The decline in CD4+ T-cell counts found in HIV infection is a hallmark of HIV disease progression, and with the advent of highly active anti-retroviral therapy allowing HIV patients to live to older ages, it has been observed that in older patients (>50 years) with HIV infection, CD4+ and CD8+ cell counts are lower than in younger HIV patients. One mechanism of T- lymphocyte loss during HIV infection is through apoptosis of uninfected bystander CD4+ and CD8+ T-cells which can occur through the viral induction of death ligands, such as the type I interferon-inducible TNF-Related Apoptosis Inducing Ligand (TRAIL). Plasmacytoid dendritic cells (pDC) are potent producers of type I interferons and are also known to express TRAIL during HIV infection. With pDC dysfunction also common to normal aging and HIV infection, it is unknown whether TRAIL plays a role during normal aging, as it does during HIV infection. We hypothesize that in older HIV-infected individuals, lower CD4+ and CD8+ T-cell counts are due in part to the additive effects of age and HIV infection on the chronic pDC production of IFN-, which mediates the expression of TRAIL, a death ligand. This leads to bystander apoptosis of these cells, with depletion of these cells leading to immune dysfunction and increased susceptibility to infections. We propose to study older HIV-infected subjects, comparing them to younger HIV-infected subjects and age-matched controls. We will study samples from HIV-infected subjects to determine the relationship between TRAIL expression and pDC activation in vivo, then study the mechanisms of TRAIL potentiation in pDC from older HIV-infected subjects. In the second part of our study, we will study the mechanisms by which T cell subsets from older HIV-infected subjects are more susceptible to TRAIL-mediated apoptosis than younger HIV-infected subjects. Data from this study will help elucidate the mechanisms of pDC dysfunction during HIV infection in aged patients, as well as why older HIV-infected individuals exhibit lower CD4+ and CD8+ cell counts that make their prognosis worse than younger HIV-infected individuals. PUBLIC HEALTH RELEVANCE: Though anti-retroviral therapy has allowed people with HIV-infection to live longer lives, these individuals show signs of early aging, including changes in the immune response usually seen in much older individuals. Our work is important because it studies the ways by which the combination of older age and HIV-infection contributes to the loss of T cells, and how plasmacytoid dendritic cells are involved in this process.