what?

Thomas-- You are not a lurker. Lurkers dont comment, or do so rarely. Youve only commented on a few XMRV posts, a very new topic on this blog, so technically, youre a newb.

Also, your 'newb dead giveaway' is lurkers know that Ive done/do lots of presentations to the general public, which are available here on ERV, and some of them I didnt even know I was being recorderd. So Prom was poking fun at your newbness.

hehe. Newb.

Vene--

One of the really interesting things about these studies is we only isolate one thing out of these people. When we do the sequencing, itâs clean. We donât isolate quasi-species. We donât have the virus have these changes here in one week or one year⦠we have patient samples across dozens of years. We isolated XMRV from a 1984 plasma sample from a patient. So we got it in 2008 and we got it in 1984, which again suggests that the virus has been around at least 25 years and it might have a role in disease. But itâs not plausible, so yes indeed, it could play a role in other things⦠Did I answer the rest of that question?

Do a google search for "XMRV". See what comes up. You're #1.

re quasispecies

I've still not seen the presentation and don't know enough about retroviruses to really comment anyway, but the tone of the Mikovits quote certainly emphasises that she sees this as unusual and something that needs to be investigated. Have we heard from any other researchers working specifically on XMRV that it does behave as a quasispecies?

It does seem that the WPI think XMRV is behaving unusally, and that certainly makes me nervous about their results. Data that implies a big change in our understanding is usually just wrong, but I'm nowhere near well informed enough to draw my own conclusions on this (I'm not sure that anyone currently is). However, unusually for CFS research, I'm confident we will be able to know one way or the other in the near future.

@ ERV: have you e-mailed the WPI with your questions? I'd be interested to hear what they had to say to someone who think's that they're cranks (although I'm sure you'd phrase it rather more delicately in any correspondance).

interesting....

Virology. 2010 Jan 26.
Host range and cellular tropism of the human exogenous gammaretrovirus XMRV.

Stieler K, Schulz C, Lavanya M, Aepfelbacher M, Stocking C, Fischer N.

full text is online:
http://www.ncbi.nlm.nih.gov/pubmed/20110097?itool=EntrezSystem2.PEntrez…

I just stumbled upon this quote from John Coffin - would this relate to the quasispecies stuff?

-This is part of what he said in his testimony to the CFS Advisory Commity in October, 2009:

"Itâs not that this virus has a lower mutation rate than HIV. These viruses probably have all about the same mutation rate. But its suggestive in fact that there are very few cycles of replication that separate the viruses thatâs in one person from the virus thatâs in another."

" And in some ways the implications of that are both good and bad news. The bad news is that it suggests the virus is not actively undergoing ongoing replication during the course of infection of a single individual and that would not be good news if one were trying to use antiviral therapy. "

Thomas, you're right. My diagnosis is actually fibro, with CVID and other immune defects. But we still have not figured out what is destroying my immune system, thus my interest in XMRV. I have been refering to my condition as the "mirror image of AIDS" for years.

Over the years, we have discovered that many of my opportunistic infections go undetected using common antibody tests. We have to find alternative tests that use the sections of my immune system that are still intact or alternative methods.

I have often suspected that many people diagnosed with CFS actually have immunodeficiencies similar to mine, thus the difficulty in diagnostics. After all, many of these patients have limited medical coverage and the testing gets expensive. If they can be put off by a trash can diagnosis without the testing, there is a temptation to avoid going any further to more specifically diagnose something that still cannot be cured, but only managed.

Heidi, do you produce antibodies to Tetanus? And I'm curious: have you had a PCR for EBV, and if so, was there a detectable viral load?

Actually, part of the CFS dilemma is how much money they inevitably cost to treat. I'm not sure it's true that many of them "have limited medical coverage". The typical CFS patient has had many, many tests done. But perhaps not enough of them are being sent to immunologists for extensive work-ups.

And why do your docs think the CVID is secondary? Again, I'm just curious.

Sorry you're so sick.

