Abstract Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented in human. We report that our genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To further test this, we characterize in detail the envelope-derived protein, Suppressyn . We found that Suppressyn is expressed in preimplantation embryos and developing placenta using its ancestral retroviral promoter. Restriction assays in cell culture show that Suppressyn , and its hominoid orthologs, can restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope cooption for host immunity and genome defense. Summary We found that the human genome expresses a vast pool of envelope sequences of retroviral origin and provide proof of principle that such proteins can restrict zoonotic viruses.

Evolution and antiviral activity of a human protein of retroviral origin