XMRV = ERV

Hey, you all know earlier this year, this summer, shit kinda hit the fan here at SciBlogs?

I didnt care about the idiots leaving. I was more annoyed at the lack of communication from The Overlords.

They will be watching my blog while Im gone.

This is my revenge for that.

XMRV and the MLV-Related Viruses? The sequences that have been submitted to GenBank indicate that these ‘Magic Eye Viruses’ are almost certainly ERVs.

Not a real human pathogen.

Contamination.

Disease-associated XMRV sequences are consistent with laboratory contamination

Pop-Sci article from Welcome Trust.

This paper intensely scrutinized the published sequences, and conclusion is pretty incontrovertible. Open access, you all can read it.

And just to make one thing perfectly clear to all of the patients, all around the would who have gotten their hopes up and now dashed: This was all avoidable. Sequencing insertion sites, seeing a sequence go humanhumanhumanhumanVIRUSVIRUSVIRUSVIRUShumanhumanhumanhuman or mousemousemousemousemouseVIRUSVIRUSVIRUSVIRUSmousemousemousemouse would have clarified all this.

If I recall correctly, that is precisely what an independent reviewer asked Harvey Alter to do in his PNAS paper, and he refused. Because he could. That was an unwise decision. But he wasnt the only one who didnt do it.

All of this was avoidable.

To everyone else just watching– Evolution told us this wasnt real. Kinda like how we can use evolution to tell us who infected whom and when with HIV-1. I think thats cool. :)

Comments

  1. #1 gf1
    December 20, 2010

    So does this apply to all previous findings of XMRV?

    I don’t understand how they can be so confident. They’ve found the sequences which were previously thought to be XMRV actually could be mouse ERVs? They’ve found possible ways inwhich contamination could be introduced, and the lack of diversity found means they can’t be a replicating virus?

    Didn’t Alter find that the sequences had altered in patient samples taken years apart? Or are we meant to expect diversity of sequences in one patient at one time?

    I think I’m lacking some basic virology here, but I don’t really understand how they can be so certain.

  2. #2 Mu
    December 20, 2010

    Calling Dr. Wakefield, we need your experience in explaining science away.
    PS How do you get that kind of news in Antarctica?

  3. #3 Charl
    December 20, 2010

    Didn’t Alter find that the sequences had altered in patient samples taken years apart? Or are we meant to expect diversity of sequences in one patient at one time?

    Some of the variation was a change of one base, or an N (based not called!) – not what would qualify as mutation and variation in HIV/flu/any virus that infects humans. And if one batch of samples were amplified with batch A of contaminated Taq, and another batch of samples were amplified with batch B of contaminated Taq… you could see different sequences in samples separated in time.

    There’s no good reason for all the samples from ONE cell line to be more diverse from geographically separate cases. Swine flu, HIV, pretty much any other virus you can think of evolves like crazy under the selection pressures of infecting a human (transiently or chronically). So yes, this applies to previous discoveries, right back to all the Urisman/Silverman prostate stuff.

    I like watching scientific **** hit the fan…

  4. #4 Levi
    December 20, 2010

    ERV So,

    If XMRV=ERV, then there should not be any immune response to it in humans. Right?

  5. #5 Charl
    December 20, 2010

    Levi – it’s a mouse ERV, not a human one. Except in the Rv21 cell line/whatever it’s called, where the tumour seems to have endogenised it when the cell line was grown in mice with no immune systems. As happened when they used to grow tumours in the brains of kittens (ewwwww) and the tumours picked up feline ERVs and leukaemia viruses.

    (Very poor simplification there, but I can’t think of a more elegant way to phrase it…)

  6. #6 RRM
    December 20, 2010

    @Levi:

    I have seen lots of people on forums cling to the idea that the antibody reports rule out contamination. While it certainly remains food for thought, I think one of the first negative studies already showed that this idea is not very strong.

    Groom et al found 14% of the controls positive for antibodies and none of the CFS samples. Thus, either your statement is not correct, or Groom et al provided solid evidence that XMRV is correlated with good health. Right?

  7. #7 Eric J.
    December 20, 2010

    Certainly, there’s big odds that you’re right, ERV.

    But, while I know you’re not personally a fan of Mikovits, there’s the question of her serological results. Also there was at least one report regarding prostate cancer biopsies of seeing the virus by FISH, and at least one by immuno-histology. So, what gives? Is all that stuff wrong? I dunno.

    I haven’t fully metabolized all the papers, but I may end up remaining a ways more agnostic than ERV. I know, I know, it’s easy enough to just remain agnostic til the End of Days, but…

  8. #8 Richard Jefferys
    December 20, 2010

    To my knowledge, there’s not been a single report of CD4 or CD8 T cell responses to XMRV in humans. And people have been looking.

