Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction
Souheil-Antoine Younes, … , Benigno Rodriguez, Michael M. Lederman
Souheil-Antoine Younes, … , Benigno Rodriguez, Michael M. Lederman
Published November 1, 2018; First published October 15, 2018
Citation Information: J Clin Invest. 2018;128(11):5083-5094. https://doi.org/10.1172/JCI120245.
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Categories: Research Article AIDS/HIV Metabolism

Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction

Abstract

Immune nonresponder (INR) HIV-1–infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1–infected subjects who fail to restore CD4+ T cells during antiretroviral therapy.

Authors

Souheil-Antoine Younes, Aarthi Talla, Susan Pereira Ribeiro, Evgeniya V. Saidakova, Larisa B. Korolevskaya, Konstantin V. Shmagel, Carey L. Shive, Michael L. Freeman, Soumya Panigrahi, Sophia Zweig, Robert Balderas, Leonid Margolis, Daniel C. Douek, Donald D. Anthony, Pushpa Pandiyan, Mark Cameron, Scott F. Sieg, Leonard H. Calabrese, Benigno Rodriguez, Michael M. Lederman

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Figure 3

INR Tregs are dysfunctional.

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INR Tregs are dysfunctional. Heatmaps showing the expression of Treg sig...
Heatmaps showing the expression of Treg signature genes (A), FOXP3 upregulated genes (B), TGF-β signaling genes (C), IFN-α response genes (D), and OXPHOS genes (E) in cycling memory CD4+ T cells from the 3 donor groups of the Russian cohort. Treg frequency, as defined by FOXP3+CD25+CD127– cells among cycling memory (CD71+CD45RA–CD4+) T cells, is shown as a continuous variable (green gradient). Samples were ordered according to the increasing expression of genes associated with the outcome (mean-rank ordering). Mean-centered gene expression is represented with rows as genes and columns as samples. The bar plot above the heatmap represents absolute CD4+ T cell counts for the subjects. (F) Proportion of GARP- and LAP-expressing cells among FOXP3+CD127–CD25+CD45RA–CD4+ T cells from HCs (n = 9), IRs (n = 20), and INRs (n = 16) of the Cleveland cohort. P values were determined by Wilcoxon rank-sum test (*P < 0.05). Data represent the mean ± SD. (G) Spearman’s correlation between the proportion of GARP+LAP+ cells among Tregs versus the absolute CD4+ T cell count in IRs (n = 20) and INRs (n = 16) of the Cleveland cohort.