Figure 6. Glycolysis downregulation is a hallmark of HIV‐1 latency and sensitizes infected cells to oxidative stress.

Schematic model of the regulation of glycolysis during sequential stages of HIV‐1 infection and of its potential therapeutic targeting (created with BioRender). Uninfected cells become susceptible to HIV‐1 infection upon activation by upregulating a number of metabolic pathways including glycolysis (Valle‐Casuso et al, 2019). During productive HIV‐1 infection, glycolysis is progressively downregulated, a process which is in part compensated by reliance on the parallel pentose phosphate pathway. Latent HIV‐1 infection can ensue either spontaneously, leading to further glycolysis downregulation, or be induced by agents such as dexamethasone (DEXA), which can directly inhibit glycolysis. During latency, the pentose phosphate pathway remains active and fuels, through NADPH activity, regeneration of the two main antioxidant molecules, i.e., Trx and GSH. Reversion to a productively infected state is accompanied by partial reactivation of the glycolytic pathway. Blocking Trx and GSH inhibits downstream effects of NADPH without restoring glycolytic activity, thus favoring death of latently infected cells. TrxR = thioredoxin reductase; GCLC = glutamate‐cysteine ligase; GSSG = oxidized GSH.