There is no CURE for HIV. Although Antiretroviral Therapy (ART) can maintain viral load below detection threshold, HIV escapes and persists in long-lived HIV latent reservoirs. Similarly, although ART restores CD4 T-cell count, T cells display signs of chronic inflammation/exhaustion, which impair immune control of HIV infection. Dysregulated T cell metabolism is underpinning defective host antiviral responses, and HIV reservoir persistence, even in patients under effective and suppressive ART. This strongly supports that lowering metabolic barriers to T-cell effector functions and HIV gene expression in latent reservoirs could potentiate current HIV CURE strategies. Indeed current “shock and kill” approach, using Latency Reversing agents (LRAs) to force HIV gene expression and induce viral cytopathic effects or immune-mediated killing have had limited impact in clinical trials. These studies highlight that additional layers of control limit the impact of current strategies and need to be collectively unlocked if we want to eradicate these latent reservoirs.
In this context, our proposal seek to explore T cell metabolism reprogramming for potential therapeutic intervention in the development of novel HIV Cure strategies aiming at achieving HIV Remission via targeting and reducing the size of the HIV reservoirs, so they can be controlled by the host immune system without ART. More specifically, we have previously identified Zaprinast, a Mitochondrial Pyruvate Carrier inhibitor (MPCi) for its capacity to reprogram CD4+ T-cell metabolism via increasing glycolytic pathway at the expense of mitochondrial respiration. Interestingly, Zaprinast treatment in ex vivo HIV reactivation assays, resulted in the release of virion from HIV+ patient circulating latent reservoirs suggesting that MPCis could act as a novel class of LRAs. Here, we propose to capitalise on this finding and investigate the capacity of newly described MPCis to have dual-action on both immune control of HIV infection and latency reversal from HIV reservoirs.