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NIH/FDA XMRV Paper by Dr. Alter Out!

Discussion in 'XMRV Research and Replication Studies' started by Esther12, Aug 23, 2010.

  1. oceanblue

    oceanblue Senior Member

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    Next step for negative studies?

    The major difference between the Lo study that detected MLVs and the negative studies that did not was the PCR primer used. The Lo primers detected a broader range of MLVs. So all the negatives study teams have to do is repeat their work using the same samples but with the primers used by Lo.

    This sort of follow-up shoud be the norm: it will be interesting to see if the likes of McClure do do this.
     
  2. oceanblue

    oceanblue Senior Member

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    Patient selelction

    I agree, a great study but 100+ patients would seem more worthwhile.

    And it's a shame they didn't use current case defintions. The patients met the 1988 CDC (Holmes) but only about half also met 1994 CDC Fukuda. Given the lengths the authors went to in other respects e.g. developing a new ultra-sensitve test for mouse DNA to rule out contamination, you think they'd have really nailed the patient sample too. Hopefully other will go on to do this.
     
  3. VillageLife

    VillageLife Senior Member

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    I know people are saying its a small study.....but I think when you take a very small number like 37 people and find a retrovirus in like 32...it leaves me speechless!!

    Thats just 37 CFS sufferers, imagen what there going to find in millions of CFS sufferers!! :eek:

    What Alter has found is amazing, there are retroviruses in CFS sufferers and this is huge. I think when they start expanding this into huge groups, they may even find more variants.
    Dr Alter & Dr Silverman have nailed our viruses!! :victory:
     
  4. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    Behind closed doors


    I agree with you Penny. :Retro smile:

    That's exactly what I suspected was going on during the "holding" period.

    Ultimately though, whilst (potentially) a bit irritatingly macheavelian, it won't make any difference to how the science proceeds from here .

    Better days are ahead :victory:
     
  5. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    It doesn't matter what they say they found as long as the science moves forward.

    Andrew,
    The politics of the situation dictated that they were never going to explicitly find XMRV.
    Alter cleverly had to find a way of delivering the same overall conclusion without making the CDC look stupid and he succeeded in doing that.

    I think that some of the other commentators on here have described the situation very well.
    These are some of the standout comments for me:
    Anciendaze - Post #31
    Sunshine -Post #32
    Mark - Post # 36

    The science will move on quickly from this point (and already is doing) and I feel very hopeful now.

    Regards,

    TGOP
     
  6. Megan

    Megan Senior Member

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    I disagree about the 'nomenclature' issue being a softening up thing. It was clear from the 'leak' way back that Alter was always talking about MuLV related viruses as well as, or instaead of, XMRV.

    Also he has been very supportive of the WPI in his tone and what he has said in the paper and even more so in the journalists teleconference. As mentioned above the paper is not exactly complimentary to the CDC's patient selection process.

    Instead I see his findings as helpful in explaining some of the differences. eg. he has clearly indicated that the German prostate cancer study of over 500 patients could not have picked up the viruses he found in his study because their primer was XMRV specific and would have missed these related viruses. The German study was the one at the Robert Koch-Institute, the same people that validated the CDC's zero/zero findings in their study!
     
  7. alex3619

    alex3619 Senior Member

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    Hi oceanblue, I think it was entirely deliberate that they didn't use current case definitions. They took old patient samples - so old they could not have been contaminated in labs with XMRV because they were sealed. It helped eliminate the possibility of lab contamination, and they still found PMLVs. Future studies should indeed use independent samples, from the same patients but drawn separately if necessary. Some are already doing this. Bye, Alex

     
  8. Sunshine

    Sunshine Senior Member

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    NEW reasons to be positive over XMRV, at last:

    1) Lombardi: +
    2) Alter/Lo: +
    3) De Meirleir's patients in Europe: + & results shown at September XMRV conference.
    4) Mikovits finding's of UK patients: unknown
    5) Swedish study: unknown

    If it was possible to get 5 positive associations of XMRV/MULV's in CFS before the end of the year, there would be a real sense of movement that great things can be found in 2011/2012.

    Then drug trials can start.
     
  9. justinreilly

    justinreilly Stop the IoM & P2P! Adopt CCC!

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    My brief take on paper

    The significance of the study is hard for many of our friends and family to grasp.
    FWIW- here is my take on the study that I sent to my family:

     
  10. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Given that the Alter/Lo paper was such a small sample size, and in light of WPI's comments over the last few months, there is going to be many more than four. Also did WPI record the same variations, but chose to lump them under one umbrella XMRV? In other words perhaps WPI's definition of XMRV was never limited to a single MLV. I think they always knew this but did not explain it well enough.
     
