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. Aviraemic HIV patients with nadir CD4+ T-cell counts <100 cells/μl 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.
Impaired upregulation of the costimulatory molecules CD27 and CD28 on CD4+ T-cells from HIV patients receiving ART is associated with poor proliferative responses.