Histone Deacetylase Inhibitors (HDACis) as Latency-Reversing Agents in HIV Cure Strategies: Chemistry, Selectivity, and Clinical Perspective

Latently infected resting CD4+ T cells represent the principal barrier to HIV eradication. Their immunological quiescence renders them invisible to combination antiretroviral therapy (cART) and host immune surveillance, sustaining a reservoir that mandates lifelong treatment. The ‘shock and kill’ strategy seeks to reverse this latency using pharmacological latency-reversing agents (LRAs) so that immune effectors and cART can eliminate reactivated cells. In this narrative, structured review, we examine histone deacetylase inhibitors (HDACis) as LRAs from a medicinal chemistry perspective. The review places particular emphasis on structure–activity relationship (SAR), isoform selectivity, and the mechanistic basis of differential clinical performance, synthesizing evidence from preclinical, ex vivo, and clinical studies published between 2010 and 2026. Four structural classes of HDACis—hydroxamic acids, benzamides, cyclic depsipeptides, and short-chain fatty acids—differ substantially in isoform selectivity, potency, pharmacokinetics, and tolerability. No single agent has achieved statistically significant reservoir reduction in clinical trials, highlighting the apparent inadequacy of the ‘shock’ phase alone and suggesting a need for complementary ‘kill’ strategies. Rational design of HDACis informed by isoform-selective SAR, combined with emerging combination LRA strategies and immunological ‘kill’ components, represents a promising direction toward a functional HIV cure, though substantial translational hurdles remain.