People living with HIV (PLHIV) are 18 times more likely to have an active TB infection than people without HIV. Though significant epidemiological evidence highlights the significantly worse outcomes for HIV and tuberculosis (TB) co-infections, the mechanisms underlying this increased risk have not been identified. This is particularly important since all-cause mortality is four times higher for people living with HIV (PLHIV) that also have a history of active TB compared to PLHIV without TB, regardless of TB cure and effective ART. This research team's preliminary data suggest differences in the HIV reservoir, the latent HIV virus integrated into host cell DNA throughout the body, as a potential culprit. Their data show T is mechanisms more intact HIV provirus per million circulating CD4+ cells in people with HIV-TB coinfection compared to those with no history of TB. The objective of this proposal to determine how TB impacts the HIV proviral CD4 reservoir with the long-term goal of identifying actionable that can be targeted to eradicate the HIV reservoir, the primary barrier to curing HIV. The concurrent diagnosis we the to goal of Aim 1 is to determine how HIV infection is distributed in immune cell subtypes in people with active TB-coinfection. At GHESKIO Centers in Port au Prince, Haiti, we will enroll people with a new of HIV (n=75) with or without concurrent diagnosis of TB in a cross-sectional study From this cohort, will compare the diversity of T cell receptors in HIV-infected CD4 cells in people with vs. without TB. From cross-sectional cohort, we will follow people with (n=10) vs without (n=20) TB longitudinally over 18 months document the changes in their peripheral immune cellular profiles with HIV and TB treatment . with hypotheses that i) CD4 of PLHIV with TB coinfection will have more “exhausted” phenotype than in PLHIV and ii) this exhaustion phenotype will not resolve with TB treatment or ART. We will quantitate HIV provirus after 1 year of therapy to associate proviral levels with immune subsets. Phenotypic immune exhaustion may contribute to the etiology of increased all-cause mortality in PLHIV who have had active pulmonary TB. The goal of Aim 2 is to determine HIV proviral burdens in Mycobacterium tuberculosis (Mtb)-specific CD4+ T- cells in comparison to other antigen specificities. We will conduct a case-control study in New York City where people living with HIV with (n=10) vs without (n=10) history of TB will have 5 billion white blood cells collected via leukapheresis. We will stimulate leukapheresis-derived cells with peptide pools and quantitate HIV provirus in CD4 cells responsive to different antigenic stimuli. Digital droplet PCR will be used to measure the percentage of CD4 cells containing HIV. We hypothesize that Mtb peptide-responsive CD4 will be most likely to contain HIV provirus, and thus contribute to the larger HIV reservoir seen in HIV-TB coinfection. Fundamental understanding of TB's impact on HIV res...