Dynamics of the mammalian APOBEC3 locus and the relationship between mammalian APOBEC3 and Lentiviral Vif proteins.

Abstract

The mammalian immune system must be dynamic in the face of a diverse and ever-changing array of pathogens. Successful pathogens have evolved to overcome host immunity. One of the most successful pathogens in the last century is the human immunodeficiency virus (HIV), which is the etiological agent responsible for the global acquired immune deficiency syndrome (AIDS) epidemic. Currently, one of the most studied host-pathogen interactions is between the cellular anti-retroviral APOBEC3 (A3) proteins and HIV viral infectivity factor (Vif) protein. A3 proteins are cytosine deaminases that primarily inhibit retroviruses and retrotransposons by mutating cytosines to uracils in retroviral DNA during reverse transcription. When HIV Vif is present, it can bind to certain A3 proteins and recruit cellular degradation complexes to target these anti-retroviral proteins for proteasomal degradation. HIV-like viruses (lentiviruses) infect other mammals and are the inspiration for studying A3 proteins in other mammals. The ultimate goal of this comparative study was to gain a better understanding of how the lentiviral Vif protein counteracts host A3 proteins. The first component of this dissertation is dedicated to the process of determining the complete A3 protein repertoires of cow and sheep (representatives of the artiodactyl lineage), which are both infected with a lentiviruses. The second component of this dissertation was to test if these artiodactyl A3 proteins were functional. Cow and sheep A3 proteins demonstrate intrinsic DNA cytosine deaminase activity and localize in cells similar to human A3 proteins. Furthermore, certain cow A3 proteins are capable of restricting HIV and are neutralized in the presence of cattle-specific lentiviral Vif (bovine immunodeficiency virus). The last component of this dissertation, a panel of conserved mammalian A3 proteins were tested to determine if each A3 protein interacts specifically with its species lentiviral Vif protein. It was shown that each representative host A3 protein is degraded in the presence of its species specific lentiviral Vif, suggesting a conserved interaction between mammalian A3 proteins and their species specific lentiviral Vif protein.