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HTLV-1's replication: Perhaps it can explain XMRV's low degree of mutations

Discussion in 'XMRV Research and Replication Studies' started by omerbasket, Jun 9, 2011.

  1. omerbasket

    omerbasket Senior Member

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    Today I read a post by "ukxmrv", and that's what he said there:
    So then I searched for papers about HTLV-1's replication, to see if it can give us hints about why XMRV has a low mutation rate, if it has a low mutation rate (which I'm not sure of - because I don't know if the Lo/Alter sequences shouldn't be called "XMRV" - in fact, I don't understand why they don't call them by that name - and they represent a significant mutation rate from VP62).

    Anyway, I think that I found some interesting stuff (Warning: I'm not a scientist, and it's very possible that I'm wrong in some of the things that I say. If you know that I'm wrong, or think that I'm wrong - please say so and say why):
    1) It seems that HTLV-1's main route of replication is not by reverse transcriptase of the virion (virion is the infectious virus particle when it's OUTSIDE of the host's cell) - like most of the retroviruses (inlcudin HIV-1) - but through another mechanism: It replicates with with the cell - when the cell replicates, the virus replicates. Here are some parts of studies where they talk about that:
    http://jnci.oxfordjournals.org/content/93/5/367.full

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC112382/
    So, perhaps XMRV is replicating like HTLV-1 - mostly through cell division and less by reverse transcriptase of the virion. And that would cause it to have less mutations:
    http://jnci.oxfordjournals.org/content/93/5/336.full.pdf
    2) HTLV-1 has an oncogene - it's called "tax". XMRV doesn't have an oncogene (its only genes are gag, envelope and polymerase). Now look what they say about the "tax" gene in HTLV-1:
    http://jnci.oxfordjournals.org/content/93/5/367.full
    http://jnci.oxfordjournals.org/content/93/5/336.full.pdf
    So, when HTLV-1 is causing cancer - you should expect - if I understand it correctly - to find a greater variability than when it doesn't, and that's because when you have cancer, you cells are dividing more often - which would give HTLV-1 more opportunity to change his genome. Also, theye say that the "tax" gene interferes with cellular DNA repair pathways, so perhaps that's also helping it mutate, I think.

    Now, a cancer caused by XMRV might be a different thing, but when you are talking about XMRV in patients without cancer - and if XMRV replicates in a similar way to HTLV-1, meaning, mostly by cell-division - I think that you should expect that XMRV would even have less mutations, because if there is no cancer, than the cells are dividing much slower, giving XMRV much less opportunities to change its genome. And even if you do have cancer - if I understand correclty, retroviruses without oncogenes (as XMRV is) can cause cancer, but in a different way (I think it depends on where they integrate - whether they integrate into an oncogene or something like that), and XMRV won't have the "tax" gene that would interfere with cellular DNA repair pathways - so even if you have cancer, you might expect lower variation of XMRV, in comparison to HTLV-1.

    3) Even when HTLV-1 virions are replicating, using reverse transcriptase, it seems that their mutation rate is significantly lower than the mutation rate of HIV-1:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC112382/
    4) You must remember that while HTLV-1 is a complex retrovirus, XMRV is a simple retrovirus. As far as I understand it, simple retroviruses, because of the small number of genes, are mutating less than complex retroviruses, which have more genes (while XMRV has 3 genes - gag, polymerase and envelope - HTLV-1 has 5 genes: gag, polymerase, envelope, tax and rex).

    Now, it seems that XMRV is a retrovirus that is replicating slowly and that usually has little variation. One way of explaining this would be to say: "It's just contamination". But another way would be: "Hey, we already know of a human retrovirus that replicates slowly and that has little variation. And we can also see that if XMRV replicates mostly by cell-division, than it would be expected that it would replicate even less than HTLV-1 and would have even less variation than HTLV-1".

