Slow progression of pediatric HIV associates with early CD8+ T cell PD-1 expression and a stem-like phenotype
Vinícius Vieira, Nicholas Lim, Alveera Singh, Ellen M. Leitman, Reena R. D’Souza, Emily Adland, Maximilian Muenchhoff, Julia Roider, Miguel Marin Lopez, Julieta Carabelli, Jennifer Giandhari, Andreas Groll, Pieter Jooste, Júlia G. Prado, Christina Thobakgale, Krista L. Dong, Photini Kiepiela, Andrew J. Prendergast, Gareth Tudor‐Williams, John Frater, Bruce D. Walker, Thumbi Ndung’u, Veron Ramsuran, Alasdair Leslie, Henrik N. Kløverpris, Philip Goulder
Abstract
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.