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 1

Cycling memory CD4+ T cells are enriched in Tregs.

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Cycling memory CD4+ T cells are enriched in Tregs. Frequency of cycling ...
Frequency of cycling CD4+CD45RA– T cells detected by (A) Ki67 expression in HCs (n = 20), IRs (n =21), and INRs (n = 16) or by (B) CD71+ expression in HCs (n = 10), IRs (n = 20), and INRs (n = 16) among subjects from the Russian cohort (A) and the Cleveland cohort (B) (*P < 0.05). (C) Heatmaps of cell-cycling–related modules comparing cycling and noncycling memory cells (P < 0.05) from HCs, IRs, and INRs of the Russian cohort. (D) Heatmaps of the Treg signatures showing upregulation (P < 0.05) in the cycling memory (CD45RA–CD71+) CD4+ T cells compared with signatures in noncycling memory (CD45RA–CD71–) CD4+ T cells from HCs (n = 6), IRs (n = 6), and INRs (n = 6) of the Russian cohort. P values for A and B were determined by a Wilcoxon rank-sum test. Data represent the mean ± SD.