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

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 analysis, 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, the antioxidant 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.

Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis

“…At the biological level, there could be possible mechanisms associated with metformin-associated antiviral, immunomodulatory and preventive activity for acute lung injury. In this regard, the relationship between glucose metabolism and viral replication have, in the past few years, started to be the object of thorough investigation, starting from HIV-1 [56,57]. The antiviral activity of metformin has been demonstrated in dengue virus infection, by restoring AMPK activity in early stages of infection [58], in animal models with Coxsackievirus B3 (CVB3) infection [59], and Kaposi sarcoma herpesvirus [60].…”

Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individuals

“…Increased glycolysis is a hallmark for T cell activation but also upregulated during HIV-1 infection for cells to sustain the energy demanding process of virus production 47 48 . Generally, activation of a T cell induces a shift from OXPHOS to aerobic glycolysis in a similar fashion as the metabolic reprogramming occurring during activation from latency 49,50 .…”

Innate metabolic responses against viral infections

“…Although both glycolysis and OXPHOS are elevated in HIV-infected CD4 + T cells, a balance towards aerobic glycolysis reinforces the PPP to make deoxynucleoside triphosphate readily available for HIV reverse transcription 12,98 . The PPP is also important for maintaining redox balance of cells, including the control of the antioxidant thioredoxin and glutathione systems shown to regulate HIV replication and latency in CD4 + T cells and macrophages 99,100 . Intriguingly, glycolytic enzymes such as GAPDH, alpha-enolase and pyruvate kinase muscle type 2 have also been shown to directly regulate HIV reverse transcriptase activity and influence the infectivity profile of progeny virus 101 .…”