  9. #9 Richard Jefferys
    December 20, 2010

    I had thought it was just one paper but apparently there’s a slew of them:
    http://www.retrovirology.com/

    http://www.guardian.co.uk/society/2010/dec/20/chronic-fatigue-me-research

  10. #10 levi
    December 20, 2010

    Charl and RRM, thanks for your posts. I only skimmed the article in retrovirology, but from my lay person take on it, it was making an eloquent and detailed argument that XMRV et al are mouse contaminants because of phylogenetic analysis and retroviral clade studies that point to the lack of mutations that you would normally expect if you looking at a bonifide human retroviral infection. Correct me if I am missing something please.

    So, my first question is; if you assume that these are truly contaminants, i.e., mouse ERVs that can not infect humans, then where did they come from, and why are they being found in prostate cancer and CFS patients by SOME researchers? Would they be of any use as potential disease`biomarkers, setting aside any issues of causation? A number of the positive research studies are finding an antibody response to XMRV et al. Is it possible to develop a human antibody response to a mouse ERV, or is that work bogus?

  11. #11 Charl
    December 20, 2010

    if you assume that these are truly contaminants, i.e., mouse ERVs that can not infect humans, then where did they come from, and why are they being found in prostate cancer and CFS patients by SOME researchers?

    If you read all the papers, there are various sources:

    A very, very popular Taq polymerase that contains some mouse genomic DNA (hence why Coffin’s stupid mouse mtDNA contamination test, as used by Lo and Alter, didn’t pick it up…) – and this could be one reason why so many UK studies were negative – a tendency to use a different brand of polymerase, or the same brand that was produced in a European factory that missed being contaminated by luck

    Other lab reagents that should be sterile but by chance aren’t (water that should be free of DNA/RNA, primers, background dies like ROX, negative control DNA – my supposedly “human” DNA, from QIAGEN, is also full of Epstein-Barr virus DNA [because the human it was isolated from had EBV...], making it a bad negative control when you want to detect EBV!)

    And finally cell lines. 1 in 50 cell lines commonly used in labs for all kinds of studies – like Daudi – are full of this virus, pumping it out all over surfaces and pipettes and researchers. All you have to do is dip a pipette tip in two different flasks, and you can move that contamination from one flask to another. Don’t quite scrub your bench with ethanol well enough? The virus could still be there on the work suface, and be accidentally picked up in your next experiment (or your colleagues’). Send a vial of contaminated cell lines to a collaborator and it moves from lab to lab.

    These could all have a lot to do with almost no one could find the virus in Europe.

  12. #12 levi
    December 20, 2010

    Charl,

    That is a pretty clear explanation for how contamination could show up in the US research facilities. Thanks for that. OK, if you take this contaminant, and infect Rhesus Macaques with it, why do they seroconvert?
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931451/

    Its a serious question. Could lab contaminants containing mouse ERVs cause human disease or at least act as a superantigen that would spark an immune reaction/cytokine-chemokine imbalance?

  13. #13 Charl
    December 20, 2010

    The virus is replication competent (partly because one of the clones is recombined with a well-known mouse virus, Moloney), so if you stick it in monkeys – yes, they’ll react (and they’ll react to a load of other things with the same unspecific antibodies too!). I’m not an immunologist, but as I understand it, the human body can mount an immune response to a lot of things (look at all the allergies people have), whether they’re an infectious agent or not.

    BUT the main thrust of the paper is that XMRV IS NOT OUT THERE. It’s not in the community, mking people ill. Those samples the labs are testing are coming in XMRV-free, and XMRV is getting in to them some way or another during all the steps needed to take blood to the point of PCR product. The paper Erv is talking about above says – if you think you have a new virus causing a disease, you have tobe as careful looking for that viral DNA as you would be for ancient DNA. You screen all your reagents. You work clean (if necessary, ‘space suit’ clean, with face masks etc). You make damn sure that that virus isn’t coming from your lab. It happens to very careful scientists (eg Robin Weiss) with the very best intentions.

    XMRV is not in the environment. It’s not naturally (however you think about it) infecting people/disturbing their immune systems/causing auto-immunity.

    If you want to read a paper about a GOOD body of evidence for a new pathogen, look up Mimi viruses (as blogged about here). That was a pathogen found in some clinical samples that went on to infect a lab technician. If XMRV is disease causative, in any way, you should see an over-representation of people who work with lab or wild mice showing up in the diseases associated with XMRV. But we’re not.

