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

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 LusicJonathan Karn, David Alvarez-Carbonell, Andrea Savarino

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Article numbere13901
JournalEMBO Molecular Medicine
Volume13
Issue number8
DOIs
Publication statusPublished - 9 Aug 2021

Keywords

  • glycolysis
  • HIV-1 latency
  • oxidative stress
  • pentose cycle
  • pyrimidine metabolism

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