  11. Bob

    Bob

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    MLV-related viruses - an explanation

    UPDATE: I've now written a much shorter and simpler explanation of MLV-related viruses, which might also be helpful, here:
    MLV related viruses - a simpler explanation http://www.forums.aboutmecfs.org/blog.php?b=518



    Harvey J. Alter, one of the authors of the NIH/FDA paper, has said that many viruses which cause a single disease, such as Hep C and HIV, have multiple variants. Alter says that the variations of virus, found in CFS/ME patients both in his study and the WPI's Science paper, is exactly the pattern that he would expect from a human retrovirus.

    In the published paper, Alter refers to three different types of virus that he detected in CFS patient blood samples, and there was also a fourth type in a blood donor sample. This is in addition to the XMRV detected in the Science paper.

    Alter refers to these virus types specifically as 'CFS Type 1', 'CFS Type 2' and 'CFS Type 3'. It is not clear what Alter is exactly referring to by these terms (i.e. a type of CFS, a type of virus or a type of gene sequence?), but it seems that he is at least referring to the "viral gag gene sequences" that he was detecting.

    Alter has very firmly stated that his study complements, validates, strengthens, and builds on the WPI's work, and it does not weaken the XMRV research in any way. The new study has brought to light a range of new virus types that are associated with ME/CFS. It is possible that these new variants might be found in even more ME patients than are currently testing positive for XMRV. At the moment, I think about half of the members of the Phoenix Rising forum (about 40%) are testing negative, and so it might end up that these patients test positive for these other variants in the future. I personally believe that this makes the collective future of ME patients even more hopeful.

    So, in the case of ME/CFS, Alter seems to be saying that a group of viruses (or variants of a virus) are associated with a single disease, or syndrome. These viruses are all MLV-related viruses. There are a number of different strains, or varieties, or variants, or types (whatever you want to call them) of these MLV-related viruses.

    MLV’s (Murine Leukaemia Viruses) are mouse retroviruses that cause cancer in certain types of mice, whereas MLV-related viruses are human viruses which are closely related to MLV’s. It seems that the MLV-related viruses are different enough from mouse viruses to be designated new human viruses, rather than mouse viruses.

    In this published paper, all the variants which were discovered, except the ones detected in the blood donors, are all shown to be associated with ME/CFS. The possibility of multiple infections, with different MLV-related viruses, in an individual, may yet prove to contribute to increased severity of symptoms, or a wider range of symptoms. It might yet been shown that patients exhibit different symptoms relating to being infected by the different types of virus. The viruses might also be associated with other diseases, such as MS, Autism, Gulf War Syndrome and Lyme Disease. My understanding is that there is ongoing research looking into all of these diseases.

    See here for a diagram, extracted from the Alter & Lo paper, of a 'phylogenetic tree' (i.e. a virus family tree) of MLV-related viruses and MLV's. Specifically, the diagram shows the relationship between the viral gag gene sequences detected in Alter's paper and XMRV's (XMRV variants) and MLV's:

    http://www.cfids.org/mlv/phylogenetic-tree.pdf

    The diagram shows the viral gag gene sequences detected in Alter’s paper (detected in blood samples of CFS patients and blood donors), labelled: ‘CFS type 1’, ‘CFS type 2’, ‘CFS type 3’, BD22, BD26, BD28.


    All of Alter’s and Mikovits' viruses are MLV-related viruses. XMRV is one of these MLV-related viruses, as Judy Mikovits has always said. The Alter study, and Judy Mikovits, have now also confirmed that there are multiple variants of XMRV. The Alter paper specifically refers to "XMRVs" in the plural. There are also diagrams in the Alter paper showing how the XMRVs relate to the new polytropic MLV-related viruses.

    Human Gamma Retroviruses (HGRV) seems to be the umbrella term for these MLV-related viruses. So far, the only known Human Gamma Retroviruses (HGRV’s) are MLV-related viruses.
    UPDATE: It has now been reported from the 1st international XMRV Conference that Judy Mikovits has suggested a new name: HMRV (Human MLV-related virus), which would encompass both Xenotropic and Polytropic MLV-Related Viruses.

    The viruses, that Alter and Mikovits have published papers on, have all been designated as MLV-related-viruses. Alter seems to base his findings on virus gene sequences, rather than whole virus genomes.

    Alter's viruses were previously unknown viruses, but similar to existing MLV's.
    These viruses have mutated enough, since entering into the human population, such that they can be called new types of human viruses, and not mouse viruses.