  14. #14 Charl
    December 20, 2010

    Mimivirus on Wikipedia, complete with links.
    http://en.wikipedia.org/wiki/Mimivirus

    More interesting than XMRV, in my opinion…

  15. #15 Levi
    December 20, 2010

    Charl,

    Right, it would just be too simple if folks were allergic to mouse ERVs, or having some kind of toxic reaction to a mouse contaminant in the environment. So, I am sensing some divergence in your opinion and ERVs. She seems to be saying that there IS no XMRV. Period. A vaporvirus. You seem to be saying that XMRV exists, and is replication competent, but is not actually found outside the lab. So you believe that Silverman actually sound XMRV? And that is is a theoretically feasible human retrovirus, but not actually found in humans.

  16. #16 Charl
    December 20, 2010

    You seem to be saying that XMRV exists, and is replication competent, but is not actually found outside the lab. So you believe that Silverman actually sound XMRV? And that is is a theoretically feasible human retrovirus, but not actually found in humans.

    I’m not sure my view is different to Erv’s just phrased differently…

    You can “make up” viruses (as Erv has blogged about with resurrecting dead viruses – get a harmless virus, replace it’s envelope with the envelope of a virus now fossilised in a genome, see how it got in and out of cells…). Likewise, when you order artificial D/RNA from a company (eg one that designs artifical plasmids with your sequence of interest in them, a handy way of getting a reliable positive control sequence) they are legally bound to check on that sequence to make sure you aren’t a terrorist trying to bioengineer some sort of horrible chimeric virus/bacterial strain of super pathogenicity. You can create viruses that would in no other way exist, viruses with various features – which are there in a little Eppendorf tube on your bench/freezer/liquid nitrogen store, but which aren’t in the environment.

    Obviously Erv DOES think XMRV exists, because you can sequence it. I’m sure Erv will post again with her opinions when she has time, but I think she was trying to convey when she said “Evolution told us this wasn’t real” is what she said above – “Not a real human pathogen… contamination”.

    Sorry if I’m putting words in your mouth, Erv!

  17. #17 Poodle Stomper
    December 20, 2010

    Not to butt in (although I am) but it is apparent that ERV does accept that XMRV exists, just not that it is going around causing CFS. She seems to be simply saying that the findings of XMRV in human samples are a contamination by XMRV (it exists) from a source other than the patients themselves. This is not the first time this happened. There were reports a while back of the discovery of a novel human retrovirus that turned out to be a rabbit retrovirus that had contaminated some samples (I believe it was through serum). In the end, it was found to be a contaminant (of a real virus, just not in humans) through the hard work of multiple labs.

  18. #18 Levi
    December 20, 2010

    Poodle Stomper,

    Fine by me if you butt in here, but I am not letting you anywhere near my poodles. ERV states that XMRV=ERV (i.e. mouse ERV). So, without trying to put words in anyones mouth, either mouse ERV is a human pathogen/toxin (no evidence for that), or XMRV/mouse ERV is NOT a human pathogen. So it could not cause prostrate cancer or CFS.

    There are lots of well stated reasons here for how XMRV/mouse ERV could show up in labs. This particular study talks about lab techs shedding exosomes that could confuse things (not really clear about exosomes yet):
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704771/

    My question is, assuming all positive studies to date are not indicative of XMRV infections and are merely lab artifacts, then, IF assuming for the sake of argument, you were a mad scientist type, could you (hypothetically) take XMRV/mouse ERV, inoculate human prisoners with it, and make them sero-convert? And if you did that, would they get a disease? If so, what disease might that be?

  19. #19 theshortearedowl
    December 20, 2010

    @ Levi

    Sero-conversion is when the body develops specific antibodies to specific antigens. Antigens can be lots of different types of small molecule; usually proteins or polysaccharides (type of carbohydrate), because that’s what bacteria and viruses have on their surfaces. Sero-conversion is not proof of active infection (ie. virus replication) – otherwise we would have to conclude pollen is infectious :)

  20. #20 Kathryn Stephens
    December 20, 2010

    Are paid-for articles in Retrovirology peer-reviewed?

    Does this mean that the Science and PNAS peer-reviewed
    papers are wrong?

    Is peer-reviewed, and science, dead in the water?

  21. #21 CG
    December 20, 2010

    No, science isn’t dead. This is a perfect example of how science is self-correcting. If you are wrong, someone will call you on it.

  22. #22 Divalent
    December 20, 2010

    @Kathryn Stephens
    “Are paid-for articles in Retrovirology peer-reviewed?”
    Not sure what you mean by term “paid-for” (most journals require the authors to pay page charges to get published), but in any event the paper ERV cites above was peer reviewed.

