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

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Shytaj, Iart Luca ^{[1, 2, 3]} ; Procopio, Francesco Andrea ^[4] ; Tarek, Mohammad ^[5] ; Carlon-Andres, Irene ^{[6, 7, 8]} ; Tang, Hsin-Yao ^[9] ; Goldman, Aaron R. ^[9] ; Munshi, MohamedHusen ^[10] ; Pal, Virender Kumar ^[10] ; Forcato, Mattia ^[11] ; Sreeram, Sheetal ^[12] ; Leskov, Konstantin ^[12] ; Ye, Fengchun ^[12] ; Lucic, Bojana ^{[3, 13]} ; Cruz, Nicolly ^[1] ; Ndhlovu, Lishomwa C. ^[14] ; Bicciato, Silvio ^[11] ; Padilla-Parra, Sergi ^{[6, 7, 8]} ; Diaz, Ricardo Sobhie ^[1] ; Singh, Amit ^[10] ; Lusic, Marina ^{[3, 13]} ; Karn, Jonathan ^[12] ; Alvarez-Carbonell, David ^[12] ; Savarino, Andrea ^[2]

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^[1] Univ Fed Sao Paulo, Infect Dis Dept, Sao Paulo - Brazil

^[2] Italian Inst Hlth, Dept Infect Dis, Rome - Italy

^[3] Heidelberg Univ Hosp, Dept Infect Dis, Heidelberg - Germany

^[4] Univ Lausanne, Lausanne Univ Hosp, Serv Immunol & Allergy, Lausanne - Switzerland

^[5] Armed Forces Coll Med AFCM, Bioinformat Dept, Cairo - Egypt

^[6] Kings Coll London, Randall Div Cell & Mol Biophys, London - England

^[7] Univ Oxford, Wellcome Ctr Human Genet, Div Struct Biol, Oxford - England

^[8] Kings Coll London, Fac Life Sci & Med, Dept Infect Dis, London - England

^[9] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 - USA

^[10] Indian Inst Sci, Bangalore, Karnataka - India

^[11] Univ Modena & Reggio Emilia, Dept Life Sci, Modena - Italy

^[12] Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH - USA

^[13] German Ctr Infect Res, Heidelberg - Germany

^[14] Weill Cornell Med, Div Infect Dis, Dept Med, New York, NY - USA

• Tipo de documento: Artigo Científico
• Fonte: EMBO MOLECULAR MEDICINE; v. 13, n. 8 JUL 2021.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 13/11323-5 - Uso de vacina de células dendríticas em associação com estratégias para eliminação de reservatórios virais almejando a cura esterilizante da infecção pelo HIV-1 em pessoas cronicamente infectadas em uso de tratamento antirretroviral
• Beneficiário: Ricardo Sobhie Diaz
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/17461-7 - Uso de vacina de células dendríticas em associação com estratégias para eliminação de reservatórios virais almejando a cura esterilizante da infecção pelo HIV-1 em pessoas cronicamente infectadas em uso de tratamento antirretroviral
• Beneficiário: Ricardo Sobhie Diaz
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisador Visitante - Internacional