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ME/CFS and the Magic of the Canine Factor
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Comparing PreXMRV-2 gag sequence diversity in laboratory and wild mice

Discussion in 'XMRV Research and Replication Studies' started by Jemal, Jul 10, 2012.

  1. barbc56

    barbc56 Senior Member

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    The plural of anecdote is not data. I'll go with the science.;)

    Barb C.:>)
  2. JT1024

    JT1024 Senior Member

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    Barb, I posted information on this thread and on another thread (http://forums.phoenixrising.me/inde...tious-agents-are-being-taken-seriously.18604/ ) regarding the MIT Consortium of Adventitious Agent Contamination in Bio-manufacturing and other efforts currently underway to minimize adventitious agents from contaminating biologics - including vaccines.

    A slide from a powerpoint presentation prepared/presented by one of the lead investigators of that consortium states:

    * Many companies have not publically disclosed virus contamination events
    ● * No obligation to disclose unless the contamination results in a material change to the business
    ● * Motivated by concerns for negative publicity.
    ● * This is well known in the industry.
    ●* Some companies do not notify regulatory authorities
    ●* Companies that have disclosed rarely describe the event in sufficient detail to be of significant value

    Who do you think controls what gets published? The medical journals have been "outed" in recent years as being skewed by big pharma.

    I'm not convinced that this DD is caused by a vaccine but I have sufficient medical knowledge and education to see how it could happen very easily. I've worked in healthcare for 30+years and had a Hep B vaccine in 1991. The following year, I was diagnosed with Fibro. Did I think it was caused by a vaccine? Hell no! Not at that time and I'm not sure that it is causal at this point either. I suspect there are many factors. However, I'm not about to discount a very viable hypothesis.

    Just my two cents...
  3. Bob

    Bob

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    Well, actually, the plural of 'anecdote' is actually 'data'. Sure, it's not rigorous double-blinded research data, but it is still data none-the-less. It's what's done next with the data that is important. It might be rather hard to carry out research into vaccines and the association with ME, because everybody has vaccines, but only a small minority of people get ME. It seems to me that vaccines might be a trigger, in some cases of ME, rather than a cause, but we don't actually know the cause of ME, so it might be helpful to keep an open mind about these things.
    jace likes this.
  4. barbc56

    barbc56 Senior Member

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    Science based medicine is not showing that vaccinations cause disease. That being said, there are some people who get reactions but it's not the vaccine per se but the medical condition of the person. For our population there have been no studies that show a link. For the population at large vaccines save lives and do greater good than harm.

    An infant just died about 50 miles from me from whooping cough as she was exposed to someone who was not vaccinated. What a tragedy.

    I don't believe about 99% of conspiracy theories. Conspiracy theories are about the least believable in terms of logic fallacies.

    So it looks like our views cancel each other.:)

    Again the plural of antecdotal is not data.

    But I will not get in a debate about this as we need to get back on topic.

    Barb C.:>)
  5. barbc56

    barbc56 Senior Member

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    Well there's crappy data and solid data and that is decided by a priori. Read my above post as we posted at the same time. :)
  6. Bob

    Bob

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    Anecdotal data is not (necessarily) 'crappy'. Much science starts with an anecdote. But I agree it sometimes has limited scientific usefulness, and usually needs following up with more rigorous research. Take Rituximab, for example: the Norwegian scientists only found out that it helped some ME patients through accidental observation of individual patients benefiting from it, before they carried out any research into it. But I agree that unless there is rigorous research into the association between vaccines and ME/CFS, then the reports of an association has limited usefulness. But it shouldn't be dismissed, in my opinion, especially as the observations are coming from clinicians.
  7. Bob

    Bob

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    I've just come across a fascinating research paper from August 2011, that I think many of you, following this thread, might be interested in...

    It's not specifically an ME related paper (it doesn't mention ME), but it talks about 'autoimmune' diseases (e.g. MS), and it seems to tie together all of the following issues:

    Treatment of 'autoimmune' conditions (e.g. MS) with anti-retrovirals; B-cells; treatment with Rituximab; viral reservoirs in B-cells; HERVs; B-cells expressing HERVs; EBV; EBV viruses hiding in B-cells.

    If anyone is interested in any of those issues, in relation to ME/CFS, then I recommend having a look at this fascinating paper. I've just posted it in a new thread:
    http://forums.phoenixrising.me/inde...se-a-role-for-new-anti-viral-therapies.18620/
    currer likes this.
  8. Mula

    Mula Senior Member

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    MLV latency is easily established. Understandable primate research would not be of benefit for studying a human infection.


    http://www.ncbi.nlm.nih.gov/pubmed/3871491

    http://www.ncbi.nlm.nih.gov/pubmed/187773


    http://www.nature.com/nature/journal/v283/n5745/abs/283404a0.html


    http://www.ncbi.nlm.nih.gov/pubmed/3719096
  9. Mula

    Mula Senior Member

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    Yes.
  10. anciendaze

    anciendaze Senior Member

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    I'm afraid the discussion of the env gene sequence went off track, and my questions in a number of other places may have prompted misunderstanding. My concern from the beginning was with the fact that the immunosuppressive domain in the envelope appears to be functional in transgenic mice with approximately human immune systems. This is not an environment in which it could be expected to have evolved and adapted. This function is quite sensitive to the three-dimensional shape of various structures, and typically degrades in sequences which are not subject to active selective pressure.

    When people are sure the entire virus was created de novo by a complex recombination event, with six changes of template, in a single mouse in a very limited time frame, and could not possibly be present outside laboratory cell lines, the question of the origin of the particular subsequence representing this domain is of no interest. I have been less certain about such an origin, and the paper which prompted this topic appears to have placed an alternative origin in a much simpler recombination event involving an undetected exogenous precursor akin to preXMRV2, (but not limited to exact homology,) on the table.

    If preXMRV2 (or whatever we end up calling it) arrived as an exogenous virus, it did so with an envelope that allowed it to enter the mouse cell carrying preXMRV1. It could not have used an envelope derived from the recombination, which had not taken place. Starting with a replication-competent virus makes recombination much less of a stretch. My question about the immunosuppressive domain then becomes, was this, or a similar structure, present in the active precursor? If viruses carrying such domains are loose in the wild, a number of convenient assumptions must be revised.

    The reasoning here is tricky. There may be more than one envelope under discussion. I've tried to be clear, but it isn't easy. I'll sit back with my fingers crossed, and see if this post is any more illuminating than previous ones.
    ukxmrv likes this.
  11. Wally

    Wally Senior Member

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    Anciendaze,

    While my response is most probably not the one(s) you were waiting for, I have been reading your posts and in my mind the questions you are asking are very thought provoking and I am also awaiting further discussion on this subject.

    Since my earlier post rec'd no response, I am going to assume that no one has an immediate interest in trying to provide information that the illness identified as ME, CFS or MECFS does not warrant additional study to determine if a retrovirus (either named, unnamed or undiscovered) could be a causative factor for this illness?

    In talking directly with Dr. Mikovitz (yes I did have the opportunity to talk to her when she was still employed at the WPI) that using the identifying label of XMRV in the Lombardi paper was in hindsight not the best choice of words, since their research had found more than one MLV. I think I have this information correct, but it was from a one on one conversation and I realize that my memory could not be an accurate reflection of what Dr. Mikovitz was trying to explain to me. Nonetheless, unless I am reading the science behind follow-up studies and other interviews with Dr. Mikovitz incorrectly, even if XMRV proves to be a contaminant this in itself does not close the door on the question of a retrovirus playing a significant role in this illness. When I have seen this question posed to other prominent researchers the answer has come back as "yes" that is still a possibility.

    So, now I would like to ask another question to see if I am understanding the questions you have raised on this thread titled "Comparing PreXMRV-2 gag sequence diversity in laboratory and wild mice". Is your question raising the possibility that "PreXMRV" conclusions in post Lombardi/Mikovitz studies have not conclusively established that wild mice or laboratory mice recombination events (or a combination of the two) cannot be the underlying cause of this illness?

    Thanking you in advance for reviewing the question I have raised above.

    Wally
  12. currer

    currer Senior Member

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    Are you suggesting that there might be a pre xmrv2 based virus with an immunosupressive envelope that has been around historically as a human /mouse virus? If the virus is so well adapted to infect human cells it must be old.
    In which case the infection could have passed from human lab worker to lab mouse, not the other way round!

    PS I'm sorry for pushing the thread off-topic. I wanted to show Dr Miller that there are good reasons for the patient community to be suspicious of official "reassurance"

    PPS With regard to part of Bob's earlier post - I remember that Dr Snyderman posted that researchers were too afraid of entering this debate and he had been refused deep sequencing by the organisation he had approached.
    So we dont know why his research was never followed up.
  13. currer

    currer Senior Member

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    Wally -
    I rememberthat there is a member on these forums - ukxmrv - who has followed all the retroviral research for decades. Because there have been previous attempts to link ME with a retrovirus which were investigated using the available technology at the time. It might interest you to look up some of her posts.
  14. Wally

    Wally Senior Member

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    Thanks Currer. I will take a look at those older posts. I realize the discussion on this thread may be aimed at those with more of a historical and/or scientific background in the subject matter of ME/CFS and a possible retroviral link, but since this is a Public section of the Forum I thought I would dip my toe into the pond and ask a few questions to see if I was following the flow of the discussion. Once again, thanks for responding to my post. I can assure you that many who may not be comfortable joining directly in this discussion are watching and thinking about what is being said. It is also very helpful to be able to get some ideas where else to go to review additional discussions related to the underlying subject matter of this particular thread.