    Does this mean that the Science and PNAS peer-reviewed
    papers are wrong?

    Yes, that would appear to be the case.

    Is peer-reviewed, and science, dead in the water?
    (Haven’t a clue what you are getting at, so I’ll pass.)

  23. #23 Cwolfpack
    December 20, 2010

    Guess what? XMRV was found in more ways than this one. A body doesn’t create antibodies to contamination. You should do your homework before posting all of this as fact. Get a clue. Read the Wall Street Journal blog. She has it right. Have you ever heard of Ian Lipkin at Columbia University? The king virus hunter. Here’s what he says: “These papers emphasize the pitfalls of molecular assays and raise concerns. Nonetheless, it is premature to rule out XMRV or related viruses as factors in prostrate cancer or CFS. Links have also been made based on serology and the presence of viral proteins as well as of viral sequences. Thus, we still need appropriately powered, rigorous blinded studies of well characterized patients and controls. One such study is underway under the auspices of the National Institutes of Health”

  24. #24 Desert Froglet
    December 21, 2010

    @Cwolfpack

    Nonetheless, it is premature to rule out XMRV or related viruses as factors in prostrate cancer or CFS.

    Prostrate cancer? Did he really say that?

    Now, what do you think about this statement:

    “There isn’t anybody any better at this than Ian Lipkin,” said Dr. Fauci. “If he can’t find it, it probably doesn’t exist.”

    That’s from an article dated 22 November 2010. How will you react if Lipkin doesn’t find it?

  25. #25 cwolfpack
    December 21, 2010

    The real question is how will you react if he does? I’m not the one with the bias anti XMRV/CFS blog. Unlike you I am withholding an opnion until this all shakes out. There is also a huge,huge money issue involved here that has to be taken into consideration with every study. First thing to do is go look at the PDF and who funds this stuff. One of the other anti XMRV studies was funded by a ‘charity’ but when you trace back who funds the charity you find that. The charity is funded by a psychiatric hospital system in the u.k. Things are so bad in the u.k., that any study I see coming for there sets off alarm bells in my head. I wish it were all about the science but unfortunately that’s not the world we live in. So while this study makes good headlines and suckers some bloggers into prematurely announcing that evolution has spoken, it’s far from being the final word. As for my view on Lipkin, I think the federal government has decided that Lipkin will be the final word and so he likely will be.

  26. #26 cwolfpack
    December 21, 2010

    The real question is how will the blogger react if he does? I’m not the one with the bias anti XMRV/CFS blog. Unlike the blogger I am withholding an opnion until this all shakes out. There is also a huge,huge money issue involved here that has to be taken into consideration with every study. First thing to do is go look at the PDF and who funds this stuff. One of the other anti XMRV studies was funded by a ‘charity’ but when you trace back who funds the charity you find that. The charity is funded by a psychiatric hospital system in the u.k. Things are so bad in the u.k., that any study I see on XMRV or CFS coming for there sets off alarm bells in my head. I wish it were all about the science but unfortunately that’s not the world we live in. So while this study makes good headlines and suckers some bloggers into prematurely announcing that evolution has spoken, it’s far from being the final word. As for my view on Lipkin, I think the federal government has decided that Lipkin will be the final word and so he likely will be.

  27. #27 Helle
    December 21, 2010

    Statement from the Whittemore Peterson Institute regarding Retrovirology December 20,2010af Whittemore Peterson Institute den 21. december 2010 kl. 05:13

    The Lombardi et al. and Lo et al. studies were done using four different methods of detection. They were not simply PCR experiments, as were the studies by McClure et al. and others who have recently reported their difficulties with contamination. Experienced researchers such as Mikovits, Lombardi, Lo and their collaborators understand the limitations of PCR technology, especially the possibility of sample contamination. As a result, we and Lo et al. conducted rigorous studies to prevent and rule out any possibility that the results reported were from contamination. In addition to the use of PCR methodology, the Lombardi team used two other scientific techniques to determine whether, in fact, we had found new retroviruses in human blood samples. We identified a human antibody response to a gamma retroviral infection and we demonstrated that live gamma retrovirus isolated from human blood could infect human cells in culture. These scientific findings cannot be explained by contamination with mouse cells, mouse DNA or XMRV-related virus-contaminated human tumor cells. No mouse cell lines and none of the human cell lines reported today by Hue et al. to contain XMRV were ever cultured in the WPI lab where our PCR experiments were performed. Humans cannot make antibodies to viruses related to murine leukemia viruses unless they have been exposed to virus proteins. Therefore, recent publications regarding PCR contamination do not change the conclusions of the Lombardi et al. and Lo et al. studies that concluded that patients with ME/CFS are infected with human gammaretroviruses. We have never claimed that CFS was caused by XMRV, only that CFS patients possess antibodies to XMRV related proteins and harbor infectious XMRV, which integrates into human chromosomes and thus is a human infection of as yet unknown pathogenic potential.

