Slow progression of pediatric HIV associates with early CD8(+) T cell PD-1 expression and a stem-like phenotype

HIV nonprogression despite persistent viremia is rare among adults who are naive to antiretroviral therapy (ART) but relatively common among ART-naive children. Previous studies indicate that ART-naive pediatric slow progressors (PSPs) adopt immune evasion strategies similar to those described in natural hosts of SIV. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8(+) T cells immediately before ATI was the main predictor of slow progression during ATI. PD-1(+)CD8(+) T cell frequency was also negatively correlated with CCR5 and HLA-DR expression on CD4(+) T cells and predicted stronger HIV-specific T lymphocyte responses. In the CD8(+) T cell compartment of PSPs, we identified an enrichment of stem-like TCF-1(+)PD-1(+) memory cells, whereas pediatric progressors and viremic adults had a terminally exhausted PD-1(+)CD39(+) population. TCF-1(+)PD-1(+) expression on CD8(+) T cells was associated with higher proliferative activity and stronger Gag-specific effector functionality. These data prompted the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in infants who received early ART with a preserved and nonexhausted T cell compartment.