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XMRV and Culturing, HERV's and more

Discussion in 'XMRV Research and Replication Studies' started by kurt, Mar 23, 2010.

  1. Jody

    Jody Senior Member

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    It's not a barrel of laughs for any of us with this disease, Knackered. You know that.

    And, you gotta stop these kinds of "jokes". They just get you in hot water. And they give me a pain in the neck.

    Now. Who is berating you? Tell me what your deal is.
  2. Knackered

    Knackered Guest

    XMRV's being berated by imagination and conjecture.
  3. kurt

    kurt Senior Member

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    Thanks Knackered, yes I know that was a joke, and I did give the opportunity... argh. But shall we say, just poor sportsmanship?

    Regarding your other comment, challenging a scientific finding like XMRV is not challenging the reality of your illness. XMRV is just the latest in a very long string of proposed explanations for CFS. For the record I am a die-hard believer in an organic cause for CFS. But I also have been around long enough to know that things are not always what they appear to be, and lots of flags went off in my head when I started evaluating XMRV. I was quickly out of my league so enlisted the help of others in understanding things. Gerwyn thinks I had the wrong experts, and I don't know, he was a lab technician of some type in microbiology and knows those processes, has apparently run those types of tests. Is he the real expert here? Again, I don't know, but what I do know is that this is science and there are some requirements for the scientific method, and the scientific consensus process, and unless we go through that process we are just gambling by believing that a given explanation like XMRV is the only valid cause of our illness.

    So I am not trying to be vitriolic (but maybe come across as oppositional sometimes? my wife might agree with that). Sorry if you feel that way. Here for the record is a short list of my concerns. I would love to see HONEST assessment by those here of these issues, not just dismissing them with a few inspiring words as usually happens. LOOK into this and if these are not to worry about then fine, I won't bring them up again. Promise.

    OK, I'll post my concerns separately. Have at it!
  4. julius

    julius Watchoo lookin' at?

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    It was imagination and conjecture that brought Dr. M to look at XMRV in the first place. In fact, every great discovery that wasn't pure serendipity began as imagination and conjecture.
  5. Jody

    Jody Senior Member

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    There you go, you've got Kurt and Julius talking with you on this score. If you've got a bone to pick with anybody, ... tell them what you want to say, instead of ... what you WERE doing.:rolleyes:

    You wanna tell me why a discussion about XMRV has you worried?
  6. kurt

    kurt Senior Member

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    XMRV Concerns List Item 1 - Overpromotion of XMRV by WPI

    1. WPI came roaring out of the gate after their Science article. While the Science article was fairly timid in its assessment of XMRV, saying things like 'might be just a passenger virus' and 'correlation only' meaning no proof yet of cause, no causal model, they started a type of campaign to promote their new center, raise funds, sell PCR and Antibody tests for XMRV, etc. They pretty much violated the 'preliminary study message' by their behavior. Maybe the CFS patient community and the early presence of a competitor forced them into that position. But still, they were encouraging hope, which obviously has gotten to you, before a scientific consensus process had even started. The consensus process is critical due to the way things work in single studies. And what is strange is that WPI has so many OTHER very good studies going, why are they only really promoting XMRV to the patient community? This says to patients 'we know the cause of CFS and it is XMRV and just support us'. Well, they may believe that and I would believe it myself if it was a consensus view, but this is just premature promotion, which just makes me suspicious. Some here interpret that to mean that they must really, really know what they are doing. But I know business in the US and to me it says 'strike while the iron's hot' and that worries me. Not because I don't believe XMRV could cause CFS, but because I hate to see CFS patients hurt and a well-promoted false finding could really hurt things for us.
  7. kurt

    kurt Senior Member

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    XMRV Concerns List Item 2 - history of HERVs giving false results in retrovirus hunts