    “The coauthors stand by the conclusions of Lombardi et al. Nothing that has been published to date refutes our data.” Judy A. Mikovits

  28. #28 gf1
    December 21, 2010

    From the responses I’ve been reading from other scientists, it does seem that the UK groups are making rather exaggerated claims. Coffin seems deeply sceptical of XMRV and CFS, but is distancing himself from their claims. Lipkin doesn’t sound impressed.

    I don’t have the knowledge to make a meaningful judgement of my own, but to me, it looks like this paper hasn’t done much to settle this controversy. Hopefully it will spur on better studies from those groups who are finding XMRV in CFS and PC patients.

  29. #29 titmouse
    December 21, 2010

    The real question is how will the blogger react if he does? I’m not the one with the bias anti XMRV/CFS blog. Unlike the blogger I am withholding an opnion until this all shakes out.

    A conclusion based upon available evidence isn’t the same thing as “bias.” New evidence will lead to revisions of previous conclusions. No big whoop.

    In science you don’t get gold stars for being “right all along” like in the movies. You only get points for weighing the *available* evidence appropriately.

    If you bet against the available evidence and it turns out you’re right, that’s just dumb luck. It’s not impressive.

  30. #30 daedalus2u
    December 21, 2010

    Titmouse, excellent comment.

  31. #31 Levi
    December 21, 2010

    “New evidence will lead to revisions of previous conclusions.” Precisely right titmouse.

    The new evidence in the study that ERV linked to which really interests me is the support for hypothesis that XMRV is not actually an exogenous virus transmitting among individuals. It proposes an alternative explanation that the full length clones of XMRV originated from the 22Rv1 cell line, and are actually lab artifacts which are incorporated into multiple lines.

    Presumably, those cell lines are used to produce biologicals. By companies doing business, and by governments. Dr. Racanciello of the Virology Blog has weighed in on these new contamination research studies, and states that an important missing piece of information here is the prevalence of (whatever this is) as it is found in the general population.

    Of course, it would take a clean lab, careful procedures, good assays etc. to get this information, but looks like folks are working on it. If indeed this contaminant is found in a significant portion of the general population, what kind of follow-up scientific research would you anticipate?

  32. #32 Cwolfpack
    December 21, 2010

    Are you all reading the same blog I am. XMRV was founf in more ways than just the sequencing and yet this blogger is acting like the decision is final. The blogger is not just responding to new evidnece. How do you explain all the people who get blood work done and have antibdies to the retroviruses? Are you aware that London College is the home of all things related to the ‘it’s all in their heads’. The people their have staked their entire careers on the CFS is mental philosophy. Please blogger wait until the science is finished before saying evolution has spoke and saying that because of one this study in a vaccum is bias. Discussing it is not bias

  33. #33 daedalus2u
    December 21, 2010

    cwolfpack, they have sequences. PCR is many orders of magnitude more sensitive and many orders of magnitude more specific than the immunogenic tests.

    Humans have only something like 10^15 possible different antibodies. In a DNA strand with 382 bases there are 4^382 possible combinations, or ~ 10^230. Antibodies don’t have the kind of specificity that DNA sequences do.

    The real killer paper is this one

    http://www.retrovirology.com/content/7/1/109

    Which is by the Tufts group.

    They found sequences that were identical in multiple samples, and so close that it is virtually certain that they are related. That the multiple samples were so identical is problematic for an infection in free living humans as a source. It is my understanding that the fidelity of viral replication during infection and transmission is expected to be less than the fidelity what this group observed. If my understanding is correct, that pretty much precludes these viruses being from infections. In that case they must be contamination from mouse DNA because eukaryote DNA replication has much higher fidelity than does viral DNA replication.

    In other words, mice have virtually identical ERVs even though those ERVs became endogenized many thousands of years ago. If those ERVs become “free” and start replicating they rapidly develop mutations (as in tens of replication cycles). Mutations are not observed, the ERVs did not become “free”. The observed sequences are contamination from mouse DNA, not “free” infective virus from multiple individually infected individuals.

    The source timing of some of the samples also seems to preclude an infection source. A virus can’t hang out in in blood, it has to be inside a cell and either actively replicating or reverse transposed into the cell genome (and than activated to become a virus again). How many cycles of cell infection, virus release, cell infection would have to occur for an XMRV infection to persist for years? If there are many cycles of viral replication, then there has to be mutation of the viral genome and accumulation of mutations.

