Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses.
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.
Unité Mixte de Recherche 8122 Institut Gustave Roussy, 94805 Villejuif, and Université Paris-Sud, 91405 Orsay, France.
Géraldine
G
Schlecht-Louf
Martial
M
Renard
Marianne
M
Mangeney
Claire
C
Letzelter
Aurélien
A
Richaud
Bertrand
B
Ducos
Isabelle
I
Bouallaga
Thierry
T
Heidmann
D000818:Animals; D005622:Friend murine leukemia virus / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D007942:Leukemia, Experimental / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D041681:NIH 3T3 Cells; D012192:Retroviridae Infections / Q000276:immunology* / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014412:Tumor Virus Infections / Q000276:immunology* / Q000517:prevention & control; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
D014759:Viral Envelope Proteins; D014765:Viral Vaccines; D037521:Virulence Factors