Targeting HIV at its core: A mathematical model for optimizing Tat Inhibitor-based therapies toward enhanced functional cure strategies

Abstract

Human immunodeficiency virus (HIV) persistence remains a major barrier to cure due to the existence of long-lived latent reservoirs that evade immune clearance and persist despite combination antiretroviral therapy (ART). Although ART effectively suppresses viral replication, treatment interruption often leads to rapid viral rebound originating from these latent reservoirs. In this study, we develop a deterministic mathematical model describing the in vivo dynamics of HIV infection incorporating uninfected CD4+ T cells, infected cells, latent reservoirs, deep latent reservoirs, and infectious and non-infectious virions, while explicitly accounting for the therapeutic effects of reverse transcriptase inhibitors (RTIs), protease inhibitors (PIs), and Tat transcription inhibitors. Analytical results establish positivity and boundedness of solutions and derive the effective reproduction number Re using the next-generation matrix approach. Stability analysis shows that the virus-free equilibrium is locally asymptotically stable when Re < 1, while viral persistence occurs when Re > 1. Numerical simulations were performed to investigate therapy interactions, viral rebound following treatment interruption, and the impact of drug efficacy on viral set-points and latent reservoir dynamics. To further explore therapy interactions, three-dimensional viral set-point surfaces and heat maps were generated to examine how combinations of infection inhibition, viral production inhibition, and transcriptional inhibition influence viral dynamics. The simulations reveal that Tat inhibition suppresses viral transcription, thereby reducing the transition of infected cells into productive infection and limiting viral propagation when combined with conventional ART mechanisms. The therapy parameter planes further demonstrate that strong transcriptional inhibition promotes the transition of infected cells into deep latency, supporting the emerging block-and-lock strategy for functional HIV cure. In addition, a three-dimensional eradication boundary surface and therapy cube were constructed to identify regions of parameter space where Re < 1, corresponding to successful viral control. These visualizations show that viral eradication is unlikely when therapies act independently but becomes achievable when multiple therapeutic mechanisms act simultaneously. Overall, the results highlight the critical role of transcriptional inhibition through Tat-targeting therapies in complementing existing ART regimens. By simultaneously suppressing viral replication and promoting deep latency, Tat-based combination strategies may significantly reduce viral rebound and contribute to long-term functional control of HIV infection.