    Now, there is another thing, and that's regarding the PMRVs found by Lo and Alter (and their colleagues - I must mention them as I think it's unfair to them that we never mention their names... so: Natalia Pripuzova, Guo-Chiuan Hung, Bingjie Li, Richard Wang and Anthony Komaroff): These sequences are "just" 84%-96% (mostly about 95%) identical to the VP62-strains. Since HIV-1 and HCV (and probably many other viruses that I did not check) has strains that are only 85% and 79% identical to one another - and still all of these are named "HIV-1" and "HCV", I currently don't understand why some of the scientists say that the PMRVs and XMRV are different viruses. So, let's assume that they are the same virus - which in my unscientifically-educate opinion is the more reasonable thing to think - how would we explain why those strains have more variability? I mean, we just explained why you might not expect XMRV to have a large variability. I think I might have an explanation for that:
    http://jnci.oxfordjournals.org/content/93/5/336.full.pdf

    http://jvi.asm.org/cgi/reprint/67/2/1015.pdf
    So there, they found a strain of HTLV-1 that was "only" 91.5% identical to the reference strain (and actually, I think, that was about the percentage of difference from other strains too). All of the other strains (and I did not find many complete genome strains, unfortunately) are highly identical to one another, as was said in one of the quotes above. It should be said, however, that this strain was found in Oceania while the reference strain was from Japan - and in our case the PMRVs were found in the USA, although in another state (but anyway Dr. Mikovits is finding the P strain also in her samples, which I guess are mostly from Nevada, although I can't be sure of that - but it's probable that she finds the P variant at least in some samples from Nevada). So I don't know how to explain that, but even if nobody knows how to explain that, there could be an explanation - and actually I guess that scientists can give numerous explanations for that, at least if they would think about it deeply.

    Anyway, I think that what we can see is the following:
    1) There is already an example of a human retrovirus that replicates slowly and have little variability in the vast majoirty of its strains.
    2) It's reasonable to expect that XMRV would have even less variability, and I explained why.
    3) Despite usually having a low degree if variability, HTLV-1 does have a strain that is subtantially mutated - although that's from another part of the world, and the PMRVs are from a place pretty close to where the XMRVs where found (and anyway the WPI found PMRVs in their samples - probably from Nevada also - and XMRVs in the Lo/Alter samples).
    4) I didn't talk about it in the above text, but I think that one bad, very bad thing that we might have to deal with if the thoery that XMRV replicates much like HTLV-1 is correct (and it's important to say that right now it's just a theory, and we, or at least I, cannot know if that theory is correct or not) is that it would probably be hard to fight it with antiretrovirals - because, at least as far as I understand it, when the virus is replicating by the cell-division route, it doesn't do all the reverse transcription and things that it does when it replicates outside of the cells, and therefore - and correct me if I'm wrong - the antiretrovirals that works against HIV won't be of a major help, because I think that they are acting only against a virus that replicates in a way different from replication by cell-division. I would like to say, however, that my hunch is that in the very-sick patients there is probably more viral replication by the reverse transcriptase route, and therefore perhaps anti-retrovirals can help them more, although just to some degree (because than you arrive at the cell-division replication, and as I said, I think that antiretrovirals does not act against that). By the way, I think that somewhere here or in the other forum it was posted before about scientists who are trying to eliminate retroviruses with a method that is based on chemotherapy - and it seems to me that this is the kind of things that can help those who are sick due to integrated retroviruses (in order to eliminate the cells that have retroviruses integrated into them). If they would be able to attack only, or at least mostly, the cells that have a provirus of XMRV integrated into them, I think that might be fantastic.

    I would very much like to hear your thoughts about that - and if I was mistaken somewhere, please correct me (but also explain why you think I was wrong).
     
  2. omerbasket

    omerbasket Senior Member

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    By the way, I don't know how to change the title from "explains" to "explain" - can a moderator change that for me? Thanks :)
     
  3. Jemal

    Jemal Senior Member

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    Omer, I enjoyed reading it and I think you did a good job of making yourself understandable, even when talking about a complex topic. I can only say I think you have a point. I say "I think", because you are going pretty deep into the science here and to evaluate if you really have a point, we would need someone who understands the science better than you and I do.

    As for point 4: I think we heard quite soon after XMRV was linked to CFS by the WPI, that the virus probably replicates slowly (and maybe differently, as you said). As antiretrovirals hit a virus when it replicates, that didn't bode too well...
     
  4. alex3619

    alex3619 Senior Member

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    Hi omerbasket, wow. I am too brain dead at the moment to follow up on most of this, so I just want to write a few comments.

