Grant: Operating Grant

The human immunodeficiency virus type 1 (HIV) establishes a lethal infection by mechanisms that are not clearly understood and viral eradication is not achieved under the current antiretroviral therapies (ART). HIV infection is associated with a rapid depletion of memory CD4+ T-cells from the gut-associated lymphoid tissues (GALT), impaired mucosal integrity, and microbial translocation from the gut. These alterations are a cause for chronic immune activation and disease progression in HIV-infected individuals, including subjects with slow disease progression. Among CD4+ T-cells, Th17 cells play a critical role in maintaining mucosal barrier integrity and immunity against bacterial pathogens. Th17 cells are preferentially depleted from the GALT of HIV-infected individuals and their functional restoration under long-term ART is only partial. We and others demonstrated that Th17 cells are highly permissive to HIV infection. However, in preliminary studies we identified a new Th17 subset that is preserved during disease progression and is potentially resistant to HIV infection. Our hypothesis is that HIV infects some but not all Th17 subsets. We propose to identify molecular mechanisms underlying differences in immunological function and viral permissiveness between Th17 subsets. This research proposal will reveal new therapeutic strategies to prevent HIV replication in Th17 cells, while improving their role in mucosal immunity.