Reprogramming T cell Metabolism: A New Approach for HIV Cure

Despite the success of Antiretroviral therapy (ART), HIV-1 persists transcriptionally silent yet replication-competent cellular reservoirs, facilitating viral rebound upon treatment interruption. In these latent reservoirs, HIV-1 gene silencing is mediated by multiple mechanisms, including epigenetic silencing, transcriptional, post-transcriptional and translational blocks, along with a quiescent metabolism. The Shock & Kill strategy, part of HIV CURE research, aims to reactivate HIV-1 from latency by targeting these blocks and eliminating infected cells via immune-mediated clearance or viral cytopathic effects.
Recent evidence indicates that HIV-1 infection, gene expression and the establishment of latent reservoirs are linked to cellular metabolic activities. However, targeting the cellular metabolism to reverse HIV-1 from latency remains largely unexplored. This PhD thesis evaluates Zaprinast, a Mitochondrial Pyruvate Carrier inhibitor (MPCi), for its capacity to reverse HIV latency in viral reservoirs using two ex vivo latency assays with primary immune cells isolated from ART-suppressed People Living with HIV-1. Zaprinast successfully induced viral gene transcription in 50% of the cases using ex vivo latency assays with primary CD4+ T cells, achieving 75% of maximal HIV reactivation compared to global T cell stimulation. Additionally, Zaprinast facilitated efficient viral release in 64% of samples using CD8+ T-deplected PBMCs, inducing viral production at 69% compared to maximal reactivation by TCR activation. Importantly, Zaprinast treatment did not induce cytotoxicity, T cell activation or proliferation, or ROS production. Additionally, Zaprinast reprogrammed the quiescent metabolism of resting CD4+ T cells, increasing aerobic glycolysis and mitochondrial respiration leading to enhanced ATP production. This findings demonstrate that MPCi represent a potent new class of LRAs capable of inducing robust HIV-1 latency reversal from circulating viral reservoirs ex vivo. This stronly support the potential of targeting the quiescent metabolism of CD4+ T cells as a promising appraoch for HIV cure research.