Viruses circulating in wild and domestic animals pose a constant threat to human health. Identifying human genetic factors that protect against zoonotic infections is a health priority. The RD-114 and Type-D retrovirus (RDR) interference group includes infectious viruses that circulate in domestic cats and various Old World monkeys (OWM), and utilize ASCT2 as a common target cell receptor. While human ASCT2 can mediate RDR infection in cell culture, it is unknown whether humans and other hominoids encode factors that restrict RDR infection in nature. Here we test the hypothesis that Suppressyn, a truncated envelope protein that binds ASCT2 and is derived from a human endogenous retrovirus, restricts RDR infection. Transcriptomics and regulatory genomics reveal that Suppressyn expression initiates in the preimplantation embryo. Loss and gain of function experiments in cell culture show Suppressyn expression is necessary and sufficient to restrict RDR infection. Evolutionary analyses show Suppressyn was acquired in the genome of a common ancestor of hominoids and OWMs, but preserved by natural selection only in hominoids. Restriction assays using modern primate orthologs and reconstructed ancestral genes indicate that Suppressyn antiviral activity has been conserved in hominoids, but lost in most OWM. Thus in humans and other hominoids, Suppressyn acts as a restriction factor against retroviruses with zoonotic capacity. Transcriptomics data predict that other virus-derived proteins with potential antiviral activity lay hidden in the human genome. ### Competing Interest Statement The authors have declared no competing interest.
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