Proc Natl Acad Sci U S A. 2010 Feb 8. [Epub ahead of print]
Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses.
Schlecht-Louf G, Renard M, Mangeney M, Letzelter C, Richaud A, Ducos B, Bouallaga I, Heidmann T. Unit des Rtrovirus Endognes et Elments 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.
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. PMID: 20142478
Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses.
Schlecht-Louf G, Renard M, Mangeney M, Letzelter C, Richaud A, Ducos B, Bouallaga I, Heidmann T. Unit des Rtrovirus Endognes et Elments 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.
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. PMID: 20142478
. But it sounds impressive. It also says; real scientists - working to help sick people. It gives a lot of hope...I think. Thank you for this Natasha. I think this thread will go viral.:Sign Good one:
