Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

A very small percentage of people (e.g., 1 percent) who are infected with HIV will not develop AIDS. These people have a natural immunity that prevents this. Long-term non-progressors and elite controllers are some of the terms used to describe HIV-infected patients who manage to control HIV's invasion into their immune system. The secrets of these 'naturally resistant' individuals are not fully known. However a certain cell type, (killer T cells) play an important role in controlling HIV replication. In an exciting novel finding, my group discovered a mechanism which could explain how HIV infection progresses to AIDS in most people and why a few are spared. Essentially, we have found that certain killer T cells are genetically different in controllers. Therefore, the killer T cells continue to function at a high level and destroy HIV infected cells to ensure that the virus cannot reproduce to the extent that is associated with HIV progression. We will use molecular biology techniques to investigate how killer T cells interact with other immune system components and identify what features within the killer T cells successfully prevent progression of HIV infection to the point of full blown disease. We have proposed to perform a wide range of experiments to understand the molecular signaling pathways that: 1) Allow killer T cells to stay protective in long-term non-progressors? 2) Determine what the structural differences are between protective and non-protective killer T cells? 3) Why some of these naturally protected individuals will ultimately experience progression to AIDS? Addressing these questions will allow us to understand how to manipulate non-protective killer T cells to become protective. Thus, this study can lead to novel therapeutic interventions and vaccines to prevent the progression of HIV-1 disease in chronically infected individuals and have far-reaching implications for chronic infection, autoimmunity, and cancer.