    These human retroviruses have now been found in a high percentage of ME/CFS patients in two published studies. (The Science paper, and now the PNAS paper).

    XMRV:

    XMRV is one type of these MLV-related viruses... It has now been confirmed that there are different variants, or types, of XMRV.

    Here's what 'XMRV' stands for:
    X - Xenotropic
    M - Murine Leukaemia Virus (MLV)
    R - related
    V - retrovirus

    So, as we can see from the 'M' (shortened from MLV) in XMRV, XMRV is related to Murine Leukaemia Viruses (MLV's), just the same as Alter's viruses are. XMRV was correctly classified as an MLV-related virus, the same as Alter's viruses. Throughout his paper, Alter refers to “MLV-related viruses” and “MLV-like viruses”.


    Why Alter's viruses cannot be called 'XMRV':

    A 'Xenotropic' virus cannot infect the species of origin (in this case, mice) with complete, replicating viruses but can infect another species (in this case, humans) with complete and replicating viruses.

    A 'Polytropic' virus can infect both the original host species (i.e. mice) and another species (i.e. humans) with complete and replicating viruses.

    The MLV-related virus sequences that Alter found most closely relate to 'Polytropic' MLV's, not 'Xenotropic' MLV's.

    This means that they cannot be referred to as 'XMRV' because the 'X' (Xenotropic) does not apply to these viruses.
    Instead, they are 'Polytropic-Murine Leukaemia Virus-Related Viruses' (So, I suppose he could have named them 'PMRV' instead of 'XMRV').

    Alter’s MLV-related viruses are referred to as 'polytropic', because the MLV's which they related to can infect both the original host species (mice) and another species (humans) with whole and replicating viruses, whereas Xenotropic viruses cannot infect the species in which they originate (i.e. mice) with whole, replicating viruses, but can infect another species (i.e. humans) with whole and replicating viruses.
    (Please see notes at the bottom of the page on the meaning of 'Xenotropic'.)

    So, Alter's viruses are polytropic-MLV-related-viruses (the MLV's they are related to can infect mice with whole, replicating viruses), whereas XMRV is a xenotropic-MLV-related-virus (the MLV's it is related to cannot infect mice with whole, replicating viruses). The only difference in the terminology is the use of the words 'xenotropic' and 'polytropic', or a 'P' and an 'X'.

    So, we have Alter's new p-MLV-related-viruses and Mikovits' X-MLV-related-viruses (XMRV). Both of these are 'MLV-related viruses', and they both fall under the informal umbrella terms ‘Human MLV-related virus’ (HMRV) and 'Human Gamma Retroviruses' (HGRVs).
    There are multiple varieties of both types of viruses. Alter has found CFS Type 1, CFS Type 2 and CFS Type 3 (although these terms seem to relate to gene sequences, rather than the actual viruses), and another, fourth type, in a blood donor sample.
    Alter and Mikovits both seem to be saying that Judy Mikovits has also found multiple variants of Xenotropic-MLV-related viruses (XMRVs), and it has now been reported that Mikovits has also found Polytropic MLV-Related Viruses in some of the patient samples from her original Science paper.

    Amy Dockser Marcus' Wall Street Journal blog says that Judy Mikovits has found polytropic type MLV-related viruses in some of the samples in her original Science study (so, along with XMRV, this means she is finding more than one MLV-related virus infection in individual samples), and I imagine that she is working furiously to find out the significance of this.

    One other interesting thing to note is that the 'commentary' in PNAS says that:
    So I believe that whether these new viruses are related to polytropic or xenotropic MLV's is not clear cut and is not particularly significant... it's just a case of wording, and possibly an unfortunate case of using an 'X' in the naming of XMRV.

    Alter and Lo have only detected gene sequences for their polytropic MLV-related viruses, and have not sequenced the whole virus genome. So it might be possible that their 'polytropic MLV-related viruses' might also turn out to be hybrids of polytropic and xenotropic MLV's once their whole genome has been sequenced.

    UPDATE: It looks like it might be more convenient, and appropriate, to use the name that Judy Mikovits has now suggested (at the 1st International XMRV conference): Human MLV-Related Virus (HMRV), which covers both 'X' and 'P' type MLV-Related Viruses.


    Discussion about the meaning of 'Xenotropic':

    Note that XMRV is an infectious human virus and is not, itself, a Xenotropic virus. It is only the MLV's (that XMRV relates to) which are referred to as Xenotropic, because of the behaviour of the viruses in mice.

    A Xenotropic virus is not a complete, replicating virus in the original host species (i.e. mice), but can only become a whole, replicating virus once it jumps to another species.

