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

Autor: Iart Luca Shytaj, Francesco Andrea Procopio, Mohammad Tarek, Irene Carlon‐Andres, Hsin‐Yao Tang, Aaron R Goldman, MohamedHusen 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, Jonathan Karn, David Alvarez‐Carbonell, Andrea Savarino
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 8, Pp 1-20 (2021)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202013901
Popis: 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.
Databáze: Directory of Open Access Journals
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