Title: The role of APOBEC3G and APOBEC3F in HIV-1 pathogenesis
Description: AIDS remains a major global public health issue. Since the discovery of HIV over twenty years ago, much has been learned about its pathogenesis, and this knowledge has led to the development of drugs that have helped to reduce AIDS-related mortality among infected people. Despite advances in understanding of HIV-1 pathogenesis, many aspects of HIV-1 pathogenesis remain unknown; for example, it is not well understood why some infected individuals develop AIDS after short time (about 3 years) of being infected while others remain healthy without any AIDS symptoms for over 15 years. Both viral and host factors are thought to determine the pathogenesis of HIV-1. Recently host factors APOBEC3G and APOBEC3F have been shown to restrict HIV-1 viral replication. Despite potent antiviral activities displayed by both APOBEC3G and APOBEC3F, their influence on viral replication and overall HIV-1 pathogenesis among infected individuals is not known. The goal of this dissertation was to explore the role of APOBEC3G and APOBEC3F in pathogenesis of HIV-1. We first examined the association between APOBEC3G and APOBEC3F and HIV-1 viral setpoint. We found a significant inverse correlation between the levels of APOBEC3G expression and the viral setpoint. We also observed a significant increase in expression of both APOBEC3G and APOBEC3F after HIV-1 infection. This study established that HIV-1 stimulates expression of APOBEC3G and APOBEC3F; it also elucidated the association between APOBEC3G and viral setpoint.

Second, we analyzed the APOBEC mediated G-to-A mutations among HIV-1 infected individuals. We found that there was a significant correlation between the levels of APOBEC3G and G-to-A mutations; however, there was no correlation between the viral load and G-to-A mutations. We also examined the relationship between APOBEC levels and the levels of viral DNA. We found a significant inverse correlation between the amount of total viral DNA and the levels of APOBEC3F mRNA. In conclusion, our findings demonstrate that both APOBEC3G and APOBEC3F interact with HIV-1 in infected patients and might play a role in pathogenesis of HIV-1. This idea is supported by the presence of APOBEC mediated G-to-A mutations in HIV-1 sequences isolated from patients and the inverse correlation between the levels APOBEC3G mRNA and the viral setpoint.