Because the gastrointestinal mucosa is a critical early site of viral replication and CD4 T-cell depletion, as well as the largest lymphoid organ in the body, assessment of the adaptive immune mechanisms functioning in this tissue may provide important new insights relevant to our understanding of the host-pathogen relationship. Our studies to date indicate that a robust, often polyfunctional CD8 T-cell response is mounted in gut mucosa during chronic HIV infection. We will build upon prior studies to test three complementary hypotheses concerning the role of mucosal immunity in HIV pathogenesis. Our studies will focus on (1) Polyfunctional mucosal T-cells as an immune correlate of non-progression; (2) The effects of antiretroviral therapy (ART) on CD8 T-cell phenotype and function in the gut; and (3) The role of mucosal regulatory T-cells in shaping polyfunctional adaptive immune responses. These studies will be conducted on paired blood and mucosal samples from HIV+ subjects on and off ART, including a well-characterized group of HIV controllers, and healthy controls.

Taken together, these studies should greatly advance our understanding of the HIV-host relationship in mucosal tissues during chronic infection.