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Susceptibility of (XMRV) to retroviral restriction factors

Discussion in 'XMRV Research and Replication Studies' started by RedRuth, Jul 23, 2011.

  1. RedRuth

    RedRuth Senior Member

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    I thought this was worth its own thread as it has important implications for the type of cells XMRV can infect and replicate in.
    Apparently both Human and Mouse tetherin/CD317 and APOBEC restrict XMRV efficiently and there doesn't seem to be any viral accessory proteins that counteract these factors (like Vpu - an HIV-1 accessory protein). This is important as PBMCs and all hematopoietic cells express tetherin/CD317. If XMRV is an infective Human virus it's not likely to replicate in these cells. I also know that alot of prostate cancer cell lines don't express tetherin.

    Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors
    http://www.pnas.org/content/107/11/5166.full

  2. eric_s

    eric_s Senior Member

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    This paper is from 2010, are you sure there is not already a thread about it? I have read about it before.
  3. currer

    currer Senior Member

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    Thanks, Redruth,
    This paper comes from last year, but I have a better chance of understanding it now. It will be interesting bedtime reading.
    There may be something more recently published on this subject though, can you find anything?
  4. RedRuth

    RedRuth Senior Member

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    I had a quick look and didn't see a thread then I did a better search and found it. The main reason I posted it though is because I have a research interest in some of the proteins but from a different perspective. But I can ask a mod to delete it, I hadn't seen the paper so I was interested in it.
  5. RedRuth

    RedRuth Senior Member

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    you're welcome, there's usually a 'cited by' list so I'll have a look.
  6. eric_s

    eric_s Senior Member

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    I don't mind, but maybe it's better to continue the discussion in the already existing thread.
  7. RedRuth

    RedRuth Senior Member

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    This is a very recent paper that also looks at restriction factors http://jvi.asm.org/cgi/content/full/85/10/4888 They infected activated PBMCs and cell lines that are +/- for APOBEC proteins with XMRV from 22Rv1 cells and looked at virus replication. A couple of points from the discussion

    and

    Has the Mikovits lab ever reported hypermutated XMRV at GG postions?
  8. currer

    currer Senior Member

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    Hi Redruth,

    The WPI are having trouble getting their research published so no-one knows.

    Thanks for finding this.

    I cant get access to read the whole paper, unfortunately.
  9. alex3619

    alex3619 Senior Member

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    Hi RedRuth, Judy Mikovits did discuss hypermutation at the New York Academy of Sciences workshop some months ago, iirc. They find it all the time, but it does not seem to stop the virus so much as slow it. I do not know if the data was published though. Bye, Alex
  10. Mark

    Mark Acting CEO

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    Regrettably my recollection is hazy once again...but this does seem to be an important area.

    My recollection of the earlier threads from a year or so ago is that there were apparently conflicting results, and that it rather looked to me as though APOBEC inhibits XMRV but also XMRV 'inhibits' APOBEC...I probably have this wrong but my take-home from that discussion was the suggestion that XMRV and the inhibition factors seemed to be locked in battle...

    The hypermutation processes also seemed very significant, and the suggestion that XMRV may be resistant to APOBEC's mutation seemed most intriguing. My layman's understanding (please forgive any inaccurate terminology) was this: APOBEC causes mutations in foreign DNA (from invading retroviruses), by switching (eg) G to A so as to inactivate them....but it has been suggested (but perhaps not published) that these induced mutations in XMRV happen to result in the same proteins, such that XMRV can in certain circumstances be resistant to the hypermutation process. In other words, after the mutations have taken place, the mutated sequence still replicates to produce XMRV again.

    It's probably not quite as I've described, and I'm not sure whether that information was ever published (though I'm pretty sure there was one paper suggesting inhibition of APOBEC itself by XMRV under some circumstances), but: what intrigued me was that if this was indeed the case, then this process would seem to be highly selective for the XMRV sequence, and I wondered whether this could explain the low sequence diversity of XMRV. Such a process would seem to be highly selective of the retroviral sequence, because only very specific sequences would survive the editing process.

    I'd be very interested to hear from RedRuth whether this rough hypothesis makes any sense.

