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Restricted Replication of XMRV in Pigtailed Macaques

Discussion in 'XMRV Research and Replication Studies' started by Jemal, Jan 12, 2012.

  1. Jemal

    Jemal Senior Member

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    Sucks to be a macaque! Several people we know are authors on this paper: Coffin, Pathak.

    http://jvi.asm.org/content/early/2012/01/04/JVI.06886-11.abstract?related-urls=yes&legid=jvi;JVI.06886-11v1
  2. Jemal

    Jemal Senior Member

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    Recently a paper got published that suggests XMRV might have ways to downregulate APOBEC, by the way.

    I also wonder if 119 days was long enough for the experiment to yield any valuable results. What if this virus takes years to do damage?

    These are just some questions that popped up in my head.
  3. natasa778

    natasa778 Senior Member

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    In additon to the question of APOBEC restriction by XMRV few others spring to mind:

    Is APOBEC present in the gut? Is it active in lung/respiratory lining tissue? Assuming that natural in vivo route of transmission of this type of viruses to humans, if it happens, would not be exclusively via blood, how much could we rely on APOBEC to act fast enough to prevent the virus establishing residence in say gut lymphoid tissue?

    In the cases of direct blood-to-blood or saliva-to-blood transmission, does APOBEC act fast enough to stop the virus infecting endothelial cells (and then switching to latency)? I havent read the full paper but wondering if they actually investigated endothelial tissue, esp near the injection site, for viral presence. Anyone?

    As Jemal mentioned 119 days not nearly long enough for a virus that likes to lie low for prolonged periods of time and to spread by direct cell-cell contact.

    This study appears designed to answer political questions rather than scientific ones.
    Overstressed likes this.
  4. Firestormm

    Firestormm Guest

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    Thanks Jemal. Hope to get access to the full paper.

    My first question was immediately: Can this be compared to those other poor macaques?

    Even if it can't specifically, or in terms of conclusion, I am pleased to see Coffin and Pathak and the others of course revisit this controversially interpreted area.
  5. Daffodil

    Daffodil Senior Member

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    so now coffin believes in the virus??
  6. Firestormm

    Firestormm Guest

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    He has never said he didn't. XMRV is 'real' but not a human pathogen. Pump a macaque full of the stuff and see what it does. Same as in the last experiment. I would need to compare the two papers though and have asked someone to have a look and see if this is indeed possible.
  7. Overstressed

    Overstressed Senior Member

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    Hi Jemal,

    not only that -it is for retroviruses rather common to cause disease many, many years later- but what about other infections ? Most people are infected with Human Herpes viruses... What if this retrovirus comes with a helper virus ?

    Lots of valid questions, and I would like to see what the outcome would be if you take 'xRx' and you add for instance EBV to it...

    OS.
  8. currer

    currer Senior Member

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    This paper could be said to argue FOR a relationship between MLVs and ME, precisely because XMRV does not replicate like mad in the body. If it did none of us would be here after decades of illness, - we would be dead.

    A slow, limited infection sounds like just the thing to me, so I'm sorry this paper is not as reassuring as it wants to be.

    Just think, if their research showed that the xmrv multiplied like mad and killed the macaques, we could be pretty certain that it was not the pathogen that occurs in ME.

    For some absurd reason research into this illness keeps being blocked by the benign nature of ME, benign, in that it does not kill.

    The fact that the infection did not kill these animals is an argument in FAVOUR of XMRV-like viruses being linked to ME, not the reverse, as they seem to try to argue here.

    Do they know anything about the clinical presentation of ME or how it affects sufferers as a low level disease for years, with few signs and symptoms?
  9. Firestormm

    Firestormm Guest

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    Hi Currer,

    You must surely recall though the 'fall-out' and speculation that resulted from the last paper using macaques in this way? Are you saying this one from Coffin and Pathak does nothing to settle the 'debate' that arose previously?

    I don't yet have access to the full paper and so unfortunately I cannot conclude anything. Other than what is said above. I have though - as I've said - asked a scientist to see if this paper can indeed be compared to the last one.

    Until then - or until I get access to the full paper - it is very difficult to state anything really - wouldn't you agree?

    Original paper: http://www.mecfsforums.com/index.php/topic,5599.msg63495.html#msg63495

    Discussion on this forum of original paper: http://forums.phoenixrising.me/show...sponses-of-Rhesus-macaques&highlight=onlamoon
  10. natasa778

    natasa778 Senior Member

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    Interesting little detail concerning APOBEC, wondering if Coffin is aware


    http://www.ncbi.nlm.nih.gov/pubmed/22145963


    another one discussing influence of APOBEC host gene polymorphisms on viral protein variability and disease outcomes http://www.ncbi.nlm.nih.gov/pubmed/21571098
  11. currer

    currer Senior Member

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    Firestormm,
    Chimpanzees do not develop AIDS when they are infected with HIV. So I think studies on macaques, who are more divergent from humans than chimps can only have a suggestive value.