    2. The XMRV study in science was compelling. Outside researchers thought this would be easy to test, as WPI showed so many ways they could find XMRV. Their careful reading of the article convinced them to invest their resources. And I am not just talking about the UK and Dutch studies, but also many others, including in the US. When rumors went around that labs were having trouble finding XMRV I started to study alternative explanations and learned the history of retroviral searches for diseases like MS, Breast Cancer, Lupus, and others. Generally the confounding problem in those studies have been endogenous viral interference (HERVs). And in many diseases HERVs are known to be expressed. Interestingly many of the failed studies failed because they had used MuLV antibody tests, and MuLV has been proven to react to some HERV species. Was this somehow happening with WPI? I don't know but thought it was worth exploring. Here is the most interesting reference, listing over 500 publications from studies, mostly failed attempts to link retroviral infection with diseases and many using MuLV:

    http://mmbr.asm.org/cgi/reprint/72/1/157.pdf

    Obviously this raised some questions. Mostly, could the MuLV antibody studies used by WPI, and being called XMRV antibodies (when they were not), be actually finding activated HERVs? That would be a cross-reactive false finding, it does not identify the role of HERVs in CFS, they could be harmless. However, if present and if cross-reactive with MuLV they could be creating false positives on antibody studies, and many of tests run by WPI relied on those MuLV antibodies.
  8. kurt

    kurt Senior Member

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    XMRV Concerns List Item 3 - HERVs are active in CFS

    3. Looking further at HERV expression I learned that they were already being studied for CFS. Note that this is separate from the possibility that HERVs might be interfering with the antibody studies. There was actually a causal model for HERVs in CFS, including studies at Tufts by Dr Bridgette Huber into HERV K18, which is believed to be triggered by HHV infection.

    So that is interesting, particularly if WPI found HERVs and not XMRV by the MuLV antibody study. That could be big news given the high rates of positives.

    Also I learned that glutathione depletion might play a role in all this, as glutathione levels apparently interact with HHV infection status. At normal glutathione levels herpes can not replicate, but once herpes is active it actually depletes glutathione. So I reasoned that if something was initially depleting glutathione in CFS, such as high oxidative stress from a chronic enterovirus, and if the person has weak methylation genetics as Rich has proven we have, then might that start a vicious cycle that helps activate HHV? The combination of poor methylation, low glutathione and HHV might be activating the HERV. Adequate methylation in the cells is essential for keeping HERVs from expressing.

    I guess this point is not so much a concern as an alternate hypothesis for why there would be HERV expression in CFS, if that was what the MuLV antibodies were finding. Also this suggests there might be a causal model for HERVs in CFS in which case the WPI study might have inadvertently revealed some new and important information about CFS pathogenesis and the high rate of HERV activation in CFS.

    I can give more references if anyone like, but they are not hard to find. The most groundbreaking work right now for HERVs in disease is probably in MS research. One recent study found high levels of HERV W in the brains of MS patients (tissue studies, not blood), and no expression at all in controls.

    So while some HERVs are probably harmless, some maybe even helpful parts of a DNA 'immune response' as Gerwyn has pointed out, some may also be pathogenic. Therefore their presence in CFS is noteworthy. The fact they can be sometimes found with MuLV and the fact they are active in CFS is also noteworthy in light of the WPI study.
  9. hope

    hope

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    I thought the WPIs work was replicated by the NCI and Cleveland Clinic.
  10. gracenote

    gracenote All shall be well . . .

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    A lot of us are looking for a study not connected to the original Science study to replicate WPI's findings.

    hope, welcome aboard.
  11. kurt

    kurt Senior Member

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    XMRV Concerns List Item 4 - Epidemiology

    4. The epidemiology of CFS is strange. We have both outbreaks and individual cases. And both sudden and gradual onset. Some familes have several cases, some have only one. Most partners of CFS patients are not sick with CFS, although a few are and some have other illnesses. Here is the concern, if CFS was a blood-borne disease, like an exogenous retrovirus, that would have been obvious in the epidemiology right from the start, it would be clear CFS was either an STD or had vertical familial transmission. And MuLV type retroviruses are identified in the literature as requiring blood transfer. So for XMRV to be causal for CFS, all CFS patients would need to have a transmission vector that was harmonious with the type of virus involved. Some have suggested that XMRV might be a breakthrough retrovirus that has other transmission vectors. That would make sense if XMRV were the cause of CFS/ME, but it would be a novel finding for that type of retrovirus.