    Wally
  15. Ecoclimber

    Ecoclimber Senior Member

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    I want to thank the patient community for asking such great questions! :) I know many of you are trained in the medical field while others are scholars, researchers, and patients with a lot of experiences dealing with this illness. Dr. Miller is working on a project with a tight schedule and is working long hours so at times he may not respond as quickly as he want to, he also reviews the material presented such as an eg: Aciendaze and researches the articles mentioned in the comments so he can give his opinion on them. I didn't think we would end up with New Zealand Black Mice although at one time I was asked to go trapping for some other mice closer by. At any rate, please be patient and he will get to you when he has more available time. The tone on this thread is going good.:thumbsup:

    Eco
    Firestormm and ukxmrv like this.
  16. jace

    jace Off the fence

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    Hi Wally, the fact is that the possibility of retroviral involvement in ME/CFS is still open. An awful lot of rather sloppy papers have been hurriedly published to disprove 'XMRV' in 'CFS/ME' or ME/CFS or even just CFS, but since most avoided the use of an accurate diagnostic protocol, correct PCR techniques, and other flaws, the struggle to shut the door on speculation has not yet succeeded.

    Bring into the picture the extraordinary treatment of Dr. Mikovits, including her arrest and brief incaceration, and remembering the treatment of other, earlier researchers in the field, it is no surprise that this time round, some patients have got themselves educated in the finer points of retroviral research.

    The name game is still tripping us up. XMRV has come to mean VP62, despite there being other clones about, because that's what Silverman sequenced in his lab as his contribution to the 2009 Science paper. I know most of you know this, but we get sloppy with language, and the debate devolves into meaninglessness. Or meaning less mess :confused:

    The VP62 Silverman sequenced was actually, unbeknownst to anyone at the time, contamination. It was not the virus contained in the samples sent from the other labs. We know this, because reserved aliquots were subsequently tested and found to be free of VP62. VP 62 is the clone that was subject of the immaculate recombination of the Paprotka paper, the one that invented the terms Pre-XMRV1 and Pre-XMRV2.

    We know that Mikovits is under a legal gag because of the case brought against her by the Whittemores. Therefore she cannot speak up freely. The recent interview from the Daily Beast (so established! So trustworthy! :cautious: smells fishy, for more than one reason, as discussed on its own thread here.

    There's another paper in Retrovirology available today, on the infectivity of XMRV, used in the broader sense to mean the family of Xenotropic (infects species other than the original host) Murine Leukemia virus-related viruses, not just the clone VP62, here http://www.retrovirology.com/content/9/1/58/abstract

    Moloney murine leukemia virus glyco-gag facilitates xenotropic murine leukemia virus-related virus replication through human APOBEC3-independent mechanism

    Background
    One of the unique features of gammaretroviruses is that they contain an additional extended form of Gag, glyco-gag, which initiates in the leader sequence. MuLV glyco-gag, gPr80Gag, promotes retrovirus replication and disease progression. Although virtually all infectious MuLVs encode glyco-gag, XMRV (xenotropic murine leukemia virus-related virus) lacks the classical gPr80Gag sequence. We examined XMRV to determine if its leader sequence contains glyco-gag activity, whether the presence of conventional gPr80Gag affects replication of XMRV, and we describe the evolution of glyco-gag-deficient MuLVs in Mus.


    Full provisional paper available here http://www.retrovirology.com/content/pdf/1742-4690-9-58.pdf

    But the retrovirus putatively found in people with ME aka CFS has also been stated to be a MuLV of a polytropic nature (infects across species). As far as I'm concerned, the jury is still out.
  17. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Good pick up Jace. I think it is disingenuous for researchers to limit their discussion to the narrower definition of XMRV if they suspect that their reasoning does not extend to the wider family, particularly when they, more than anyone, understand the possibilities.
    Adamskitutu and currer like this.
  18. Bob

    Bob

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    Hi Wally,

    Great questions.

    The answer to your earlier question is that the association of retroviruses with ME/CFS has not been disproved.
    It's difficult to prove the absence of a virus, because if you can't find a virus, you can't be certain whether it's not there, or you just can't find it. So, instead, scientists tend to rely on proving the presence of pathogens, and if they can't prove the presence of them, using the best known technology and methodolgy, then scientific interest in the subject tends to drift.

    Currently there are not any published positive retroviral studies, for ME. This is a bit of a stumbling point, to say the least. There have been two positive studies published, but they've both been retracted. But it seems that research into MLVs is ongoing, and my personal opinion is that the research will continue to flourish and will provide ever increasing answers. I personally believe that the research will play out, and that we will gain a better understanding of these viruses.


