Emerman, MichaelCompton, Alex2013-04-172013-04-172013-04-172012Compton_washington_0250E_11137.pdfhttp://hdl.handle.net/1773/22587Thesis (Ph.D.)--University of Washington, 2012The emergence of AIDS in the early 20th 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 simian strains (known as Simian Immunodeficiency Virus) 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, and to determine whether past and present lentivirus infections exhibit pathogenesis, we tracked the interaction between host and virus on a molecular level over evolutionary time. Specifically, we characterized the lentivirus-driven evolution of host restriction factor APOBEC3G (A3G) in Old World Monkey (OWM) species. We found that residues 128 and 130 of A3G, which determine susceptibility to antagonism by the lentiviral accessory protein Vif, are undergoing recurrent adaptive evolution in both ancestral and contemporary primate populations. We used a broad panel of SIV Vif isolates to 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 approximately 12 MYA blocks the activity of Vif, suggesting an even more ancient origin of SIV. In response to these two adaptive strategies employed by OWM hosts, Vif proteins have counter-evolved to target distinct surfaces of the A3G substrate. Furthermore, some Vif proteins, like that of SIVsm infecting sooty mangabeys, have evolved broad specificity that may facilitate cross-species transmission events. Our findings support that a genetic conflict between primates and lentiviruses has been underway for millions of years and continues to this day. The ancient and ongoing conflict we described may have important implications for our understanding of HIV pathogenesis and spread in human populations. Our studies reveal that, while primate lentiviruses may have modern consequences for human health, they have ancient origins in our non-human primate relatives.application/pdfen-USCopyright is held by the individual authors.APOBEC3; host-pathogen interactions; human immunodeficiency virus; innate immunity; lentivirus; virus evolution and host adaptationVirologyEvolution & developmentImmunologymolecular and cellular biologyThesis