Glucose-Fueled Histone Modifications Drive HIV-1 Latency Reversal at Hypoxia

The major barrier to curing HIV-1 infection is the persistence of a latent reservoir in CD4 T cells within tissues which readily fuel viral rebound upon antiretroviral therapy (ART) interruption. Clinical trials aimed at purging these viral reservoirs with latency reversal agents (LRAs) have been unsuccessful owing to our incomplete understanding of the molecular and physiological determinants that underlie latency reversal in these virus-harboring tissues. Here, using a combination of complementary pharmacological and metabolomic approaches, we uncover glucose as a conditionally essential nutrient for HIV-1 latency reversal at hypoxic conditions. By modelling physiological variations in both glucose and oxygen availability as found in vivo within tissues that may harbor the HIV reservoir, we show that hyperglycemic conditions potentiate HIV-1 latency reversal. Importantly, we found major classes of clinically relevant LRAs, PKC agonists (PKCags) and histone deacetylase inhibitors (HDACis) have disparate efficacies under glucose-limiting conditions. Mechanistically, we show that this differential glycolytic dependency is due to distinct capacities of LRAs to induce glycolytic flux during adaptation to hypoxia, a condition that increases glycolytic dependence. Furthermore, we show that PKCag-induced glycolysis drives histone lactylation, a post-translational modification (PTM) we found to be associated with HIV-1 latency reversal and promotes increased chromatin accessibility at the HIV promoter. Importantly, we identify KAT2A as a lactyl-transferase critical for histone lactylation induced upon latency reversal. Taken together, our findings uncover glucose and oxygen availability as critical metabolic determinants of HIV-1 latency reversal and underscore the importance of modeling physiologically relevant experimental conditions in vitro aimed at identifying therapeutic agents that effectively target the latent reservoir in vivo.