Disease Progression in Children With Perinatal Human Immunodeficiency Virus Correlates With Increased PD-1(+) CD8 T Cells That Coexpress Multiple Immune Checkpoints

Background. PD-1 marks exhausted T cells, with weak effector functions. Adults living with human immunodeficiency virus (HIV) have increased levels of PD-1(+) CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1(+) CD8 T cells in children with perinatal HIV. Methods. We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells; their coexpression with immune checkpoints (ICs) 2B4, CD160, and TIM3; correlates with immune activation and HIV disease progression; and HIV-specific and -nonspecific proliferative responses. Results. PD-1(+) CD8 T-cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1(+) CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1(+)2B4(+)CD160(+)TIM3(-) in PD-1(+) CD8 T cells predicts weaker HIV-specific proliferative responses, suggesting that this subset is functionally exhausted. Conclusions. Children with perinatal HIV have high levels of PD-1(+) CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1-directed immunotherapies for pediatric HIV remission and cure.