  34. #34 Cwolfpack
    December 21, 2010

    http://www.prohealth.com/library/showarticle.cfm?libid=15810

    It ain’t done til the fat sequence sings. And there’s a whole lot of singing left to be done.

  35. #35 CFS Patient
    December 21, 2010

    I’m glad more evidence is accumulating towards a relative conclusion on the XMRV front.

    I know so little about this illness that my hypothesis changes monthly. It makes treatment choice impossible.

    My current hypothesis is repeated infectious insult damages the BBB, and allows T-lymphocytes to enter the reticular activating system. The t cells then release nitric oxide to destroy an intruder (imaginary or real, who knows) and the sensation of fatigue occurs. The increased levels of nitric oxide inhibits release of hypothalamic CRH. This cortisol lowering inhibits the ability of the subject to accommodate stress. Of course, I’ll look back six months from now and discount all that.

    Or I’m a malingerer. I’d lean towards the latter, Occam’s Razor.

    If people knew how young I was, and dealt with a plethora of doctors not giving a shit, I would surely get a deal with the Oprah. Or if someone knows a 21-year old girl who likes an average looking guy who needs to spend a lot of time in the fetal position.

    Well, this discovery may save me $500. Time will tell.

  36. #36 daedalus2u
    December 22, 2010

    CFS patient, it is not high NO that causes CFS, it is low NO. See this

    http://www.chronicfatiguetreatments.com/wordpress/treatments/chronic-fatigue-syndrome-nitric-oxide/

    Immune system stimulation starts with and causes what is called the “respiratory burst”. This generates superoxide to generate hydrogen peroxide and to also lower NO levels. It is the lower NO levels that trigger many of the downstream effects of immune system activation. One of those effects is expression of iNOS, which transiently (for a day or so) increases NO level. That increase is transient and only occurs during the acute phase of immune system stimulation. The iNOS is transient, and when it is gone, then NO levels fall back to baseline, or below (the high NO during the acute phase can reduce basal NO levels by skewing nNOS and eNOS regulation). It it the long term low NO that causes CFS.

    The problem with CFS is that the NO does not go back up after the immune system stimulation and physiology gets stuck in a chronic low NO state.

  37. #37 dt
    December 22, 2010

    @wolfpack
    The fat sequence lady hasn’t quite finished singing yet, but it does appear as though she has started. You may hope against hope that she’ll breakdown mid aria, but I think you had better prepare for disappointment.

    If you think the psychiatrists who deal with management of ME such as Wessely and co will take a career hit if XMRV is shown to be a cause of ME you will be wrong. The syndrome is multifactorial, and there will be life yet in the methods such as CBT and GET irrespective of the cause of someone’s symptoms, and the people working in the field will continue to do clinical and research work regardless. It might be less easy to get some grant funding that’s all.

    The real career-threatening/financial blow is to the WPI and its commercial testing arm. They have put all their eggs into this rickety basket, and sell PCR tests so people with CFS can make fortunes for Mikovits et al and fund her tests which can only tell patients whether their sample is contaminated or not as the case may be.

    Kerching! That will be $500 a pop, thank you. VISA/Express/Amex accepted.

  38. #38 CFS Patient
    December 22, 2010

    For sure, daedalus. This depends on the body having low NO outside the BBB to prevent extra inflammation in the brain, thus allowing a lower quantity of offending molecules to invade the CSF. We can measure the Th2 skew in the serum, but that does not reflect any sensory outputs. Shifting that feedback loop, though, is not something I currently can fathom.

    Most CFS patients look hilariously healthy by standard lab metrics because of the situation you described.

    I’m fine with that sounding like pseudoscience. It’s not the most absurd idea ever, and it is mildly related to virus-killing.

    Hope the CFS Viagra study helps people to be able to walk at least. I think it will definitely help muscle output, because it does that for healthy people. It should come out in six months maybe…

    Anyways, ERV keep up the awesome. I hope you believe CFS exists.

