Grant: Operating Grant - PA: CHVI Vaccine Discovery and Social Research

APOBEC3 enzymes are expressed in cells that are targets of HIV infection. These enzymes attack the DNA copy of HIV after it infects the cell. Consequently, they restrict the replication of HIV in experimental systems that measure infection of cultured cells outside the body. Therefore, APOBEC3s have been perceived as a first line of defense against viral replication, whilst more specific anti-HIV immunity takes weeks-months to develop. The discovery of these enzymes less than a decade ago led to the promise of new anti-viral therapies based on manipulating their activities. On the other hand, it has recently become appreciated that the activity of APOBEC3s is actually subverted to a large extent by HIV towards its own benefit. Thus, the role of A3G/F in HIV infection is more complex than heretofore appreciated. We are interested in the impact of APOBEC3 activity on the recognition of HIV-infected helper T cells by anti-viral cytotoxic T cells, which is one of the most important facets of the anti-viral immune response. To date, two studies have examine this role: One utilized a bioinformatics approach and reported that APOBEC3-induced mutations help HIV escape from the immune system, whist another study using mice found the opposite result. Because of their experimental design, both studies have inherent biases: the first towards detection of the pro-virus activities of APOBEC3s and the second towards the detection of their pro-immune system activities. Importantly, the impact of APOBEC3-induced mutations on cytotoxic T cells in human patients has not been examined. In this proposal, we aim to examine the extent and mechanisms through which APOBEC3-induced mutations modulate the immune response in HIV+ individuals. Our results will inform us and other researchers whether modulating APOBEC3 activity can be an effective approach of HIV therapy, and if so, how to modify their activity such that optimal gain goes to the immune system rather than the virus.