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

Area of Science:

• Virology
• Immunology
• Metabolic Research

Background:

• The persistent HIV-1 latent reservoir in CD4 T cells is a major barrier to curing HIV infection, causing viral rebound after antiretroviral therapy (ART) interruption.
• Current strategies using latency-reversing agents (LRAs) are limited by an incomplete understanding of latency reversal mechanisms in tissue environments.

Purpose of the Study:

• To investigate the role of metabolic factors, specifically glucose and oxygen availability, in HIV-1 latency reversal.
• To identify molecular determinants of differential LRA efficacy in physiologically relevant conditions.

Main Methods:

• Employed pharmacological and metabolomic approaches to model glucose and oxygen variations found in vivo.
• Assessed the efficacy of major LRA classes, PKC agonists (PKCags) and histone deacetylase inhibitors (HDACis), under varying metabolic conditions.
• Investigated the mechanistic link between LRA-induced glycolysis, histone lactylation, and chromatin accessibility at the HIV promoter.

Main Results:

• Glucose was identified as a conditionally essential nutrient for HIV-1 latency reversal, particularly under hypoxia.
• Hyperglycemic conditions were found to potentiate HIV-1 latency reversal.
• PKCags and HDACis exhibited disparate efficacies under glucose-limiting conditions, linked to their differential induction of glycolytic flux.
• PKCag-induced glycolysis promoted histone lactylation, a post-translational modification associated with latency reversal and increased chromatin accessibility.
• KAT2A was identified as a critical lactyl-transferase for latency reversal-associated histone lactylation.

Conclusions:

• Glucose and oxygen availability are critical metabolic determinants influencing HIV-1 latency reversal.
• Findings highlight the importance of in vitro modeling that reflects physiological conditions for identifying effective in vivo therapeutic agents targeting the latent HIV-1 reservoir.