T cell dysfunction upon ongoing antigen exposure is a cardinal feature of chronic infections and cancer inanimals and humans, leading to T cell impairment and failure to eliminate virus or tumor cells. Thesedefective T cell responses are thought to play a major role in HIV infection and progression to AIDS.Previous work performed at our center and by other investigators of this program grant has shown in bothHIV infection and animal models that the Programmed Death-1 (PD-1) pathway is a crucial mediator of T celldysfunction, and that blocking this pathway can reinvigorate CD8 (CTL) and CD4 T cell responses. PD-1, itsligands PD-L1 and PD-L2, and the PD-L1 ligand CD80 participate in a network of pathways that modulate Tcell function The goal of this proposal is to elucidate the role of PD-1 and its ligands in AIDS-related Tcell dysfunction; successful achievement of these aims will help guide the design of new clinicalinterventions to reverse immune failure in HIV-infected subjects.
In Aim 1, building on previous resultscorrelating PD-1 expression by HIV-specific CD8 and CD4 T cells with disease progression, we will comparethe expression and functional impact of PD-1 on T cells from subjects with acute infection, chronic infection,or spontaneous viral control (elite controllers). Using state-of-the-art imaging techniques from Core C, wewill determine the role of PD-1 in modulating exocytosis of cytolytic granules by HIV-specific CTL. We willalso investigate PD-1 expression and function in elite controllers who present a polymorphism in the PD-1gene or in PD-1 regulatory elements, as identified in Projects 2 and 4.
In Aim 2, we will determinequalitative differences between HIV-specific CTL expanded in the presence or absence of PD-1 blockade,with respect to immunodominance, cytokine production, and cytotoxicity. We will determine the roles of PD-1 expression and TCR avidity in the response of HIV-specific CTL to PD-1 blockade.
In Aim 3, we willdetermine the relative contributions of multiple pathways engaged by PD-1, PD-L1, and CD80 a key antiviralCTL function, namely the ability to suppress HIV replication in vitro. Starting from established methods tomeasure viral suppression, we will systematically knock down or block various PD-L1-mediated pathways todetermine the role of each pathway in antiviral function. We will determine the relative roles of CTLproliferation, survival, cytokine secretion, and killing of infected targets in PD-L1 modulated antiviral activity.Relevance to public health: The immune system of HIV-infected people includes cells (T cells) thatrecognize HIV, but fail to block the virus and to prevent progression to AIDS. Our previous studies haveshown that these T cells express a protein, called PD-1, which inhibits their function. We are studying therole of PD-1 in preventing proper T cell responses, and looking for ways to rescue the ability of T cells tocontrol HIV.
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