We have previously demonstrated that the envelope proteins of a murine and primate retrovirus are immunosuppressive in vivo. This property was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to have the env-expressing cells escape (at least transiently) immune rejection. Here, we analyzed the immunosuppressive activity of the human and murine syncytins. These are envelope genes from endogenous retroviruses independently coopted by ancestral hosts, conserved in evolution, specifically expressed in the placenta, and with a cell-cell fusogenic activity likely contributing to placenta morphogenesis. We show that in both humans and mice, one of the two syncytins (human syncytin-2 and mouse syncytin-B) is immunosuppressive and, rather unexpectedly, the other (human syncytin-1 and mouse syncytin-A) is not (albeit able to induce cell-cell fusion). Delineation of the immunosuppressive domain by deletion analysis, combined with a comparison between immunosuppressive and nonimmunosuppressive sequences, allowed us to derive a mutation rule targeted to specific amino acids, resulting in selective switch from immunosuppressive to nonimmunosuppressive envelope proteins and vice versa. These results unravel a critical function of retroviral envelopes, not necessarily ''individually'' selected for in the retrovirus endogenization process, albeit ''tandemly'' conserved in evolution for the syncytin pairs in primates and Muridae. Selective inactivation of immunosuppression, under conditions not affecting fusogenicity, should be important for understanding the role of this function in placental physiology and maternofetal tolerance.endogenous retrovirus ͉ fusogenicity ͉ immunosuppression ͉ HERV T he placenta is an autonomous and transient organ essentially intended for feeding and oxygenating the embryo and the fetus during intrauterine life. In several mammalian species, including Homo sapiens, the fusion of trophoblastic cells into a multinucleated layer called syncytiotrophoblast constitutes a key process of placental morphogenesis. The syncytiotrophoblast, being the main maternofetal barrier in direct contact with maternal blood, performs the essential trophic exchange functions between mother and fetus, along with the secretion of hormones and growth factors, maintenance of homeostasis, and the necessary inhibition of the mother's immune response against the allogeneic determinants of the fetus (1-3).Little is known about the molecular mechanisms involved in trophoblastic differentiation. However, a major advance has been made by the identification of envelope (Env) proteins encoded by endogenous retroviruses (ERVs) and likely involved in the formation of the syncytiotrophoblast (4-7). The human and murine genomes indeed harbor thousands of ERV elements that display a structure close to that of the integrated proviral form of exogenous retroviruses and that most probably are the remnants of past infections of the germ line by ancestral retroviruses (8-11)...
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 envelopemediated 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.infectious retrovirus | immunosuppression | innate immunity | adaptive immunity | vaccination
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