Albin, John Squire2014-12-152014-12-152012-10https://hdl.handle.net/11299/168149University of Minnesota Ph.D. dissertation. October 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor: Reuben S. Harris. 1 computer file (PDF); xviii, 349 pages, appendix 1.The human immunodeficiency virus accessory protein Vif protects the viral genome from the mutational activity of APOBEC3 subfamily DNA cytosine deaminases by facilitating their proteasomal degradation, thereby preserving viral infectivity. A comprehensive understanding of the components of the Vif-APOBEC3 interaction is therefore important for consideration of the potential for novel antiretroviral approaches aimed at modulating this critical host-pathogen interaction. Here, we establish APOBEC3F among the seven subfamily members as a valid model for the study of the APOBEC3-Vif interaction. By utilizing this model as a starting point, we further define the APOBEC3-Vif interaction sites in each protein and the downstream ubiquitin acceptor sites modified en route to APOBEC3 degradation, in the process deriving broader insights into the nature of the interactions between different APOBEC3 proteins and Vif. In contrast with the diversiform APOBEC3-Vif interactions proposed in the extant literature, we find that the interaction of Vif with different APOBEC3 proteins likely proceeds through a conserved helix-helix interaction. Even if one were to successfully block this interaction for therapeutic purposes, however, the virus may develop accessory mechanisms of APOBEC3 evasion to bypass the intervention. While we find that this can occur, present evidence suggests that such alternatives may be insufficient to circumvent restriction in cells that naturally express multiple APOBEC3 proteins. Thus, it may be possible to potentiate the action of multiple endogenous antiretroviral proteins to counteract human immunodeficiency virus infection by targeting a conserved interaction motif as described herein.enAPOBEC3APOBEC3FAPOBEC3GHIVHuman immunodeficiency virus,VifMicrobiology, immunology and cancer biologyThesis or Dissertation