Metabolic reprogramming of CD4⁺ T cells by Zaprinast induces HIV-1 latency reversal ex vivo

HIV-1 latency and persistence of viral reservoirs within memory CD4⁺ T cells remain a fundamental obstacle to achieving a cure despite suppressive antiviral treatments. HIV-1 persistence is sustained by the dynamic interactions between viral regulatory mechanisms and the host cellular environment. At the intersection between immunometabolism and virology, the quiescent metabolic profile of resting CD4⁺ T cells, defined as the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, supports the long-term maintenance of latent viral reservoirs. Existing "Shock and Kill" strategies have shown limited clinical impact, partly due to the metabolic constraints that limit robust viral reactivation. Targeting metabolic junctions to overcome this barrier may provide a complementary therapeutic avenue.

We evaluated Zaprinast, a mitochondrial pyruvate carrier inhibitor (MPCi), for its capacity to reprogramme CD4⁺ T cell metabolism and promote latency reversal. Across multiple primary T-cell based models of HIV-1 latency, Zaprinast induced a moderate yet reproducible increase in HIV-1 gene expression and viral particle production, including in circulating reservoirs from antiretroviral-treated individuals cultured ex vivo. Metabolic profiling revealed a biphasic response: an initial, transient inhibition of mitochondrial respiration followed by a shift from an OXPHOS-dominant to a more glycolytic metabolic state, while maintaining mitochondrial function. This metabolic reprogramming of resting CD4⁺ T cells by Zaprinast was reversible and did not impair cell viability, trigger non-specific T cell activation or proliferation, nor elevate reactive oxygen species levels.

These results highlight that selective targeting of the quiescent metabolic state in resting CD4⁺ T cells can facilitate HIV-1 reactivation without compromising cellular integrity. This study identifies host metabolic reprogramming as a promising strategy to enhance latency reversal and complement existing cure strategies. Our work provides new insights into the importance of host metabolic states in governing viral persistence and underscores the translational potential of metabolic interventions in HIV-1 eradication research.