Naturally circulating lentiviruses are abundant in African primate species today, yet their origins and history of transmitting between hosts remain obscure. As a means to better understand the age of primate lentiviruses, we analyzed primate genomes for signatures of lentivirus-driven evolution. Specifically, we studied the adaptive evolution of host restriction factor APOBEC3G ( A3G) in Old World Monkey (OWM) species. We find recurrent mutation of A3G in multiple primate lineages at sites that determine susceptibility to antagonism by the lentiviral accessory protein Vif. Using a broad panel of SIV Vif isolates, we demonstrate that natural variation in OWM A3G confers resistance to Vif-mediated degradation, suggesting that adaptive variants of the host factor were selected upon exposure to pathogenic lentiviruses at least 5–6 million years ago (MYA). Furthermore, in members of the divergent Colobinae subfamily of OWM, a multi-residue insertion event in A3G that arose at least 12 MYA blocks the activity of Vif, suggesting an even more ancient origin of SIV. Moreover, analysis of the lentiviruses associated with Colobinae monkeys reveal that the interface of the A3G-Vif interaction has shifted and given rise to a second genetic conflict. Our analysis of virus-driven evolution describes an ancient yet ongoing genetic conflict between simian primates and lentiviruses on a million-year time scale.
The emergence of AIDS in the late 20 th century has provoked studies to better understand the evolutionary history of viruses and the factors that govern their spread. Pandemic human immunodeficiency virus-type 1 (HIV-1), which currently infects 34 million people worldwide, emerged following the transmission of a lentivirus between chimpanzees and humans. A growing list of apparently nonpathogenic, species-specific strains has now been characterized in dozens of African primates, suggesting that primate lentiviruses are older and more widespread than originally thought. To estimate the extent to which primates and lentiviruses have coexisted, we examined the interaction between host and virus on a molecular level and tracked its dynamics over evolutionary time. We report that the immunity factor APOBEC3G is evolving in tandem with the lentiviral accessory gene vif, allowing us to associate instances of host evolution with instances of lentivirus infection in deep and shallow timescales. Specifically, we show that the region of APOBEC3G targeted by Vif is adaptively diversifying in independent primate lineages in a manner that suggests that lentiviruses are millions of years old. Our study reveals that, while primate lentiviruses may have modern consequences for human health, they have ancient origins in our non-human primate relatives.