    It is not possible to infect the original host species with a Xenotropic virus because the host species has a genetic resistance to that virus such that the virus cannot exist as a complete and replicating virus in the host species.

    So, a Xenotropic virus cannot infect the original host (e.g. mice) but can only infect another species (e.g. humans). It is only when a Xenotropic virus jumps to another species (e.g. to humans) that it is able to start replicating and forming whole, or complete, viruses, thus becoming an infectious exogenous virus.

    Endogenous/Exogenous.
    Exogenous viruses are what we typically think of as a virus. They are complete viruses which are transmitted via infection.

    Endogenous viruses are hereditary sequences of the host species' DNA. They are passed from parent to offspring via reproduction. They are not stand-alone viruses. In humans, endogenous viruses are usually thought to be inactive and benign, although some still actively code for proteins. The DNA of an endogenous retrovirus is an integral part of the host species’ DNA, and endogenous viruses are transmitted from parent to offspring via the DNA of the germ lines cells (eggs and sperm), as an integral part of the species’ DNA.

    My understanding is that a Xenotropic virus is always an endogenous retrovirus in the original host species. It would make sense if a Xenotropic virus was an endogenous virus in the original host species because endogenous viruses are an integral part of the host species' DNA and can exist in the host without forming whole, complete, replicating viruses. Host species are genetically resistant to their endogenous viruses. In the case of an endogenous Xenotropic virus, viral particles (partial viruses, viral RNA/DNA, or viral proteins) can jump to another species (e.g. to humans) where they become active and able to form whole, or complete, viruses and start replicating, thus becoming an infectious exogenous retrovirus in the new species. The original host species (e.g. mice) would be genetically immune to being infected by whole, replicating viruses, even though they harbour the virus particles that can cause a full infection of another species.

    Benign?
    Some definitions of 'Xenotropic' state that a Xenotropic virus is 'benign' in the original host species. A question that has been raised is, if Xenotropic viruses are, by definition, 'benign' in the host species, then why are MLV's referred to as 'Xenotropic', when they are known to cause cancer in certain types of mice (so they are clearly not benign)? This question is explored in the discussion after my blog entry.
    I wonder if it is more accurate to say that Xenotropic viruses are non-infectious, and non-replicating in the original host species, rather than entirely 'benign'. I can see why there could be confusion here as endogenous retroviruses, for example, are usually thought to be benign, but in certain circumstances they might not be (i.e. wild mice are vulnerable to infection from certain endogenous retroviruses in bred mice.) In humans, endogenous retroviruses are generally thought to be benign, but they are being investigated for possible association with diseases such as schizophrenia. Prof Huber is researching the human endogenous retroviruses, HERV-K18, for a possible association with ME/CFS.

    XMRV:
    It is thought that XMRV originated as a mouse virus (an MLV) which jumped species and then mutated in the human population (or before it reached the human population if another species was also involved), such that it is no longer an MLV (it is not genetically identical to any known MLV's).
    XMRV has 'Xenotropic' in its name because it is closely related to a Xenotropic mouse virus, not because it is actually a Xenotropic virus. XMRV is an exogenous human retrovirus, not a Xenotropic MLV.
    I imagine that mice still have a resistance to XMRV and so cannot be infected with it, but I'm not clear about this. If the virus mutates enough, then mice could lose their resistance to it.
    XMRV is a human retrovirus but it is not a xenotropic human virus... it is a [Xenotropic mouse virus]-related virus.


    A Question regarding MLV research:
    I do have a question that doesn't seem to be answered... If we know that polytropic and xenotropic mouse retroviruses exist, then why hasn't there been more studies done on these viruses before? Polytropic and Xenotropic viruses, by definition, can infect other species (i.e. humans), so why have these MLVs only been investigated in humans recently?


    Notes:

    It's important to keep in mind that Alter's study is based on the detection of gene sequences from the viruses, rather than whole virus genomes.

    MLV's are also known as MuLV's.
    Some types of MLV's are also known as mERV's (mouse endogenous retroviruses), but not all MLV's are endogenous.

    Alter checked all of his blood samples for contamination with mouse DNA, which showed negative for all mouse DNA.
    This proves that there is also no contamination from endogenous mouse viruses, but I believe that this method does not prove that there is no contamination from exogenous mouse viruses. The variability of the MLV-related viruses found, along with other safeguards in the study, satisfied the journal PNAS that there was no contamination with MLV's.
     
