Switching off immunosuppression - Enter Dr. Coffin

jace

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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
 

Rrrr

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

thanks!
rrrr
 
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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
 

richvank

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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
 

Hope123

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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.