    I am interested to hear you refer to "fall-out" on the previous macaque study. Can you elaborate on that please?

    I think that if we are looking for an infectious agent underlying ME it will need to behave much as xmrv does in this paper, - set up a limited or a latent infection.
    That is quite an uncontroversial statement.

    The authors did not provoke the macaque's immune system by challenging it - it would be interesting to see whether the viral load increased again under these circumstances as they state that viral DNA was detectable throughout the 119 day period of the experiment in peripheral blood mononeuclear cells, ie in B cells. These would produce more XMRV as they divided to respond to an infection.

    Combined with a continued antibody response, which also lasted the whole research period, the reassuring tone of the abstract is a bit disingenuous. It is clear that the macaques immune systems were both infected with xmrv (in the PBMCs - the immune system cells) and reacting to defend themselves from a recognised infection with an antibody response.

    Why are we asked to believe that such a condition would be completely benign?
    Despite xmrv being cleared from plasma, (which is the watery intravascular fluid of the blood once all the blood cells are removed) the xmrv DNA persisted in the PBMCs.

    If that DNA is integrated into the genome of the PBMCs then your immune system cells are permanently infected. We do not know whether APOBEC in humans can effectively edit the viral DNA silence it. Judy Mikovits found that the "XMRV" was able to escape silencing.

    natasa is saying in the previous post that individual variations in APOBEC may contribute to some individuals' susceptibility to infection as the APOBEC will differ in the efficiency with which it can edit DNA.
    So some people may be immune to XMRV and others will not be.

    The authors also cannot deny that the XMRV went to the prostate. "limited or no spread"
    ie. there was some prostate infection.

    I think LN refers to lymph nodes, and viral DNA was detected in the lymph nodes too, but not producing RNA ie no active infection going on.

    The first paper was on rhesus macaques, and this paper is studying pig tailed macaques - different species - which probably accounts for some of the differences.
  12. Firestormm

    Firestormm Guest

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    Hi Currer,

    I have some comments from those better able than I at interpreting this paper and I have the full paper now, so should be able to put something together later today. Assuming of course I manage any sleep that is!

    Thanks for replying - I haven't yet read all of it - my reference to 'fall out' was in terms of speculation really. Especially relating to the notion that XMRV disappeared from blood and therefore studies should only look in tissue when in fact XMRV was effectively killed off in blood and did buggar all in the tissue.

    Anyhoo, I shall endeavour to put it all together. Basically this study proved little different that the original one I understand. Here's a great analogy from one of those who kindly took the time to read the paper through for me:

    '...This is also data that we could have guessed from previous studies, that is APOBEC from humans, rhesus macaques, and now apparently pigtailed macaques, happily restricts XMRV (think of it like the coackroach hotel-- viruses check in, but they dont check out)...these folks did a real viral infection, and got neutralizing antibodies...'

    I liked that one. It appealed. But I will try and be more 'rational' later if such a thing is possible of course.
  13. Jemal

    Jemal Senior Member

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    Yet despite immune response the virus could be found in certain organs I think? Or am I looking too simplistic at it? I read the study, but unfortunately I am in way over my head here...
  14. currer

    currer Senior Member

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    Jemal,

    As I understand it, the viral DNA was found in the Lymph nodes (assumung this is what LN is) but not producing acive virions ie no RNA packaged as virions was detected. But the XMRV had integrated its DNA into the cells. This means that the viral DNA is incorporated into the host DNA. The infection is now latent - not producing virions.

    Similarly the viral DNA was integrated into the peripheral blood mononeuclear cells, that is T cells, B cells. and NK cells.
    Judy Mikovits has suggested that when these blood cells actively divide in response to an infection they copy more XMRV via mitosis, (their own division) as each time they copy their genome they are going to copy the vitral genome as well.

    This means that the virus will be LATENT when there is no immune challenge, but actively copied once an infection is encountered. I expect the same goes for the lymph nodes, because white bliood cells are retained in the lymph nodes, they are important for the functioning of the immune system and can become inflamed in response to infection. The lymph nodes are part of the immune system, they filter material from the blood and any foreign material will meet a white blood cell here and find an immune response.

