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.

中文翻译：

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糖酵解下调是 HIV-1 潜伏期的标志，并使受感染的细胞对氧化应激敏感

HIV-1 感染淋巴和骨髓细胞，这些细胞可能含有潜在的原病毒库，负责维持终生感染。糖酵解代谢已被确定为 HIV-1 感染易感性的决定因素，但其在 HIV-1 潜伏期的发展和维持中的作用尚未阐明。通过结合转录组学、蛋白质组学和代谢组学分析，我们在此表明​​，向潜在 HIV-1 感染的转变会下调糖酵解，而传统刺激下的病毒重新激活会恢复这种效应。^{潜伏感染细胞中糖酵解输出的减少与 NAD +} /NADH的下调有关。因此，受感染的细胞依赖于平行的磷酸戊糖途径及其主要产物 NADPH，为维持 HIV-1 潜伏期的抗氧化途径提供燃料。值得注意的是，阻断 NADPH 下游效应子、硫氧还蛋白和谷胱甘肽，有利于 HIV-1 在淋巴和骨髓细胞模型中从潜伏期重新激活。这提供了一种“休克和杀伤效应”，减少了艾滋病毒/艾滋病患者细胞中的前病毒 DNA。总体而言，我们的数据表明，糖酵解的下调是 HIV-1 潜伏期的代谢特征，可用于通过根除策略来针对潜伏感染的细胞。