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Slow progression of pediatric HIV associates with early CD8+ T cell PD-1 expression and a stem-like phenotype
Vinicius Vieira, … , Henrik N. Kløverpris, Philip Goulder
Vinicius Vieira, … , Henrik N. Kløverpris, Philip Goulder
Published January 5, 2023
Citation Information: JCI Insight. 2023;8(3):e156049. https://doi.org/10.1172/jci.insight.156049.
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Research Article AIDS/HIV Immunology

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

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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.

Authors

Vinicius Vieira, Nicholas Lim, Alveera Singh, Ellen Leitman, Reena Dsouza, Emily Adland, Maximilian Muenchhoff, Julia Roider, Miguel Marin Lopez, Julieta Carabelli, Jennifer Giandhari, Andreas Groll, Pieter Jooste, Julia G. Prado, Christina Thobakgale, Krista 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

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Figure 1

Upregulation of PD-1 on CD8+ T cells before ATI is associated with slow progression.

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Upregulation of PD-1 on CD8+ T cells before ATI is associated with slow ...
(A) Longitudinal plasma HIV-RNA for all infants who underwent analytical treatment interruption (ATI) after 1 year on ART. The horizontal dashed line represents the limit of detection and the vertical line the time of ATI. (B) Time to restart ART after ATI for each participant according to their group: rapid progressors (RP), intermediate progressors (IP), and slow progressors (SP). FP, fast progressors. (C) Individual longitudinal absolute and relative CD4+ T cell count in each group. The 10th, 50th, and 90th percentiles for HIV-uninfected children are represented by the 3 black lines. Hashed red line represents the threshold to restart ART according to the 2003 WHO guideline (≤20% if younger than 18 months or 15% if older than 18 months of age). (D) Markers before ATI significantly associated with time to restart ART after ATI are shown in the correlation matrix. FACS plot showing PD-1 expression on CD8+ T cell in an FP and an SP. HLA-DR on terminal effector CD4+ T cells and PD-1+ on effector memory CD8+ T cells were selected by the LASSO model that best associated with time to restart ART after ATI. (E) Markers on CD4+ T cells before ATI significantly associated with PD-1 expression on CD8+ T cell subsets before ATI. Spearman’s rank tests were used for correlations. The best-fit line and 95% confidence bands are shown. Red, yellow, and green dots represent FP, IP, and SP, respectively.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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