  12. bullybeef

    bullybeef Senior Member

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    Thanks Bob, I think I completed followed that, and from what I have read elsewhere, it makes complete sense. I also note that Alter said in the Q&A transcript that we could all carry different variants/varieties at the same time too, which can combine and mutate, becoming new variants. We all must be riddled!! I have this image of mice retrovirus running on wheels in our cells!! Like rats in a maze!

    You should write the commentary next time, Bob!! I'm gonna try and get the wife to read this later! Wish me luck!! :D

    BB
     
  13. Bob

    Bob

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    An interesting snippet from the Alter paper:

    So, of the patients who had been 'rigorously evaluated', to confirm that they had ME/CFS, using the diagnostic criteria that the study employed, 96% tested positive.
    96% is almost identical to the final WPI figure for their cohort... It's effectively a 100% result, which I think is an astonishing result.

    The other patients were diagnosed by their Doctors, and these patients were not (necessarily) rigorously evaluated for ME/CFS.

     
  14. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Hi Bob, I am still a little confused. Not so much with what your wrote, but how it conflicts with other posts. From what you have said, very clearly I might add, XMRV is a separate MLV-related virus from the MLV-related viruses Alter found. This opens up a bit of hole. Alter never found XMRV and WPI never found Alter's MLV-Rs. How does this point support the premise that XMRV is in the wider population at 90%. Or is there a suggestion Alter's cohort probably also has XMRV and WPI's cohort also has the main Alter MLV-R.
     
  15. Bob

    Bob

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    I think that this new research is very good news for our community, as it furthers our understanding of the retrovirus/retroviruses associated with ME/CFS, and it means that many of the CFS/ME patients who have so far tested negative for XMRV, might now test positive for one of these new MLV-related viruses.

    XMRV might not be found in all of the ME patient population (or 90%, 96% or 97% or whatever), but maybe a variety of MLV-related viruses (aka Human Gamma Retroviruses) will be.

    It is a bit confusing because the WPI samples were sourced from various geographical areas, so I'd have thought that Alter might find at least one XMRV positive sample, but he only looked at a very small number of samples. It is possible that Alter was just unable to detect XMRV, but I wouldn't have thought this was likely, because I think he was communicating with, and working with, Judy Mikovits. (Don't know if that's right.)

    Maybe the WPI's samples were positive for other MLV-related viruses, but the WPI was not looking for other viruses, they were only looking for XMRV, so maybe that's why they didn't detect any other viruses.

    Does that make any sense? I might have it wrong, but that's my understanding of it, so far.
     
  16. SickOfSickness

    SickOfSickness Senior Member

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    Thanks for the explanation Bob. Hope to read more of your explanations in the future.
     
  17. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    From Amy Dockser Marcus' latest blog. It is becoming apparent that each CFS patients has more than one MLV-R in their system. Alter's cohort should have had XMRV, but Alter didn't find it (it could still be there?).

    WPI's finding of XMRV wasn't confirmed. However the WPI appears to have known about the MLV-R variants to XMRV - exhibit A: their new testing; exhibit B: the above statement from Mikovits - yet they didn't really come clean with this information earlier. Without understanding the reasoning for their actions, I feel this has slightly muddied the purity of their Science paper. Is this a fair assumption?
     
  18. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    So now has Meirleir found XMRV in Europe or has he found other MLV-Rs?
     
  19. free at last

    free at last Senior Member

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    I havent said anything at all till now. but i sure been taking it all in. Dont want to get too heavy at the mo just wanted to say i didnt know what to expect. but i certainly didnt expect this. Its great news everyone a day to remember, It also seems to make perfect sense why some are more severly ill than others, indeed, why some may even recover more than others, these variations of MLV may affect the immune systems differently. And am i wrong in assuming that if one is only looking for XMRV that they will miss these mutations. if anyone could clarify that, its something ive been thinking about. as a possible reason ( patient cohorts too ) that explain so many negative studys. Congrats everyone lets hope this research continues to pour cold water on the likes of wessley and sharp. bet they was pissed off. what goes around comes around, and for once its not our dizzyness and nausea. pour that on cornflakes Simon, ive been smileing a lot since i finally managed to get on line with the forum crash, aint stopped smiling since, and our media ignore it, IDIOTS but make a big deal when nothings found. whats new. WE AINT NUTS THATS WHAT NEW, Alter and others are now proving it i feel. Way to go Mr Alter, And Mr K great Cohort selection Mr k we are in your debt.
     
  20. Wonko

    Wonko Senior Member

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    I'd say your probably right - XMRV is a specific MLVRV variant - so a fliter which was set to pick only XMRV would exclude the other MLV related virus'es
     

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