    XMRV seems to have widely been accepted as being a contaminant in Mikovits' & Lombardi's Science paper.
    A clone of XMRV was artificially created in a lab by Silverman, and it seems that this is what caused the contamination.
    But, yes, just because that specific strain of MLV-like virus (XMRV) contaminated the study, it doesn't mean that other retroviruses weren't present in the patient samples. Mikovits has long said that she has been detecting a range of other MLV-related viruses in her work, but she has not published any so far, so we are in the dark about it all. Alter and Lo also detected a different MLV-related virus (PMRV), but they have retracted their paper.
    Ruscetti has also said that he is working on a range of viruses.
    But until we know the source of these viruses, then it doesn't give us any answers. They could have originated in mice, and be contamination, or they could potentially be from human samples, but we have no evidence of this.
    It should also be noted that although XMRV was cloned by Silverman, and is now considered to have contaminated the Mikovits paper, XMRV has also been detected as a virus in the 22RV1 cell line, and similar cell lines, so it is a real virus that lives in human tissue. The cell lines are made of human tissue, so the virus is able to live and replicate in human tissue. So it is possible XMRV is a human virus in the wild, but it hasn't yet convincingly been detected in humans.


    The Paprotka paper, in which PreXMRV-2 was discovered, proposed that XMRV was created by the recombination of two mouse viruses PreXMRV1 and PreXMRV2 in a laboratory human cell line. However, the Paprotka paper was not conclusive for a wide variety of reasons, but just suggested a model of how the virus could have been created. (But maybe they are too certain about their model in the discussion in their paper, which is a bit annoying.) There was another research paper (I can never remember the details) which said that recombination possibilities of MLVs are almost endless, and so it would be premature to make some of the conclusions of the Paprotka study.

    The Paprotka paper reasonably suggested that the strain of XMRV found in the Mikovits paper, could not be a wild human virus because it did not vary enough in genetic data for it to be a wild virus. But as others have been pointing out, XMRV is just one strain amongst other strains that have been said to have been detected, so it is not the be-all-and-end-all.

    The finding of PreXMRV2 in the wild doesn't change much in my opinion, because the Paprotka paper was just a hypothesis, and didn't provide any definite answers. But the new paper, discussed in this thread, does seem to open up more of a possibility, in my opinion, that XMRV could have been formed in the wild, and got into cell line via another route other than the recombination of PreXMRV1 and PreXMRV2 in the cell line.

    But the understanding of XMRV depends on its genetic data, so the new paper still doesn't change much, unless a wider variety of XMRV strains are detected and published. (I'm not certain if there have been a wider variety published so far - it's impossible to keep on top of it all.)

    But, as others have been discussing, XMRV is just one strain of MLV-like retrovirus that has been discovered, and so the XMRV-specific papers, such as Paprotka, might not be relevent to the wider story of MLV-like viruses any way. I think we shouldn't focus too heavily on just the XMRV-specific papers, as there is a wide range of MLV-related research.

    MLVs have not been convincingly detected in humans so far. And until someone publishes a paper which convincingly finds a human MLV-like virus then there isn't any evidence for scientists to sink there teeth into.

    I hope that helps answer some of your questions, Wally.
    They are really helpful questions, because they help to clarify what the situation is.
    Remember that I'm not an expert, so I'm just passing on my own understanding as a patient, but if I can help any more, then please ask.

    Bob
    currer likes this.
  19. Bob

    Bob

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    I haven't followed this specific discussion very closely, but here's my comments and observations, in case it's any help...

    I think that the env region for XMRV is from around the 5600 nt position to around 7600, which is included in the GenBank data.
    It seems to me that this region was detected separately in both 22RV1 and CWR-R1 in the Paprotka study, in the form of gDNA. (See the Paprotka supplementary material here.)

    I don't yet fully understand the Paprotka study's methodology, but it seems to be that they say they detected the same sequences, separately, in 22RV1 and CWR-R1.
    I haven't yet worked out how carefully they confirmed the sequences that they detected.

    It appears to me that full sequences (when stitched together) have been found separately in both 22RV1 and CWR-R1 in the Paprotka study, in the form of gDNA.
    See the supplementary details for details. Supplemental Fig. S3.
    http://www.sciencemag.org/content/suppl/2011/05/31/science.1205292.DC1/1205292s.pdf
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  20. Wally

    Wally Senior Member

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    :aghhh::(:mad::ill: - I just spent over an hour trying to type out a thank you for all the very helpful responses that were posted regarding my post/questions about this thread. My hand slipped while typing on my laptop and viola the draft response I was typing vanished. Perhaps little green men do live inside computers just waiting to torture unsuspecting tech neophytes?? :alien::D So before I inadvertently shut my computer down completely. Thanks for all the information that was provided. I will write more later after taking a rest and rebooting my brain.

    Wally :balanced:

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