Apologies for the confusion. I have seen a many professionals and have gotten as many diagnoses as I have had doctors. After a number of years, my immunologist, GP and I just kind of settled in with what we had, as even if we went further, we were not likely to find anything that was going to change treatment. I don't think the Fibro is actually prioritized, but I do tend to mention it first, as most nonprofessionals have a better understanding of Fibro than CVID.

We have done nothing but maintenance testing for the last two years. I was tested for EBV twice, although I am not certain which test was used. I suspect the second may have been PCR, as it was conducted after we discovered the immunodeficiency. Will have to check with MD on whether I produce tetnus antibodies.

I consider myself very fortunate to have gotten to an immunologist very early in my treatment. My grandfather was a test patient for Dr. Chediak, and when I informed my GP of this, he sent me to the immunologist immediately. I strongly suspect I may never have gotten there under other circumstances, and agree that many of those with Fibro and CFS should make this an early stop on their journey.

Anything is particular I should run past my MDs?

"I have no doubt CFS is a real disease"

Disorder perhaps, like the Autistic Spectrum Disorders. Not any particular thing (which a disease is), but a number of things not understood yet which have common symptoms. Unfortunately people who have such problems don't seem to have anywhere to go when they're diagnosed with "non-specific illness" and there's a growing business in preying on such people.

Thomas Bernhard love your quote "De natuur duldt geen ongeneeslijke gezondheid."

As CFS has been used as a dumping group for many diseases, including ME, it is not suppressing that it doesn't make sense to you. If XMRV is the cause, it will most likely be for a subset of patients.

John Coffin said that the 'Science' paper was as good a first paper as you will ever get, but that it was a first paper. After the UK study, he said that both papers may be right. After all the tests were different. He called the PLoS ONE paper too "preliminary" to settle the debate and said XMRV could show more genetic variety, and thus be harder to detect, than anyone assumed.

I'm going to see what happens over the next 6 months to a year, leave the scientists investigating the link to discover the truth. Hopefully by then the answer will be know. Just one last point, I think the PLoS team overstepped the mark suggesting that,

"we take no pleasure in finding colleagues wrong or dashing the hopes of patients, but it's imperative the truth gets out."

and

"Based on our molecular data, we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K.

What truth? The investigation is on going. They should have left their paper to speak for itself.

I call BS on "XMRV could show more genetic variety, and thus be harder to detect, than anyone assumed." McClure used XMRV AND MuLV primers so WTF. Every CFS XMRV sequence from WPI is like almost 100% identical to Silvermans sequences but now you say people in London have a XMRV which is not recognizable as a MuLV? Do you know how stupid that sounds?

Poor dude probaly got misquoted.

ERV - Here's a question for you.

If the Imperial College in London did not find one single positive CFS patient for XMRV in their PLoSOne study, would it be cynical and money grubbing of them to offer their own XMRV test?

http://wwwfom.sk.med.ic.ac.uk/medicine/divisions/olddivisions/medicine/…

I'm not saying thing about JM and I'm not going to claim that the way that everything she has said in public was done in the best manner but this to me takes the cake. Care to give your thoughts on the IC?

Follow the bouncing ball, SC:

How do they stand to benefit from offering such a service if they are the ones publishing a study saying that CFS and prostate cancer do not show a positive correlation with a positive XMRV test? What's more, they are super up-front about it.

They have a pipeline they have developed for the test - they are making it available for a fee. They are making it available for medical practitioners - perhaps those wanting to test their own patients. It's not clear to me why - and to that extent, I think we agree. But they're very up-front about everything, even their own work, as well as work that has been with conflicting results. What you are calling money grubbing, others might call, "transparency."

Money is a benefit. £200 a test.

Science 15 January 2010:
Vol. 327. no. 5963, pp. 254 - 255
An Indefatigable Debate Over Chronic Fatigue Syndrome
Sam Kean

But some scientists, including Coffin and McClure, fear that the Viral
Immune Pathology Diagnostics clinic (VIP Dx) took advantage of that
hunger by offering the $650 diagnostic test for XMRV, 300 of which
have been administered so far and which already has a 4 to 6 week
backlog. "Leaving aside the issue of who's right and who's wrong,"
says Coffin, "the original paper did not establish the virus [caused
CFS] and didn't establish it as a viable marker."

