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)...

One contribution of 13 to a Theme Issue 'Paleovirology: insights from the genomic fossil record'. The development of the emerging field of 'paleovirology' allows biologists to reconstruct the evolutionary history of fossil endogenous retroviral sequences integrated within the genome of living organisms and has led to the retrieval of conserved, ancient retroviral genes 'exapted' by ancestral hosts to fulfil essential physiological roles, syncytin genes being undoubtedly among the most remarkable examples of such a phenomenon. Indeed, syncytins are 'new' genes encoding proteins derived from the envelope protein of endogenous retroviral elements that have been captured and domesticated on multiple occasions and independently in diverse mammalian species, through a process of convergent evolution. Knockout of syncytin genes in mice provided evidence for their absolute requirement for placenta development and embryo survival, via formation by cell-cell fusion of syncytial cell layers at the fetal-maternal interface. These genes of exogenous origin, acquired 'by chance' and yet still 'necessary' to carry out a basic function in placental mammals, may have been pivotal in the emergence of mammalian ancestors with a placenta from egg-laying animals via the capture of a founding retroviral env gene, subsequently replaced in the diverse mammalian lineages by new env-derived syncytin genes, each providing its host with a positive selective advantage.