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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 3

PD-1 expression on nonnaive CD8+ T cells is characterized by a stem-like TCF-1+ phenotype in ART-naive pediatric slow progressors.

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PD-1 expression on nonnaive CD8+ T cells is characterized by a stem-like...
(A–C) Frequency of PD-1+ on nonnaive CD8+ T cells (A) and on memory (B) CD8+ T cells and absolute levels of PD-1 of total CD8+ T cells (C) measured by MFI among HIV-exposed uninfected children, PSPs, pediatric progressors, and viremic adults. (D) Frequency of CD39+PD-1+ of nonnaive CD8+ T cells as a marker of terminal exhaustion. (E) Typical FACS plot showing PD-1+ population (pink gate) and TCF-1+ population (red dots) in PSPs and viremic adults. Frequency of TCF-1+PD-1+ of nonnaive CD8+ T cells. (F) Typical histogram and MFI levels TCF-1+ on PD-1+ of total CD8+ T cells. (G) FACS plot showing typical frequency of TCF-1+ of CD8+ T cells in PSPs and viremic adults. Frequency of CD127+PD-1+ of total CD8+ T cells according to TCF-1 expression levels (TCF-1hi, TCF-1dim, and TCF-1neg). (H) Pairwise comparison of frequency of PD-1+, CD39+PD-1+, and TCF-1+PD-1+ of nonnaive CD8+ T cells before and after 1–2 years of ART initiation and viral suppression. (I) Typical FACS plot of Tetramer+ (Gag-TL9)-specific CD8+ T cells showing Granzyme B and TCF-1 gating in a typical PSP and viremic adults. Frequency of PD-1+, T-bet+, CD39+, Granzyme B+, and TCF-1+ on Tetramer+ CD8+ T cells for each group. Memory subset distribution on Tetramer+ CD8+ T cells. Statistical comparison between 3 and 4 groups was done using a Kruskal-Wallis test followed by Dunn’s test to correct for multiple comparisons. Wilcoxon matched-pairs test was performed for pairwise comparisons.

Copyright © 2023 American Society for Clinical Investigation
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