    One other point on epidemiology is that prostate cancer patients generally do not develop CFS.

    I have raised the epidemiology point before but the general response has to be dismissive without providing any contrary facts or evidence.
  12. natasa778

    natasa778 Senior Member

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    That is simply untrue Kurt, Judy was very clear about what those antibodies were and what they were not. She talks about them at some length in the ProHealth presentation, explaining this very thing in great detail.
  13. kurt

    kurt Senior Member

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    That's all

    OK, those are the major problems I have with XMRV, the biggest reasons I have tried to keep alive some opposing viewpoints here. Over-promotion (which raises suspicions), possible HERV cross-reactions, evidence of HERV activation in CFS, and epidemiology. There are many other reasons as well, the risk of contamination for example, particularly in labs that had studied XMRV (at least one of the three had previously), and risks of false positives OR false negatives due to testing or reagent problems. And maybe other risks as well.

    I am not a biologist and probably someone else could have stated this better. There are many more details I have raised over the past months. But it is probably a bad idea for patients to argue about science (this much anyway) and maybe I should just leave people here to build up hopes they want to have.

    Could XMRV be part of CFS? I don't really know and the researchers are just starting to sort this out. Early tests have not supported the original finding, but that does not mean nobody will. There are many ways testing can go wrong, both for the original finding and for the follow-up studies. Only time will tell, and many more studies. I can not predict the final outcome and I don't believe anyone else here on the forum can either.

    Do people here want to hear more on this line of thinking, challenging the original XMRV finding? If not, I will stop posting on the subject.
  14. natasa778

    natasa778 Senior Member

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    Wow! I must say I'm stunned by that comment. Could it be what this is all about?
  15. starryeyes

    starryeyes Senior Member

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    :D That is hilarious coming from you Kurt!
  16. kurt

    kurt Senior Member

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    The VIP antibody test was listed as an XMRV test for months. Additionally, WPI has repeatedly called the antibody test an XMRV antibody test. But it is an MuLV antibody test. The fact Judy may have explained that out more in some places does not change that original fact. Consider that many CFS patients have received a positive antibody test and been told or led to believe they had XMRV, when in reality they have a positive MuLV test, which is not specific for XMRV, only supportive.

    Sorry, I do not follow why or how you are stunned by the idea that maybe patients should not argue about science. But I did edit my comment to clarify what I meant, which is that maybe we should not be arguing so much, so heavily, about this, given the preliminary nature and such.

    Anyway, this is the type of dismissive comment I was referring to, not a serious analysis or reading of what I have posted.
  17. Cort

    Cort Phoenix Rising Founder

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    I very much appreciate Kurt laying out in detail his ideas about XMRV and HERV's - I learned quite a bit.

    The transmission question has never fully been addressed and it is an important one. Its funny how some aspects of this just go by the wayside. Anyway if XMRV is a blood borne retrovirus then I think Kurt is saying we should see regular passage from the mother to her children and between sexual partners. While we see both (Mother/children and sexual partners with CFS) both are pretty rare. This would seem to argue against an obvious viral cause of CFS.

    Instead Kurt, if I got it right, lays out a theory of another breakdown in the body - first high rates of oxidative stress wiping out glutathione (Pall + VanKonynenburg?) which then results in herpesvirus activation.

    The fact that the epidemiology of CFS does not - except for those outbreaks - appear to look viral - suggests that other elements must come into play. The viral trigger is certainly there, we know that - but CFS appears to be triggered by a variety of viruses (with EBV at the top of the list) as well as other stressors as well as sometimes nothing - so there's no really clear single factor. The Dubbo studies showed us that; four pathogens, if I remember correctly -which all caused CFS. This suggests that the problem has to be deeper - in something that happens in relation to the infection.

