Frank, John Anthony2020-08-102021-06-082020-05Frank_cornellgrad_0058F_11962http://dissertations.umi.com/cornellgrad:11962https://hdl.handle.net/1813/7040089 pagesViruses circulating in non-human populations have the potential to infect humans in a process defined as zoonosis. Zoonotic infections can dramatically impact human health and the evolution of human immune factors. Endogenous retroviruses (ERV), which are remnants of ancestral germline insertions, provide a reservoir of protein-coding material with the potential to be domesticated for host cellular functions. ERV-derived envelope (env) proteins have been reported to confer resistance to exogenous retroviral infection in several vertebrates. While previous studies have shown ERV env restrict exogenous retroviral infection in non-human organisms, there is no direct evidence of human ERV env conferring resistance to extant retroviruses. We hypothesize that a subset of HERV env may function as antiviral factors against potentially zoonotic retroviruses. To address this hypothesis, we investigated a truncated and placentally expressed human ERVenv, Suppressyn (SUPYN). SUPYN binds the cell surface amino acid transporter ASCT2, which is the target receptor for diverse mammalian retroviruses dubbed the RD114 and Type-D retrovirus (RDR) interference group. RDRs are known to circulate in Old World monkeys as well as domestic cats and can infect human cells. Here we report SUPYN expression initiates in the human preimplantation embryo and persists through human placental development. We show SUPYN is necessary and sufficient to restrict RDRenv mediated cell entry. Our evolutionary sequence analyses indicate SUPYN was acquired in the common ancestor of Catarrhine primates and preserved by natural selection in Apes, where its antiviral activity is conserved. Our data suggest SUPYN can protect the developing fetus from zoonotic retroviral infection and potential invasion of the nascent germline. SUPYN represents the first example of a human virus-derived protein with antiviral activity against extant exogenous viruses and implies that our genomes may harbor further virus-derived genes with antiviral activity.enAttribution 4.0 Internationalantiviralendogenous retrovirusevolutionplacentarestriction factordissertation or thesishttps://doi.org/10.7298/k8jc-3f24