Tailor, JankiFoldi, JuliaGeneroso, MatthewMcCarty, BretAlankar, AparnaKilberg, MaxMwamzuka, MussaMarshed, FatmaAhmed, AabidLiu, MenglingBorkowsky, WilliamUnutmaz, DeryaKhaitan, Alka2023-09-252023-09-252021Tailor J, Foldi J, Generoso M, et al. Disease Progression in Children With Perinatal Human Immunodeficiency Virus Correlates With Increased PD-1+ CD8 T Cells That Coexpress Multiple Immune Checkpoints. J Infect Dis. 2021;224(10):1785-1795. doi:10.1093/infdis/jiab204https://hdl.handle.net/1805/35778Background: 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.en-USPublisher Policy2B4CD160CD8 T cellPD-1TIM-3ChildrenImmune checkpointImmune exhaustionPerinatal HIVArticle