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

EMBO Molecular Medicine

Mohammad Tarek¹  Bojana Lucic²  Marina Lusic²  Iart Luca Shytaj³  Andrea Savarino³  Mattia Forcato⁴  Silvio Bicciato⁴  Konstantin Leskov⁵  Sheetal Sreeram⁵  David Alvarez‐Carbonell⁵  Jonathan Karn⁵  Fengchun Ye⁵  Lishomwa C Ndhlovu⁶  Irene Carlon‐Andres⁷  Sergi Padilla‐Parra⁷  MohamedHusen Munshi⁸  Virender Kumar Pal⁸  Amit Singh⁸  Ricardo Sobhie Diaz⁹  Nicolly Cruz⁹  Francesco Andrea Procopio^1,10  Aaron R Goldman^1,11  Hsin‐Yao Tang^1,11 

[1] Bioinformatics Department Armed Forces College of Medicine (AFCM) Cairo Egypt;Department of Infectious Diseases Heidelberg University Hospital Heidelberg Germany;Department of Infectious Diseases Italian Institute of Health Rome Italy;Department of Life Sciences University of Modena and Reggio Emilia Modena Italy;Department of Molecular Biology and Microbiology Case Western Reserve University Cleveland OH USA;Division of Infectious Diseases Department of Medicine Weill Cornell Medicine New York NY USA;Division of Structural Biology Wellcome Centre for Human Genetics University of Oxford Oxford UK;Indian Institute of Science Bangalore India;Infectious Diseases Department Federal University of São Paulo São Paulo Brazil;Service of Immunology and Allergy Lausanne University Hospital University of Lausanne Lausanne Switzerland;The Wistar Institute Philadelphia PA USA;

关键词: glycolysis;    HIV‐1 latency;    oxidative stress;    pentose cycle;    pyrimidine metabolism;   

DOI  :  10.15252/emmm.202013901

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown