| The apparent success of Simian Immunodeficiency Viruses (SIVs) in establishing the human epidemics HIV-1 and HIV-2 may be the result of the superior genetic capabilities of RNA viruses, in which a high replication rate allows rapid diversification among virus populations. Natural reservoir hosts of SIV, such as sooty mangabeys, maintain high levels of viral replication and diversification, but do not develop disease. Thus, the experiments described in this dissertation sought to: (1) determine the characteristics of SIV in natural hosts that may facilitate cross-species transmission, (2) determine the evolutionary pattern of SIV seen upon transmission to a new host, (3) visualize specific viral evolutionary patterns that may contribute to pathogenesis, and (4) determine host-mediated selection pressure on specific regions of the SIV genome to explore the relative importance of various SIV-specific immune responses in each experimental setting.; This dissertation examines the patterns of SIV evolution in three different models of SIV infection. Chapter 1 compared patterns of viral evolution during acute and chronic infection of natural and non-natural hosts infected with a diverse quasispecies inoculum. The second study, Chapter 2, analyzed patterns of viral diversity in sooty mangabey hosts naturally infected with SIV for more than 10 years. Finally, Chapter 3 describes viral evolution in rhesus macaques infected with the molecular clone, SIVmac239, whose SIV-specific immune responses were abrogated by administration of molecules that blocked T-cell costimulation. These studies have helped us to reject virological factors and point us toward host-induced immunological factors as the main contributor to HIV/SIV pathogenesis. |
