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HIV patients beginning antiretroviral therapy (ART) with advanced immunodeficiency often retain low CD4+ T cell counts despite virological control. We examined proliferative responses and upregulation of costimulatory molecules, following anti-CD3 stimulation, in HIV patients with persistent CD4+ T cell deficiency on ART. Aviremic HIV patients with nadir CD4+ T cell counts <100 cells/μL and who had received ART for a median time of 7 (range 1-11) years were categorized into those achieving low (<350 cells/μL; n = 13) or normal (>500 cells/μL; n = 20) CD4+ T cell counts. Ten healthy controls were also recruited. CD4+ T cell proliferation (Ki67) and upregulation of costimulatory molecules (CD27 and CD28) after anti-CD3 stimulation were assessed by flow cytometry. Results were related to proportions of CD4+ T cells expressing markers of T cell senescence (CD57), activation (HLA-DR), and apoptotic potential (Fas). Expression of CD27 and/or CD28 on uncultured CD4+ T cells was similar in patients with normal CD4+ T cell counts and healthy controls, but lower in patients with low CD4+ T cell counts. Proportions of CD4+ T cells expressing CD27 and/or CD28 correlated inversely with CD4+ T cell expression of CD57, HLA-DR, and Fas. After anti-CD3 stimulation, induction of CD27hiCD28hi expression was independent of CD4+ T cell counts, but lower in HIV patients than in healthy controls. Induction of CD27hiCD28hi expression correlated with induction of Ki67 expression in total, naïve, and CD31+ naïve CD4+ T cells from patients. In HIV patients responding to ART, impaired induction of CD27 and CD28 on CD4+ T cells after stimulation with anti-CD3 is associated with poor proliferative responses as well as greater CD4+ T cell activation and immunosenescence.