Grant: CIHR REDI Early Career Transition Award - HIV/AIDS and STBBI

Natural control of HIV infection is rare but does occur. It is estimated that less than 1% of HIV-infected individuals will become survivors. Long-term non-progressors (LTNPs), controllers and elite controllers are some of the names given to HIV-infected men and women who manage to prevent HIV's invasion into their immune system. The secrets of these naturally resistant individuals are not fully known, but it is well known that killer T cells play an important role to control HIV replication in these individuals. Most killer T cells are genetically unique and recognize different pieces of foreign proteins. Once a killer T cell recognizes such a foreign protein becomes activated and starts releasing some special toxic materials in order to kill the infected cell. However, in the context of chronic infection such as HIV, these killer T cells become exhausted. It means they won't be able to release these material to kill infected cells. We have discovered that killer T cells in LTNPs through a special mechanism evade exhaustion. In contrast, we have found that another subset of HIV-infected individuals experiences rapid disease progression to AIDS in the absence of treatment. This proposal will build on these observations by defining the molecular mechanism that explains why protective killer T cells do function differently in these two subsets of individuals. We have proposed to perform a wide range of experiments at the cellular and molecular levels to understand the molecular pathways that allow killer T cells to stay protective in one group versus the other. 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 disease.