Background:  ART partially corrects immune dysfunction associated with HIV infection. The levels of T cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T cell count reconstitution among ART-treated patients in African cohorts has not been extensively evaluated.

Methods:  T cell activation (CD38⁺HLA-DR⁺) and immune exhaustion (PD-1⁺) was measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: suboptimal (median CD4 count increase 165 [43 to 298] cells/μL, N = 44), optimal (297 [94 to 435] cells/μL, N = 59) and super-optimal (564 [299 to 878] cells/μL, N = 25).

Results:  Both CD4⁺ and CD8 T cell activation was significantly higher among suboptimal CD4 T cell responders compared to super-optimal responders. In a multivariate model, CD4⁺CD38⁺HLA-DR⁺ T cells were associated with suboptimal CD4 reconstitution (AOR, 5.7 [95%CI 1.4 to 23, p = 0.014]). T cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (p <0.001) and super-optimal responders (p <0.001). T cell exhaustion was significantly associated with suboptimal responders (AOR, 1.5 [95%CI, 1.1 to 2.1], p = 0.022).

Conclusions: T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These parameters were associated with suboptimal CD4 reconstitution. Early initiation of ART prior to substantial immune damage may be required to optimize treatment outcomes.