HIV infection appears to drive premature T cell aging, as evidenced by genomic instability and shortened telomeres. However, how genome or telomere maintenance machineries are dysregulated to drive T cell aging during HIV infection remains largely unknown. The objective of this study is to elucidate the mechanisms by which HIV infection accelerates telomere erosion that may cause premature T cell aging, so as to develop effective means to improve cellular functions in the immunocompromised host. Indeed, telomere integrity is a key feature of linear chromosomes that preserves genome stability and function, whereas telomere erosion is a hallmark of cell aging or senescence that drives cell dysfunction or apoptosis. Importantly, we have recently found that CD4 T cells derived from HIV patients on antiretroviral therapy (ART), and primary CD4 T cells infected with HIV on ART in vitro, both exhibit enhanced DNA damage and telomere erosion, and both are associated with a profound apoptotic and aging phenotypes. We have also shown that 1) telomeric DNA damage and repair machineries are impaired; 2) the human telomerase reverse transcriptase (hTERT - the catalytic unit of telomerase that prolongs telomeric DNA) remains intact; 3) the telomeric repeat binding factor 2 (TRF2 - a telomere shelterin protein that protects telomeres from DNA damage) and the ataxia-telangiectasia mutated (ATM - a kinase that repairs the DNA damage) are inhibited; and 4) the human telomeric zinc-finger associated protein (TZAP - a newly identified telomere-associated protein that can compete with TRF2 for telomere binding and has nuclease activity in trimming telomeric DNA) is upregulated in CD4 T cells during HIV infection. We thus hypothesize that either an increase in nuclease-mediated telomere trimming by an aberrant telomeric DNA damage & repair signaling, and/or a compromised telomeric DNA replication and elongation, are involved in telomere attrition during HIV infection. Elucidating the mechanisms regulating telomere integrity may open new avenues to protect T cells from unwanted telomere damage, prevent premature T cell aging, and maintain immune competence. To establish this hypothesis, we will employ a translational approach using comprehensive ex vivo and in vitro systems: CD4 T cells isolated from acute and chronic HIV-infected subjects with or without ART; and primary CD4 T cells infected with wild-type HIV with or without ART - an in vitro model mirroring HIV-infected, ART-controlled patients in vivo. In Aim 1, we will identify the role of TRF2 and TZAP in the telomeric DNA damage and telomere attrition during HIV infection. In Aim 2, we will elucidate the mechanisms involved in compromising telomeric DNA elongation during HIV infection. This translational study is novel and clinically significant in that it will explore mechanisms fundamental to diminishing T cell responses, and will address important questions as to how telomeric DNA is damaged to accelerate T c...