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The role of T-cell immunosenescence and functional CD8⁺ T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8⁺ T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8⁺ T cells, besides diminished expression of CD127 (IL-7Rα) on CD57⁺CD4⁺ T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8⁺ T cells …