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Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

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Iart Luca Shytaj, Francesco Andrea Procopio, Mohammad Tarek, Irene Carlon-Andres, Hsin Yao Tang, Aaron R. Goldman, Mohamed Husen Munshi, Virender Kumar Pal, Mattia Forcato, Sheetal Sreeram, Konstantin Leskov, Fengchun Ye, Bojana Lucic, Nicolly Cruz, Lishomwa C. Ndhlovu, Silvio Bicciato, Sergi Padilla-Parra, Ricardo Sobhie Diaz, Amit Singh, Marina Lusic & 3 more Jonathan Karn, David Alvarez-Carbonell, Andrea Savarino

Original languageEnglish
Article numbere13901
JournalEMBO Molecular Medicine
Volume13
Issue number8
DOIs
Accepted/In press2021
Published9 Aug 2021

Bibliographical note

Funding Information: The authors thank Dr. Hans Georg Kräusslich and Dr. Thorsten Müller for kindly providing the HIV‐1 Δtat vector. R.S.D. acknowledges support from the Fundação de Amparo à Pesquisa do Estado de São Paulo and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (FAPESP 2013/11323‐5; CNPq ‐ 454700‐2014‐8; CNPq/DECIT 441817/2018‐1). I.L.S. acknowledges support from the Humboldt Foundation (Ref 3.3‐ITA‐1193954‐HFST‐P) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (Ref. 19/17461‐7). A. Si. acknowledges support from the Department of Biotechnology, Indian Institute of Science (# 22‐0905‐0006‐05‐987‐436). S.P‐P and I.C‐A work has been supported by the European Research Council (ERC‐2019‐CoG‐863869 FUSION to S.P‐P.). The authors thank the Microarray Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing Expression Profiling services. NL4‐3 Funding Information: The authors thank Dr. Hans Georg Kr?usslich and Dr. Thorsten M?ller for kindly providing the HIV-1NL4-3 ?tat vector. R.S.D. acknowledges support from the Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo and the Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (FAPESP 2013/11323-5; CNPq - 454700-2014-8; CNPq/DECIT 441817/2018-1). I.L.S. acknowledges support from the Humboldt Foundation (Ref 3.3-ITA-1193954-HFST-P) and the Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (Ref. 19/17461-7). A. Si. acknowledges support from the Department of Biotechnology, Indian Institute of Science (# 22-0905-0006-05-987-436). S.P-P and I.C-A work has been supported by the European Research Council (ERC-2019-CoG-863869 FUSION to S.P-P.). The authors thank the Microarray Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing Expression Profiling services. Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

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