  39. #39 Richard Jefferys
    December 22, 2010

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015632

    PLoS ONE 5(12): e15632. doi:10.1371/journal.pone.0015632

    No Evidence for XMRV in German CFS and MS Patients with Fatigue Despite the Ability of the Virus to Infect Human Blood Cells In Vitro

    Oliver Hohn1,5, Kristin Strohschein2, Alexander U. Brandt3, Sandra Seeher1, Sandra Klein1, Reinhard Kurth4, Friedemann Paul3, Christian Meisel2, Carmen Scheibenbogen2#, Norbert Bannert1,5#*

    1 Centre for Biological Security 4, Robert Koch-Institute, Berlin, Germany, 2 Institute for Medical Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany, 3 NeuroCure Clinical Research Center (NCRC), Charité Universitätsmedizin Berlin, Berlin, Germany, 4 Robert Koch-Institute, Berlin, Germany, 5 Centre for Retrovirology, Robert Koch-Institute, Berlin, Germany

    Background
    Xenotropic murine leukemia virus-related virus (XMRV), a novel human retrovirus originally identified in prostate cancer tissues, has recently been associated with chronic fatigue syndrome (CFS), a disabling disease of unknown etiology affecting millions of people worldwide. However, several subsequent studies failed to detect the virus in patients suffering from these illnesses or in healthy subjects. Here we report the results of efforts to detect antibody responses and viral sequences in samples from a cohort of German CFS and relapsing remitting multiple sclerosis (MS) patients with fatigue symptoms.

    Methodology
    Blood samples were taken from a cohort of 39 patients fulfilling the Fukuda/CDC criteria (CFS), from 112 patients with an established MS diagnosis and from 40 healthy donors. Fatigue severity in MS patients was assessed using the Fatigue Severity Scale (FSS). Validated Gag- and Env-ELISA assays were used to screen sera for XMRV antibodies. PHA-activated PBMC were cultured for seven days in the presence of IL-2 and DNA isolated from these cultures as well as from co-cultures of PBMC and highly permissive LNCaP cells was analyzed by nested PCR for the presence of the XMRV gag gene. In addition, PBMC cultures were exposed to 22Rv1-derived XMRV to assess infectivity and virus production.

    Conclusion
    None of the screened sera from CFS and MS patients or healthy blood donors tested positive for XMRV specific antibodies and all PBMC (and PBMC plus LNCaP) cultures remained negative for XMRV sequences by nested PCR. These results argue against an association between XMRV infection and CFS and MS in Germany. However, we could confirm that PBMC cultures from healthy donors and from CFS patients can be experimentally infected by XMRV, resulting in the release of low levels of transmittable virus.

  40. #40 Poodle Stomper
    December 22, 2010

    Daedalus,

    I’m curious if you can supply the peer-reviewed journals you used to reach the conclusion that CFS is caused by low NO. I haven’t looked into this much myself but I was under the impression that the cause of CFS was, as of this post, undetermined. Anyone else is free to correct me if I’m wrong. Like I said, I don’t have much background in CFS literature.

    -PS

  41. #41 CFS Patient
    December 22, 2010

    It’s just a hypothesis that fits a lot of data from CFS patients. The main purveyor is Martin Pall. His stuff is here:

    http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Pall%2BMLauth

    You might need to copy and paste that.

  42. #42 cwolfpack
    December 22, 2010

    More to think about. http://www.virology.ws/

  43. #43 daedalus2u
    December 23, 2010

    CFS patient, my hypothesis is that Viagra will make CFS worse. Viagra does make obstructive sleep apnea worse. I suspect because Viagra inhibits the PDE5 enzyme that reduces cGMP there is feedback inhibition of NO production, which then reduces NO effects not mediated through cGMP (of which triggering of breathing is one (of many)).

    Some symptoms might get better (those mediate through sGC and cGMP), but others will get worse.

    My hypothesis is the opposite of Martin Pall’s. He thinks CFS is due to too much NO, I think it is due to not enough. He thinks that the presence of peroxynitrite indicates too much NO, that is not correct. Peroxynitrite indicates too little NO. The observation of peroxynitrite damaged proteins in CFS is due to lingering in the transition from low NO to high NO because the physiological sources of NO are insufficient to overcome the hysteresis of the low NO state. This is where external NO is necessary, but it has to be administered in a physiologically appropriate way (which is extremely difficult). Consumption of arginine will not work.

    poodlestomper, as far a I know, there is no peer reviewed article that lays out the hypothesis of low NO causing CFS in detail. There are only things that I have written. I have used the peer reviewed literature as my source material, but don’t have any clinical data on using increased NO to resolve CFS.

    I have a really good anecdote, a man in his 30’s who had ARDS, lost 30 pounds while in hospital, got out as a shadow of his former self, started using my bacteria to get his NO level up, and in 2 months had gained 9 pounds, had gone hiking, had resumed his PhD program at Yale and was by every physiological measure his doctors tested him for was better than average for someone his age. They called it a “miracle”, and had never seen such a recovery. They told him he could expect to maybe feel a little better in 6 months. They did not want to talk with me about what I thought the recovery was from.

