HIV capsid inhibitors: Mechanisms, resistance, and therapeutic advances

The capsid (CA) of the human immunodeficiency virus (HIV) has emerged as a critical therapeutic target owing to its essential roles in viral replication, nuclear import, and integration. Capsid inhibitors (CIs) disrupt these processes by binding to highly conserved structural interfaces, offering a novel mechanism distinct from enzyme-targeting antiretrovirals. In this review, we summarize the molecular architecture of the HIV-1 CA and its interactions with host factors, and we compare key structural and functional differences between HIV-1 and HIV-2. We provide an overview of established and investigational CIs, explore the resistance-associated mutations, their structural basis, and their impact on inhibitor potency, alongside insights into cross-resistance patterns. Special emphasis is placed on lenacapavir, exploring data from pivotal trials and emerging applications in both treatment and prevention, including long-acting pre-exposure prophylaxis (PrEP). Moreover, we highlight future perspectives, including the need for global surveillance of CA polymorphisms, strategies to overcome resistance, and challenges in accessibility and cost-effectiveness in resource-limited settings. Collectively, CIs represent a transformative addition to the HIV therapeutic arsenal, though their optimal deployment requires careful consideration of efficacy, resistance, and implementation barriers.