Innate Immunity and Autophagy in Elite Controllers

Scott Killian, University of California, San Francisco
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)

Acquired immune deficiency syndrome (AIDS) is a lethal disease caused by the human immunodeficiency virus (HIV). In the absence of antiviral drugs, most HIV-infected individuals develop AIDS within 10 years of infection. This is due to the general inability of immune responses to eliminate HIV and the resulting persistence of harmful virus. However, rare HIV-infected individuals have been identified who naturally control HIV replication. Remarkably, these elite controllers (EC) maintain undetectable levels of HIV and can remain AIDS-free for more than 20 years. To date, the biologic mechanisms that distinguish EC from other HIV-infected individuals have not been determined. We reason that important clues, necessary for the development of an effective HIV vaccine and improved drug therapies, are concealed in the blood of EC.

The overall goals of this study are to identify the major biologic factors that distinguish elite controllers. Our specific aims are 1) to investigate the hypothesis that elite controllers feature superior innate immune responses against HIV infection and 2) to investigate the hypothesis that autophagy is a major determinant of HIV replication levels in elite controllers. We anticipate that the insight gained from this study will direct the development of clinical approaches to mirror the protective features of EC in other HIV-infected individuals and in those at risk for HIV infection.

The proposed study is ideally suited for the CHRP IDEA Award mechanism. The specific aims are novel with respect to the fact that they have not been addressed in EC. In addition, this is pilot study will be carried out by a new investigator.

Finally, this study is directly relevant to California’s HIV/AIDS crisis and its need for the improved prevention and treatment of HIV infection. Traditional vaccine approaches have not been successful. Therefore, focus must be given to studies that identify natural correlates of protection from HIV infection and disease. In this regard, the proposed study will identify new trajectories for vaccine development, particularly those that target non-classical immune responses.