The Impact of Host Factors on Retroviral Evolution and the Identification of a Novel Receptor That Was Used by an Ancient Primate Retrovirus

The resurrection of inactive endogenous retroviruses allows us to learn about interactions between extinct pathogens and their hosts that occurred millions of years ago. Two of these paleoviruses, chimpanzee endogenous retrovirus 1 and 2 (CERV1 and CERV2), are relatives of modern murine leukemia viruses that are found in the genomes of a variety of old world primates, but are absent from the human genome. The nonexistence of human CERV1 and CERV2 homologues is peculiar given the numerous apparent cross-species transmissions that occurred between ancestors of old world monkeys, gorillas, and chimpanzees. It is possible that antiviral proteins were able to protect human ancestors from colonization by CERV1 and CERV2. Indeed, sequence analyses of modern primate restriction factors has suggested that these genes have evolved under positive selection, presumably due to their combat with invading pathogens throughout primate history. Here we investigate whether TRIM5 and APOBEC3 antiviral factors were able to restrict the replication of CERV1 and CERV2. Such an interaction would imply a potential involvement of these proteins in the limited host range and, perhaps, even the extinction of CERV1 and CERV2. Reciprocally, activity against CERV1 and CERV2 would suggest that archaic gammaretroviruses contributed to the positive selection observed in TRIM5 and APOBEC3 genes. Our analyses suggest that TRIM5 proteins did not pose a major barrier to the cross-species transmission or contributed to the extinction of CERV1 and CERV2. However, we uncovered extensive evidence for the inactivation of endogenous gammaretroviruses by the action of APOBEC3 cytidine deaminases. Both CERV1 and CERV2, as well as their homologues in the rhesus macaque, bore mutational scars that are characteristic of APOBEC3 activity. A reconstructed CERV2 Gag was used in vitro to confirm that APOBEC3G was capable of restricting CERV2 infection. Therefore, it appears that primate APOBEC3 proteins were capable of targeting ancient primate gammaretroviruses. It remains possible that APOBEC3 proteins were able to limit the cross-species transmission and cause the inactivation of these viruses