LM -- you've completely missed my points.

The major point is this: if they are up-front about the lack of association, then it's not snake oil. They're up-front about the lack of association, and their methods (please see previous posts) are clearer and are considered to be less error-prone / more conventional. They're making this test available for a fee - reagents, time of those people responsible for sample processing, equipment upkeep are not free - but they're not selling it as a panacea.

It would be more profitable for them to make such a test available if they found their results to be aligned with those of JM and her collaborators.

I'm not sure if you and I are miscommunicating, but my response was to SC, who posted the competing lab with the study showing no association, also had a vested interest in the diagnostic test. My reply spoke to the idea that the argument was without merit.

SC (#29) -

As one who has been quite critical of WPI & VIPDx for offering XMRV testing on patient samples, I'm equally disappointed to see Imperial College doing the same thing.

I see absolutely no current reason for XMRV testing of any patient samples except as part of a scientific study. (If someone can offer a good reason, please do!) There's no conclusive evidence that XMRV plays a clinically relevant role in any disease. Even if there was, knowing that a given patient was positive for XMRV would have no value in treating that patient. Not given our current knowledge, that is.

So I suspect you're right - IC is simply trying to cash in on the recent XMRV notoriety.

Rather disgusting, IMO.

Jason,

It's not that they say there is no positive correlation. As far as I know, they've never said (nor is there any evidence) that they've ever done a single XMRV PCR that was positive. That's cynical and money grubbing.

The IC study authors even suggested that one explanation is that there is no XMRV is the UK.

LM, As for Coffin's comments about the VIP Dx (not the WPI), that wasn't the question. And that horse has been beaten to death. Sorry, off topic.

It comes as a real surprise, after McClure told Science that VIP Dx took advantage of patients, for them to do the same.

Jason I agree, I was only highlighting what McClure had said.

Jason, I forgot to add the accusations of contamination and sloppy methodology leveled at the WPI by the IC to explain the IC finding NOTHING and the WPI's 67%.

Doesn't anyone else here think that this is just hilarious?

I agree completely with qetzal:

I see absolutely no current reason for XMRV testing of any patient samples except as part of a scientific study.

Judy Mikovits said the same thing at the recent Pro Health presentation. She there's no need to be tested, get involved in a study, and be tested for free.

"The bad news is that it suggests the virus is not actively undergoing ongoing replication during the course of infection of a single individual and that would not be good news if one were trying to use antiviral therapy."

If one were trying to use antiviral therapy, one would be trying to block viral replication. So if the viruses are already not-replicating, why is this bad news?

Caller-- It depends on what your primers are looking for. There are really conserved regions (these are inaccessible to your immune system, or when they become accessible, escape from your immune system comes at a fitness cost), like regions of gag.

Then there are regions of env that are extraordinarily diverse. One patients sequence might look nothing like anothers, so theoretically, it could be possible.

However Ive BLASTed every primer from both papers, and the top hits from the British cohort are sequences uploaded by the Reno group.

The primers are a silly excuse for why the British group couldnt find the virus.

windy-- Just add that to the list of things that dont make sense about XMRV :-/

others-- Its weird they are offering the test, but at least their page is pretty up-front about the expected results.

@ windy: My understanding is that current treatments for HIV target the virus when it's replicating. If XMRV replicates far less frequently then it's likely that current AIDS drugs will less helpful for XMRV. (I can't remember where I read this though).

Maybe it's a homeopathic virus?

gf1- "My understanding is that current treatments for HIV target the virus when it's replicating."

Yep, that was the point: they do it by stopping it from replicating. So what were they hoping to do to XMRV other than that?

Suppose I told you that I've identified a new type of cancer. But 'the cells of this cancer are not actively undergoing division' in my patients. So the bad news is that chemotherapy is likely to be useless against this cancer. Oooh, scary - but wait, does this even make sense?

ERV- Not saying that you shouldn't be commenting on other researchers' professional conduct, but do you think you could make it more clear where you argue that their conduct is unprofessional (e.g. question 4) and where your argument is a pretty straightforward criticism of their research technique (e.g. question 1)?