    I wonder if you can fold the Dubbo projects finding of high pro-inflammatory cytokine levels in people who went on to get CFS (versus low cytokine levels in people who did not) in this scenario. In that scenario you have an infection (a stressor), high cytokine levels - then what? high rates of oxidative stress... That fits in well with Kurts scenario.

    The WPI is studying family members of CFS patients. If XMRV holds up we should know if they are possibly carriers who are not ill or if they don't have XMRV at all. Certainly not all retroviruses are as infectious as HIV. Its possible - and apparently likely, if the Science study is right - that alot more people have XMRV than come down with CFS. In that scenario XMRV is infectious just not debilitating that often. That said other than the Science and Japanese study no one has found much XMRV infection in healthy controls. We had Abbott Laboratories - apparently a big diagnostic lab - unable to find any evidence of XMRV infection in several 1,000 samples of blood from healthy controls.

    Another point is that even if XMRV doesn't work there is still some really exciting research going on and some pieces may be fitting together. What we need is MORE research of all kinds.
  18. Martlet

    Martlet Senior Member

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    Kurt - Like everyone else, I was very hopeful that XMRV would prove to be the cause and that a test and cure would quickly follow. That euphoria and optimism lasted a couple of days, then it was back down to earth, and I am glad that you have helped keep my feet on the ground. You have not - in my opinion - been trying to pour cold water on people's hopes, but simply to issue a warning that if our hopes rise too high, they risk crashing hard, taking countless patients with them. IOW, you have been a wonderful counter-balance and I hope you keep posting your views and that others can see them for what they are - another view, as yet neither proven nor disproven, but just as necessary as the unbridled optimism many of us felt just a few short months again.
  19. kurt

    kurt Senior Member

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    Yes, that would be the progression. Oxidative stress (maybe enteroviral) in susceptible individual leads to herpes activation which then further lowers methylation/glutathion, which leads to HERV activation and total overload. And MuLV may be one way to show the final step, the HERV activation. Anyway that would be the theory.

    Also, the HERV K18 hypothesis may explain the high cytokines, that is one response to the production of a superantigen protein by that particular HERV. However, other HERVs might be involved, the WPI virachip study showed several others were active.

    I agree, this does not rule out XMRV. In fact someone here suggested maybe XMRV and HERV theories are not mutually exclusive, and that might make a lot of sense in cases where blood-born transmission vectors are consistent with ME/CFS cases. Maybe even sometimes both are involved, perhaps in the more serious cases.
  20. Cort

    Cort Phoenix Rising Founder

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    I really, really want to point out that there really is alot of interesting research going on right now. If XMRV does not turn out that would be a huge letdown as it seems to simplify things so much - and gives researchers and us such a nice clear pathway- which researchers love. If it does turn out - even if its not 'it' - even if it was just shown to be one of several contributing factors - I think it would have an enormous impact on us all, simply by the amount of attention and funding it would bring to this disorder. I think it would propel us into a new era; there would be CFS pre and post XMRV. I hope to God it works out.

    If it doesn't tho, there is quite alot of potential 'breakthrough' type stuff out there; Dr. Lights study, the Dubbo projects, several of the CAA's studies, the WPI's other work, Dr. Baraniuk's fascinating brain proteome work, the Pacific Fatigue Labs exercise studies. I still think that once the word gets out that the PFL's repeat exercise stuff could blow the lid off of this thing.....its kind of surprising, actually, given how poor our funding is - how much really interesting work is going on out there.

    We'll see - I have been told several papers are in press;, Andrea has hinted at an April surprise. I just got word from someone of a pretty high bore research group that is just getting started on a CFS XMRV study. April will be interesting and I imagine May and June and July as well.

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