Patterns and Cofactors of Polyfunctional Mycobacteria-Specific T-Cell Response Restoration Following 6-Month Antiretroviral Treatment in Children With HIV

Background Despite immune restoration after initiation of antiretroviral treatment (ART), the risk of tuberculosis (TB) persists in children with HIV (CHIV). We determined patterns of immune restoration of mycobacteria-specific T cells following ART in CHIV.Methods CD4 and CD8 T-cell activation and memory phenotype and functional profiles before and 6 months after ART were evaluated in peripheral blood mononuclear cells from CHIV enrolled in the PUSH study (NCT02063880) in Nairobi, Kenya. T-cell expression of cytokines and activation-induced markers were measured following stimulation of peripheral blood mononuclear cells with a pool of 300 peptides from TB (MTB300) or staphylococcal enterotoxin B.Results Among 47 CHIV (median age, 1.5 years), staphylococcal enterotoxin B-induced Th1 cytokine+ and activation-induced marker+ CD4 cell frequencies increased significantly after 6 months of ART. Although MTB300-specific CD4 and CD8 cell frequency did not increase after ART, polyfunctional capacity of MTB300-specific CD4 cells expressing combinations of Th1 cytokines with CD40L increased significantly after ART. Baseline age, immune activation, and effector memory CD4 levels were associated with less restoration of MTB300-specific polyfunctional CD4 cells, whereas CD4 percentage and levels of naive CD4 cells following ART were associated with improved MTB300-specific polyfunctional capacity.Conclusions Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 cells persisted 6 months after ART, with higher deficits in older CHIV with more immunosuppression, higher immune activation, and lower proportion of naive CD4 cells. These findings may explain persistent TB risk during early ART among CHIV and identify those at highest risk. Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 T cells persisted 6 months after antiretroviral therapy in children with HIV. These findings may explain persistent TB risk during early antiretroviral therapy among children with HIV.