Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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Switching off immunosuppression - Enter Dr. Coffin

Discussion in 'XMRV Research and Replication Studies' started by jace, Jun 8, 2010.

  1. jace

    jace Off the fence

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    England
    Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses
    Graldine Schlecht-Loufa,b,1
    Martial Renarda,1
    Marianne Mangeneya,1
    Claire Letzeltera
    Aurlien Richauda
    Bertrand Ducosa
    Isabelle Bouallagaa and
    Thierry Heidmanna,2
    + Author Affiliations

    1. aUnit des Rtrovirus Endognes et lments Rtrodes des Eucaryotes Suprieurs, Centre National de la Recherche Scientifique, Unit Mixte de Recherche 8122 Institut Gustave Roussy, 94805 Villejuif, and Universit Paris-Sud, 91405 Orsay, France; and
    2 bFacult de Mdecine Paris-Sud, Universit Paris-Sud, 94276 Le KremlinBictre cedex, France
    1. Edited* by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved January 6, 2010 (received for review November 13, 2009)
    2. G.S.-L., M.R., and M.M. contributed equally to this work.

    Abstract
    We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins (Envs). The envelope-mediated immunosuppression was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection.

    Using this approach, we identified key residues whose mutation specifically abolishes IS activity without affecting the mechanical fusogenic function of the entire envelope. Here, we genetically switched off the envelope-mediated immunosuppression of an infectious retrovirus, the Friend murine leukemia virus, while preserving mutant envelope infectivity both ex vivo and in vivo, thus allowing us to test the functional importance of envelope-mediated immunosuppression in retrovirus physiology.

    Remarkably, we show, in vivo, that the non-IS mutant virus displays the same propagation kinetics as its WT counterpart in irradiated immunocompromised mice but that it is rapidly and totally cleared from normal immunocompetent mice, which become fully protected against a challenge with the WT retrovirus. Using cell depletion strategies, we further establish that envelope-mediated immunosuppression enables the retrovirus to escape innate (natural killer cells) and adaptive (CD8 T cells) antiviral effectors. Finally, we show that inactivated mutant virions induce higher humoral and cellular responses than their WT counterparts.

    In conclusion, our work demonstrates the critical role of Env-induced immunosuppression for retrovirus propagation in vivo and identifies a unique definite target for antiretroviral therapies and vaccine strategies, also characterized in the human T-cell leukemia virus (HTLV) and xenotropic murine leukemia virus-related virus (XMRV) retroviruses, opening unprecedented prospects for the treatment of retroviral diseases.

    http://www.pnas.org/content/early/2...ract?sid=291cc061-9f11-4858-8e6f-cdac6f33d3cc

    posted by jace with permission from Gerwyn
     
  2. Stone

    Stone Senior Member

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    NC
    This is fantastic! Glad to see this! Thnaks jace and Gerwyn!
     
  3. SpecialK82

    SpecialK82 Ohio, USA

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    Wow - really cool, thanks for posting!
     
  4. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    Hi Jace,

    One word: vaccine.

    Bye
    Alex
     
  5. Rrrr

    Rrrr Senior Member

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    what does this coffin paper saying? what does it mean? anyone up for translating?

    thanks!
    rrrr
     
  6. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Clay, Alabama
    Didn't understand any of it but this:

    "...identifies a unique definite target for antiretroviral therapies and vaccine strategies, also characterized in the human T-cell leukemia virus (HTLV) and xenotropic murine leukemia virus-related virus (XMRV) retroviruses, opening unprecedented prospects for the treatment of retroviral diseases."

    And I like the part I understand.

    Tina
     
  7. Forebearance

    Forebearance Senior Member

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    So is this paper saying that we could try to find a way to mess up the retroviruses' invisibility cloaks that keep them unnoticed by the immune system?
     
  8. richvank

    richvank Senior Member

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    Hi, Forebearance.

    Yes, I think that's basically it. According to this abstract, part of the protein that makes up the envelope around these retroviruses is able to suppress the immune response of the host. The researchers were able to mutate this part of the protein and make a retrovirus that was still able to function as a retrovirus, but was no longer able to suppress the immune system, as the original "wild type" retrovirus was able to do.

    What's more, when normal mice had been subjected to this mutated retrovirus, their immune systems were then able to protect them from the original retroviruses. This suggests that the mutated retroviruses could serve as the basis for making a vaccine.

    This sounds like a very important development.

    Rich
     
  9. Rrrr

    Rrrr Senior Member

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    thanks, fore and rich, for your smarts! -- rrrr
     
  10. Hope123

    Hope123 Senior Member

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    This is an older paper from February that was discussed on this forum earlier this year. I'm too tired to pull it up but if you search, you can find the old discussion.
     
  11. Rrrr

    Rrrr Senior Member

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