Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements

Human Endogenous Retroviruses are expected to be the remnants of ancestral infections of primates by active retroviruses that have thereafter been transmitted in a Mendelian fashion. Here, we derived in silico the sequence of the putative ancestral “progenitor” element of one of the most recently amplified family—the HERV-K family—and constructed it. This element, Phoenix, produces viral particles that disclose all of the structural and functional properties of a bona-fide retrovirus, can infect mammalian, including human, cells, and integrate with the exact signature of the presently found endogenous HERV-K progeny. We also show that this element amplifies via an extracellular pathway involving reinfection, at variance with the non-LTR-retrotransposons (LINEs, SINEs) or LTR-retrotransposons, thus recapitulating ex vivo the molecular events responsible for its dissemination in the host genomes. We also show that in vitro recombinations among present-day human HERV-K (also known as ERVK) loci can similarly generate functional HERV-K elements, indicating that human cells still have the potential to produce infectious retroviruses

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

Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants

International audienceSyncytins are envelope genes of retroviral origin that have been co-opted for a role in placentation and likely contribute to the remarkable diversity of placental structures. Independent capture events have been identified in primates, rodents, lagomorphs, and carni-vores, where they are involved in the formation of a syncytium layer at the fetomaternal interface via trophoblast cell-cell fusion. We searched for similar genes within the suborder Ruminantia where the placenta lacks an extended syncytium layer but displays a heter-ologous cell-fusion process unique among eutherian mammals. An in silico search for intact envelope genes within the Bos taurus ge-nome identified 18 candidates belonging to five endogenous retro-virus families, with one gene displaying both placenta-specific expression, as assessed by quantitative RT-PCR analyses of a large panel of tissues, and conservation in the Ovis aries genome. Both the bovine and ovine orthologs displayed fusogenic activity by conferring infectivity on retroviral pseudotypes and triggering cell-cell fusion. In situ hybridization of placenta sections revealed specific expression in the trophoblast binucleate cells, consistent with a role in the formation-by heterologous cell fusion with uterine cells-of the trinucleate cells of the cow and the syncytial plaques of the ewe. Finally, we show that this gene, which we named "Syncytin-Rum1," is conserved among 16 representatives of higher ruminants, with evidence for purifying selection and conservation of its fusogenic properties, over 30 millions years of evolution. These data argue for syncytins being a major driving force in the emergence and diversity of the placenta. synepitheliochorial | placental evolution | phylogeny | placentome | ER