    The lymph nodes are part of the blood vascular system, once the blood had been pumped from the blood vessel to the tissues, the plasma is drained through the lymphatic system before being returned to the blood vessels.
    Jemal likes this.
  15. currer

    currer Senior Member

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    Once integrated into the DNA, as I understand it the retroviral DNA is present for the lifetime of that cell.

    Even if that cell is not making virions, it is infected, and will replicate viral copies when it copies itself. You would have a very low level of virus present in the body.
    BUT IT WOULD ALWAYS BE PRESENT. You have the equivalent of a permanent pollution of the tissues, and the immune system could hypothetically recognise these infected cells as foreign and commence attacking its own tissues.

    Or you could get larger amounts of virus produced when the PBMCs divide in response to infection.

    The effect of the infection was not apparent throughout the course of the experiment with the macaques only because the time-scale of the experiment was too short for problems to emerge.

    Once infected with XMRV I would assume these macaques have a lifetime infection on their hands and we have not researched how the body responds in the long run to a continued low level infection it cannot eradicate. It looks as if there is a permanent antibody reaction to a virus that is always present in the body.

    The tone of this article is very odd to me. Why are these people suggesting by their tone that such an infection would be safe? The assumption that APOBEC can always and in every case edit the viral DNA so that it cannot replicate is an assumption. Pig tailed macaques will not tell us much about infection in humans, and the researchers do not seem to have challenged the macaques with an infection to see whether, as in the case of the rhesus macaques, high titres of virus resulted.

    The authors no-where suggest thast the XMRV was completely cleared from the macaques bodies. They admit that the virus persisted.

    No one would want a permanent infection of this sort. You do not need to die of a fulminating infection (as in smallpox) to be ill, ME is not that type of illness, such a disease process as is demonstrated in these macaques is what you would expect for a long, slow not very infectious condition that does not kill.
    ME is just this sort of disease.
    Jemal likes this.
  16. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    I am inclined to agree with currer on the tone of this paper. It seems to have similar findings as the macaque study, yet every point of agreement is couched in politically soft language as if the whole point of the paper was to negate the macaque study. Now researchers can lazily cite this paper instead of the macaque study to support their case for APOBEC restriction and evidence of viral limitation.
    currer likes this.
  17. Jemal

    Jemal Senior Member

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    Thanks for he explanation currer, it makes things more clear for me.
  18. natasa778

    natasa778 Senior Member

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    I would like to see what happens when these animals carrying the persistent virus are exposed to strong immune stressors - say a flu-like virus, active EBV infection, bacterial infections, or (multiple) vaccinations (containing a good measure of immune-stimulating adjuvants). Or what happens when animals are exposed to strong hormonal changes - natural or induced.

    Would this 'safe' retrovirus stay fast asleep in the above situations, or would it wake up and try to spread to new tissue? Which type of tissue would it go for etc. Will APOBEC gene polymorphisms determine in which animals the virus spreads to new tissue. Or will XPR-1 receptor (and other still-to-be-discovered entry receptors) polymorphisms play a role?

    This paper raises many more questions than it answers. Which is the way it should be for science I guess - but the authors should openly admit it and discuss the next step, instead of insinuating this be a conclusive piece.
  19. barbc56

    barbc56 Senior Member

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    I think a study like this would be interesting. While I don't think there would be be a clinical response of illness, if infected with XMRV/HGRVs, even if there is, that would show that it is a compromised immune system or something similar within people with me/cfs that makes them susceptible to these infections/viruses and not the infections/viruses themselves that cause me/cfs.

    This has always been my theory. That it's something in us that makes us come down with viruses that most people don't come down with. What comes to mind is Laura Hildebrand and her repeated strep infections. Most likely it was her immune system that would not eradicate the strep even with antibiotics.

    IMHO, I think this should be the next line of inquiry after the Lipkin study.

    You are absolutely right, there's nothing inherently "bad" about a study that raises questions. As you said this is the way science works. But would it be logical for the scientiest to say what you write above if their study did not come to that conclusion?

    TBH, I need to look at this study in more detail, but these would be my first questions. :>)
  20. barbc56

    barbc56 Senior Member

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    From the study:

    Even if it did escape, xmrv is benign and in fact the study says the following which is just the opposite:

    While I would like to see the whole paper I would speculate the authors felt this was enough time to show that injecting xmrv doesn't harm the monkeys. It would have given the authors a lot of attention, award winning attention if they did find xmrv is harmful, so I think it very unlikely, they would sabotage. their own experiment.

    While xmrv can infect, studies are showing that it doesn't make the macaques ill.

    I do want to reread the comments about the original study and see if any scientiest said this time period was not long enough.
    Firestormm likes this.

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