HIV-1 infection is marked by progressive CD4+ T cell destruction, antigen-specific CD4+ and CD8+ T cell dysfunction, and chronic immune activation. Although HIV-1-specific T cell responses are often generated early in infection, they progressively lose the ability to suppress viral replication in vivo. The result is AIDS in the majority of infected individuals. Dendritic cells (DCs) are potent stimulators of antigen-specific T cells and may also facilitate T cell homeostasis. DC function is determined both by DC type and an ordered process of activation, termed "maturation." Blood dendritic cells (BDCs), circulating immature precursors of DCs found in tissues and lymphoid organs, can be categorized into two major subpopulations, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), based on differences in phenotype and function. Both DC subsets are postulated to stimulate HIV-1-specific cell-mediated immunity, and pDCs may suppress HIV-1 replication via direct antiviral properties. However, we and others observed defects in both the number and function of circulating BDC subsets in HIV-infected subjects. Furthermore, we observed incomplete upregulation of costimulatory molecules and altered expression of chemokine receptors on BDCs in viremic subjects, suggesting dysregulated maturation. Importantly, these DC abnormalities failed to normalize after 6 months of suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). Although defective antigen presenting cell (APC) function has been implicated in HIV-1 pathogenesis, the impact of HIV- associated BDC abnormalities on the extent of T cell function and immune recovery before and after HAART have not been fully evaluated. To understand the mechanisms by which HIV-1 alters DC maturation and the implications of DC dysfunction on T cell function, we specifically propose: 1) to determine whether HIV-1 replication in vivo alters chemokine receptor expression, migratory responses, and endocytic capacity of blood pDCs and mDCs, 2) to determine whether HIV-1 replication in vivo is associated with an accumulation of pDCs and mDCs in lymphoid tissue, 3) to compare stimulation of recall Ag-specific memory CD4+ and CD8+ T cell populations by BDCs from uninfected and HIV-1-infected subjects, 4) to investigate the ability of BDCs obtained from HIV-1-infected versus uninfected subjects to induce proliferation of autologous naive and memory CD4+ T cell subsets in vitro. The results of these studies should facilitate development of therapies designed to restore DC number and function, thus leading to more complete immune recovery.

R01AI065275

2006-06-15

2011-05-31