HIV capsid inhibitors: Mechanisms, resistance, and therapeutic advances.

Authors

Mohamed Mahdi, Botond Lakatos, János András Mótyán, Gyula Hoffka, József Tőzsér

Published in

PLoS pathogens. Volume 22. Issue 7. Pages e1014361. Epub Jul 10, 2026.

Abstract

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.

PMID:
42430420
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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