    X/P MLVs don't care what we call them. They are similar, and recombine. A large part of the diversity is probably recombination. The thing is an X can't infect mice, a P can, but I have not looked into the details of the receptor interaction. I guess its a small mutation, one way or the the other. If this is right, its just a tiny genetic variation, with a large functional impact. That is why they say it is different, but it is best thought of as the same virus, just a slight variant in my opinion.

    The issue with whether or not ARVs are ideal for fighting XMRV has been discussed before, somewhere on PR some time ago. The idea is to reduce blood viral load, and so the immune response especially cytokines. At least that is how I see it. It will never be a cure. By reducing blood load, it will reduce spread, and reduce immune damage from us fighting it - and that damage may be a big part of ME/CFS. In other words, it might suppress ME/CFS symptoms, but leave the infection relatively untouched.

    This is a big problem, which a whole lot of very smart scientists will have to work on for a whole lot of years, and a whole lot of dollars, before we see a cure. The best we can hope for is symptom reversal - my guess is most of us can get back to severnty or ninety percent capacity, which is good enough for me to be happy about - presuming of course that XMRV is either causal or co-causal.

    I am glad you looked into HTLV, we have needed this for some time. Maybe others can add to your analysis.

    Bye
    Alex
     
  5. omerbasket

    omerbasket Senior Member

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    I totally agree with that. Although the laymen discussions are also good, even if not good enough, and we can also contribute with our ideas and with what we think about the ideas of others.

    But sure, we do need people who understand the science enough in order to help us on such matters.
     
  6. Marco

    Marco Old blackguard

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    Nice one Omer and very clearly explained.

    The lack of sequence variation has been a sticking point and clonal expansion could explain a lot; including the apparently mixed reaction to ARVs with the few who have tried them and the finding that the human immune response at least partially inhibits XMRV does not preclude an ongoing chronic infection.

    I never could buy the argument that XMRV and Lo/Alters' Poly sequences are 'not the same' while at the same time saying that lack of variation in XMRV meant contamination. At what stage is too little variation to be 'real' become too much to be the same?

    As for host range, some of the main critics even identified the variants many years ago and considered them 'closely related'.

    The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination.

    J P Stoye and J M Coffin



    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC255766/?tool=pmcentrez

    I've been doing a little reading up on HTLV's also and there's a lot of known data that can help explain the divergent findings to date. What also struck me is that the same names keep cropping up (from both sides of the argument). They all know (or know of) each other and have access to the same research going back many years if not decades.

    Good old fashioned professional rivalry and/or entrenched opinions could explain a lot.
     
  7. Bob

    Bob

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    Great research Omerbasket... Thanks very much for that... It demonstrates that the subject of virology is so much more complex, diverse and unpredictable than even many of the virologists are acknowledging when making their predictions and conclusions.
     
  8. anciendaze

    anciendaze Senior Member

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    Good work, Omerbasket.

    I would like to point out that HTLV-1 is a delta retrovirus. There are leukemia viruses in the same genus, and frequent recombination in the wild can make nonsense of taxonomy imposed by human scientists. I've been talking about bovine leukemia virus as a model for months, because it has far more latent provirus than active viral infections in blood. The reported ratio is between 1 in 5,000 and 1 in 50,000 actively infected cells. BLV interacts with the host life cycle in much the way MLV does, but the time scale is considerably longer. It is important that it slow replication so it does not kill the host before it passes the infection to a new generation.

    For human hosts, the time between vertical transmission and reproduction is longer than just about any other mammal; only elephants come close. We should expect to see exaggerated latency as a result, in a well-adapted leukemia virus. Only the relatively recent origin of the XMRV strain caused it to be found. I'm betting on the existence of other retroviruses with the same 'strategy'.
     
  9. Jemal

    Jemal Senior Member

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    I just saw another post on this forum that I thought was very interesting. In a study in 2006 they found a large part of people infected with HTLV-I had fibromyalgia.

    See:
    http://forums.phoenixrising.me/showthread.php?12325-HTLV-1-amp-2-Antibody-Test-Online

    Until now I heard that HTLV-I might cause disease in only 5 - 8% of the infected... but it might be much higher?