I understand that unprofessional conduct makes scientists more wary of other researcher's work, but when I'm trying to understand the issues at play in the research, it becomes very difficult when the personal conduct of the researchers and the correctness of their theses become so highly conflated. I had to read your questions and answers several times before I could know whether questions like question 1 were there to challenge a research technique or just as another point in the overall argument that WPI is unprofessional.

ERV, can you BLAST this compared to the other XMRV's?

Raisch KP, Pizzato M, Sun HY, Takeuchi Y, Cashdollar LW, Grossberg SE. Molecular cloning, complete sequence, and biological characterization of a xenotropic murine leukemia virus constitutively released from the human B-lymphoblastoid cell line DG-75. Virology. 2003 Mar 30;308(1):83-91.

Raisch KP, Kushnaryov VM, Grossberg SE, Cashdollar LW.
Constitutive production of a murine retrovirus in the human B-lymphoblastoid cell line, DG-75. Virology. 1998 Oct 10;250(1):135-9.

Hi John!

I BLASTed it (Accession #AF221065), and some of the top hits are XMRV sequences WPI uploaded.

I dont think this is 'new', as Silverman mentions it in the initial XMRV prostate cancer paper:

The genome is most similar to the genomes of exogenous MuLVs, DG-75 cloned from a human B-lymphoblastoid cell line, and MTCR...

But I dunno what this means, sorry. Lemme ask around!

Hi all,

Just a layperson here who has had CFS or whatever the hell it is for 25 years. I agree with you that XMRV is being overplayed by the WPI as the cause of CFS/ME. It could be yet another opportunistic infection in people with an illness that causes lowered immunity or it could be that the WPI's research was simply badly done. Frankly, I really don't care.

I had an MRI done ages ago (a few years after I got sick) that showed lesions in my brain and small, puncture-like dots. Years later I was told by another doctor looking at my MRI that it looked identical to a person with AIDS dementia. But I don't have dementia, just neurological problems. I started getting reddish purple lesions on my skin over the past year and went to a dermatologist/pathologist. He had blood drawn for an HIV test even though I was tested 3 years ago and found negative. (Haven't had any activity or procedures that would lead to HIV infection in over 9 years.) The reason he wanted the HIV test is because my lesions look like Kapaosi's Sarcoma but he's never seen KS in anybody except people with AIDS. I'm awaiting the results of the skin biopsy.

I only mention this because you guys are involved in virology. Viruses mutate, so is it possible that whatever damage has been done to my brain and body is a type of post-viral encephalitis? And if so, does it really matter what the virus was that caused it?

For example, take the worldwide outbreak of Encephalitis Lethargica that occurred from 1915 to 1928. A significant number of people who contracted whatever virus it was that caused the worldwide epidemic and survived became ill with identical symptoms with varying degrees of severity. And since 1928, no outbreaks of Encephalitis Lethargica have ever been reported. It just disappeared.

In the 1950s a British researcher and physician (can't remember his name) was dealing with a group of patients who had brain damage (found post mortem), neurological problems and pain. He named the post-viral illness Myalgic Encephalomyelitis. Again, it would seem that a certain group of people were infected with a virus and developed a post-infection illness that caused different symptoms than Encephalitis Lethargica.

So is it possible that some old virus that mutated could have caused what is being called CFS and CFS is nothing more than a particular group of symptoms caused by brain damage? If viruses mutate all the time, are they capable of doing different types of damage to the human host depending on their mutation?

I was just wondering if any of this made sense to any of you as scientists.

Thanks, Trish

Did you see the paper in Retrovirology. Another UK cohort has shown no sign of XMRV in any CFS patients. In fact, they found it in some of the controls. Tee hee.

I am late to this blog post... I am trying to understand question #1. Are you saying that the way the white blood cells were treated would likely reactivate endogenous retrovirus? Is this just for their "diagnostic test" or does this also apply to the Science paper?

Is that suggesting that what they are finding could be ERV particles and not XMRV? If that is what they are finding, wouldn't that be an interesting result too if 67% of patient samples showed this vs. 4% of controls?