Project 172242

With over 30 million people living with HIV/AIDS globally, the need for an HIV vaccine has never been so urgent. Yet the recent failure of a major phase 2b vaccine trial highlights the sobering reality that 25 years after the discovery of HIV, we are nowhere close to a vaccine. In response to major knowledge gaps in our understanding of HIV immunobiology, experts are now calling for a major paradigm shift "back to the basics of vaccine research". One of the major challenges is the virus' extreme mutational capacity, which allows the virus to escape recognition by the immune system. Understanding how HIV adapts to immune responses will help us design better vaccines. Specialized immune cells called "killer" T-cells eliminate HIV-infected cells by recognizing small viral fragments presented by Human Leukocyte Antigen (HLA) molecules on the infected cell surface. Possession of certain HLA molecules is associated with slower rates of HIV disease progression, although the reasons behind this are not well understood. It has been hypothesized that certain "protective" HLA molecules mediate a particularly strong and effective immune response that selects for escape mutations that compromise the virus' ability to replicate. The resulting "disabled" virus yields a more benign disease course. If substantiated, this hypothesis could have important implications for vaccine design. This proposal represents the first large-scale study investigating the impact of immune escape mutations on viral replicative capacity in HIV sequences obtained from infected patients. The identification of specific escape mutations that influence HIV replication capacity (and the HLA molecules that drive these changes) will help illuminate which parts of the virus would be most important to include in future vaccine strategies.