    I find this interesting, because I was a fibromyalgia patient, before I got ME/CFS (and fibromyalgia also being associated with ME/CFS and XMRV).
     
  10. Overstressed

    Overstressed Senior Member

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    Have you been tested on HTLV, Jemal ? I have been tested a few times, lastly with a test that's used in research. According to the HTLV-researcher, HTLV serological tests can give FALSE negatives, due to low virus numbers and accordingly, low antibodies. Sounds familiar ? They carried out a more sensitive test on me and it was negative.

    Just a thought...
     
  11. Jemal

    Jemal Senior Member

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    I have been tested for HIV multiple times, but I never noticed HTLV on the forms the doctor filled out. So yes, this post also made me think about getting tested for HTLV.

    At least it looks like I don't have HIV... Oh, I was also tested for mad cow disease at one time I think.
     
  12. ukxmrv

    ukxmrv Senior Member

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    That's interesting OS, I was tested for HTLV-1 at a UK NHS hospital and it was negative. I'll have to check up on more sensitive tests.

    In "Osler's Web" it was reported that a lot of Dr Cheney's patients tested positive for HTLV in the early days. I wonder if the test were reacting to something else that the patients had, it was only this one group or the modern tests don't pick up a strain CFS patients have?
     
  13. Overstressed

    Overstressed Senior Member

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    Hi UK,

    I remember something I recently read or heard from the symposium about cross-reactivity between conserved regions of XMRV and HTLV. Apparantly, the test cross-reacts to that...

    I would contact a HTLV-researcher in order to get this test used within research. Unfortunately, I forgot the name of the test.
     
  14. Jemal

    Jemal Senior Member

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    The plot thickens...
     
  15. Bob

    Bob

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    Yes, it was one of the Abbott Diagnostics studies:
    http://www.retrovirology.com/content/pdf/1742-4690-8-s1-a222.pdf
     
  16. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    probably just contamination, they just need to exercise more, lol. lots of sarcasm present in my post. I just hope they keep looking for some infectious cause as our immune profiles show something is going on with elevated l-rnase and poor nk function, unless we have an immune defiency which is why alot of us test positive to all these viruses reactiviating.

    cheers!!!
     
  17. Bob

    Bob

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    These papers are relevent to the discussion regarding low mutation rates...
    I'm just posting them so we have easy reference to them...

    Low Degree of Human T-Cell Leukemia/Lymphoma Virus Type I Genetic Drift In Vivo as a Means of Monitoring Viral Transmission and Movement of Ancient Human Populations
    ANTOINE GESSAIN, ROBERT C. GALLO, AND GENOVEFFA FRANCHINI
    21 October 1991
    http://jvi.asm.org/cgi/reprint/66/4/2288

    Complete Nucleotide Sequence of a Highly Divergent Human T-Cell Leukemia (Lymphotropic) Virus Type I (HTLV-I) Variant from Melanesia: Genetic and Phylogenetic Relationship to HTLV-I Strains from Other Geographical Regions
    ANTOINE GESSAIN, ENZO BOERI, RICHARD YANAGIHARA, ROBERT C. GALLO, AND GENOVEFFA FRANCHINI
    12 November 1992
    http://jvi.asm.org/cgi/reprint/67/2/1015.pdf

    The Low Evolutionary Rate of Human T-Cell Lymphotropic Virus Type-1 Confirmed by Analysis of Vertical Transmission Chains
    S. Van Dooren, O. G. Pybus, M. Salemi, H.-F. Liu, P. Goubau, C. Remondegui, A. Talarmin, E. Gotuzzo, L. C. J. Alcantara, B. Galvo-Castro, and A.-M. Vandamme
    January 22, 2004
    Molecular Biology and Evolution
    http://mbe.oxfordjournals.org/content/21/3/603.full
     
  18. tonydewitt

    tonydewitt

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    Omerbasket - I love your original post and find myself reading it again & again.
    Overstressed - the typical test for HTLV is the antibody test, the "more sensitive" test is for HTLV is the PCR test.
     
  19. Mula

    Mula Senior Member

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  20. tonydewitt

    tonydewitt

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    That agrees with the reference that OmerBasket provided in the beginning.
     

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