High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort

T-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were 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 129 (-43-199) cells/μl], N = 34 ], optimal [282 (200-415) cells/μl, N = 64] and super-optimal [528 (416-878) cells/μl, N = 30].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+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, 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, 1.1-2.1), P = 0.022].T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.Although antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection, abnormalities of immune activation markers persist in many patients [1-3]. ART reduces the levels of T-cell activation by mechanisms independent of viral load [1-3]. Nevertheless, immune activation (as measured by expression of HLA-DR and CD38 on monocytes and T-cells) remained significantly higher among HIV-infected patients relative to the HIV-negative controls one year after viral suppression [4].Up to 40% of individuals receiving ART have suboptimal CD4 T-cell recovery despite sustained HIV-RNA viral suppression [5-7]. HIV-RNA viremia and T-cell immune activation have been previously shown to be strong predictors of HIV disease progression [8]. In c