Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function

The adverse effects of immune activation on CD4+ T-cell recovery and the relationship between CD4+ T-cell counts and effector T-cell function were examined in HIV-1 patients receiving long-term effective ART. Patients with nadir CD4+ T-cell counts <100/μl, > 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified by current CD4+ T-cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. We assessed proliferation (Ki67), activation (HLA-DR, CD38) and replicative senescence (CD57) by flow cytometry and CD4+ T-cell responses to CMV by IFN-γ ELISpot. Proportions of CD4+ T-cells expressing HLA-DR or CD57 were strong univariate predictors of total (P = 0.0002 and P = 0.002) and naive (P < 0.0001 and P < 0.0001, respectively) CD4+ T-cell counts, suggesting that CD4+ T-cell activation drives the depletion of naive CD4+ T-cells. This was clearest in patients with a small/undetectable thymus. IFN-γ responses to CMV were similar in patients with low or high CD4+ T-cell counts.