    The other interesting angle was that there may be genetic deficiencies in the APOBEC genes which could explain why some people are more vulnerable to XMRV infection. Once again I'm hazy on the detail, but I seem to remember this APOBEC weakness linking up well with other ME/CFS research.
  11. ggingues

    ggingues $10 gift code at iHerb GAS343 of $40

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    Where is the other thread that this is being discussed on?

    GG
  12. Jemal

    Jemal Senior Member

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    This I remember reading as well. XMRV even spreading (or holding?) into cells that were supposedly protected? But I remember reading about it on other websites I think.
  13. Jemal

    Jemal Senior Member

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  14. RedRuth

    RedRuth Senior Member

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    You mean the Groom et al paper in the OP? APOBEC and tetherin both efficiently restrict XMRV and they found no evidence that XMRV expresses any counter measures (like the vpu protein of HIV) The inference being if XMRV is infecting PBMCs then the host restriction factors expressed by these cells (tetherin and APOBEC) would stop the virus replicating (or to be more precise releasing infective virus particles). Maybe you mean TRIM5 which had no effect on XMRV. This contradicts the Lombardi paper.

    The point of both papers is that XMRV isn't resistant to APOBEC or tetherin.
  15. RedRuth

    RedRuth Senior Member

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    The Groom et al paper shows that XMRV is restricted efficiently by both APOBEC and tetherin but not by TRIM5alpha. And as the say Taken together, these data demonstrate that wild-type XMRV does not encode a human, primate, or murine tetherin antagonist and is, thus, highly sensitive to these restriction factors.

    This was all done in tissue culture cells so the more recent paper went on to look at activated PBMCs infected with XMRV isolated from 22Rv1 cells. Again they found that APOBEC efficiently restricted XMRV but that the hypermutation was variable, however PBMCs aslo express tetherin so there's another line of defence. This directly contradicts the Lomabardi paper as they point out. Our observation that XMRV replication and spread is severely restricted in PHA-activated PBMCs is a novel finding that has not so far been reported. These results are also inconsistent with the report by Lombardi et al.

    They did though find that although there was efficient restriction of XMRV they could infect a co culture of canine cells meaning that there were some viable virus particles present. How physiologically relevant this is I couldn't say (I'm not a virologist) They specualte that PBMCs could be a reservoir or carrier rather than the site of replication.

    EDIT: RE what you said about XMRV 'holding on to cells', this may be a misunderstanding of how tetherin works. Like it's name suggests it tethers nascent virus particles to the host cell membrane as they are trying to bud from the host cell (after replication). The viral particles are then re internalised and degraded by the host cell lysosomes. There's some great EM images of HIV particles 'tethered' to cells in the original Nature paper.
  16. RedRuth

    RedRuth Senior Member

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  17. currer

    currer Senior Member

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    Dr Mikovits remarks about restriction of XMRV are on the thread "XMRV & Blood Supply Webinar March 29" on the media page.
    Alex put up a summary on page 5. The webinar is not publicly available now, so we cannot go back to it.

    On another tack, the webinar mentioned "aerosolizing" suggesting that XMRV might be able to be airborne.
    This is also discussed in this paper - the correspondence about the biosafety level 2 recombinant retrovirus. The Germans who authored the paper say that it is unclear how MLV contaminants spread. They suggest formation of aerosols during the splitting of a contaminated culture and subsequent contamination of cultures splitted in the same tissue culture hood via aerosols. http://www.retrovirology.com/content/6/1/86/comments
  18. Jemal

    Jemal Senior Member

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    Why do I keep running into Dusty Miller?
  19. currer

    currer Senior Member

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    No but this perhaps suggests that XMRV could spread as an airbourne disease. The weakest link in the XMRV argument for me was always the epidemic outbreaks, as this suggested some other virus, an enterovirus perhaps.
    But with the Zhang paper on the contamination problem in the lab, and this german correspondence, perhaps this retrovirus can spread through the air?
    Which will be surprising.
  20. RedRuth

    RedRuth Senior Member

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    Did she mean APOBEC induced hypermutation? APOBEC is only one of the lines of defence against retroviral infection though. BTW, someone said you had posted a summary of what she had to say about restriction factors but I can't find it. Any chance you could point me in the right direction?

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