    I appreciate it is an anecdote, but that is all I have, but it is consistent with all the data that I have been able to find in the literature. Until I get the resources to do more than anecdotes, that is all I will have. That is one reason why I get exercised about hype pushing out good science as in this XMRV stuff.

  44. #45 RRM
    December 26, 2010

    @Levi: I am not an expert in the virology field by any means. I can merely point out logical problems with Mikovits’ argument.

    One other note: I take it that you are aware of the phase IIb results of the BWG? Ruscetti “detected” XMRV antibodies in a sample from a healthy control that was pedigreed as negative for XMRV by PCR, serology and culture by Mikovits and Ruscetti. Mikovits’ argument that antibody detection is disproving the critics just does not seem to be very strong to me.

    There is one explanation I could propose with my limited knowledge but great logic ( ;-) ): when you culture cells (as Mikovits and Ruscetti do), it seems to me that antibodies can form. When you contaminate a sample and let it grow in vitro, simple evolutionary mechanics will form some sort of antibody response for you.

  45. #46 Poodle Stomper
    December 26, 2010

    Thanks Daed,

    Thanks. I’d be careful making such definitive statements if it’s only a hypothesis, though, especially with an n=1. Obviously isn’t enough to such definitive (although I’m sure you know that). You’d need to show that the NO level in the blood increased, that your bugs were the cause, ect…

  46. #47 daedalus2u
    December 27, 2010

    poodle, in science there are only hypotheses, and then, only until they are disproven then they are only wrong ideas.

  47. #48 Poodle Stomper
    December 27, 2010

    Don’t forget theories and laws =P

  48. #50 RRM
    December 28, 2010

    Yes! Another sickness will be cured by Judy Mikovits in the near future:

    “XMRV DETECTION IN SUBJECTS WITH CHRONIC LYME DISEASE

    This example demonstrates the presence of XMRV in subjects having chronic lyme disease. Methods are according to Examples 1-21 unless otherwise described. Samples from twenty subjects diagnosed with chronic lyme disease were tested for XMRV. Patients with a diagnosis of Chronic lyme disease generally fit all of the criteria of Chronic fatigue syndrome. Results showed that XMRV was detected in 20/20 cases tested.”

    http://www.wipo.int/pctdb/en/wo.jsp?IA=US2010039208

  49. #51 Levi
    December 28, 2010

    RRM,

    Interesting point about culture/comtamination possibilities. As far as the BWG is concerned, they just released a statement about the four new contamination studies to the effect that they plan to move ahead with new phase studies and be careful not to contaminate anything.

    I tend to not give much weight to the smaller studies due to the Pareto principle (rule of 80%). I wish the published works used more pedigreed ME/CFS patients. Contamination issues are important but not the whole story here.

    I am more interested in the issues of genomic comparisons of the sequenced retroviruses/fragments and their phylogenic relationships. My question for ERV is about the possibility of XMRV/MuLVs as possible adventitious agents rather than infectious pathogens. If these retroviruses are indeed eventually found by Ian Lipkin in a disproportionate percentage of ME/CFS patients, and contamination issues are eliminated, what would it mean?

  50. #52 RRM
    December 28, 2010

    @Levi

    I cannot see how this has anything to do with the Pareto principle. How does 80% of the population cause 20% of the effects and vice versa in this case?

    If anything, slidely related, the WPI had the chance to select the 20% of “best detectable” XMRV samples beforehand from the 68 positives they found in the Science study, which they did. The positive samples from the study were well pedigreed: 16 of 17 times they (collectively) tested positive for PCR(-only!), 10 out of 20 times antibodies were found, and 20 out of 23 cultures were positive for XMRV.

    Yet, in the blinded setting of the BWG, Mikovits and Ruscetti were unable to distinguish these clear and self-chosen XMRV cases from the well pedigreed negative control: Mikovits and Ruscetti found 8 positives out of 24 tests of pedigreed positive samples (33%), while the pedigreed negative sample was found to be positive for XMRV (or XMRV antibodies) 2 out of 6 times (also 33%).

    I am not saying it is defenitive, but it is not what one would expect if the results of the Science study were correct.

  51. #53 Poodle Stomper
    December 28, 2010

    My question for ERV is about the possibility of XMRV/MuLVs as possible adventitious agents rather than infectious pathogens. If these retroviruses are indeed eventually found by Ian Lipkin in a disproportionate percentage of ME/CFS patients, and contamination issues are eliminated, what would it mean?

    Well I’m not ERV but if I could venture a guess…since no trace of XMRV were found in patients with HIV/AIDS (see here), the odds are that this isn’t the case.

  52. #54 Andrew
    December 31, 2010

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