The susceptibility of CD4 T cells to human immunodeficiency virus 1 (HIV-1) infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. Here we show that glutaminolysis is the major pathway fuelling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in T-cell receptor-stimulated naïve, as well as memory CD4, subsets and is required for optimal HIV-1 infection. Under conditions of attenuated glutaminolysis, the α-ketoglutarate (α-KG) TCA rescues early steps in infection; exogenous α-KG promotes HIV-1 reverse transcription, rendering both naïve and memory cells more sensitive to infection. Blocking the glycolytic flux of pyruvate to lactate results in altered glucose carbon allocation to TCA and pentose phosphate pathway intermediates, an increase in OXPHOS and augmented HIV-1 reverse transcription. Moreover, HIV-1 infection is significantly higher in CD4 T cells selected on the basis of high mitochondrial biomass and OXPHOS activity. Therefore, the OXPHOS/aerobic glycolysis balance is a major regulator of HIV-1 infection in CD4 T lymphocytes.
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The data that support the findings of this study are available from the corresponding authors upon request.
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We thank all members of our laboratories for discussions and scientific critique and are indebted to S. Kinet and V. Zimmermann for their continual support in this project. We are indebted to E. Gottlieb for his important input into metabolic experiments and to J. Mamede for his expertise and input into viral fusion assays. C. Goujon and C. June generously provided reagents, as indicated. We are grateful to M. Boyer and S. Gailhac of Montpellier Rio Imaging for support in cytometry experiments. I.C. and D.A.M. were supported by fellowships from Sidaction. Z.V. was supported by a fellowship from the Fondation de la Recherche Medicale (FRM). S.T. is supported by funding from Cancer Research UK (C596/A17196, Award 23982). L.O. was supported by a fellowship from the Ligue Contre le Cancer and the ARC Foundation. M.S. and N.T. are supported by Inserm and V.D. and C.M by the CNRS. This work was supported by generous funding from Sidaction, the ANRS, ARC, FRM, the French national (ANR) research grants (PolarATTACK and GlutStem) and the French laboratory consortiums (Labex) EpiGenMed and GR-EX.
M.S. and N.T. are inventors on patent WO2010079208. M.S., C.M. and N.T. are inventors on patent WO/2004/096841 and M.S. is an inventor on patent WO/2012/035369. All patents are owned by the CNRS and cover the use of RBD ligands for metabolite transporter detection. N.T. no longer owns any patent rights. M.S. is a co-founder of METAFORA Biosystems.
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Clerc, I., Abba Moussa, D., Vahlas, Z. et al. Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells. Nat Metab 1, 717–730 (2019). https://doi.org/10.1038/s42255-019-0084-1
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