ArticlePLoS pathogens2025
The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir.
Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Mechanisms of HIV-1 assembly, release and maturation.Nature reviews. Microbiology · 2026Review
- Structural basis of lenacapavir-induced HIV-1 capsid defects during virion maturation.Nature communications · 2026Article
- HIV cure: from early therapies to cutting-edge strategies.Journal of neurovirology · 2026Review
- Inhibitors of HIV-1 maturation modulate conformational dynamics and heterogeneity of the immature Gag lattice.bioRxiv : the preprint server for biology · 2026Article
- Lenacapavir binding to immature Gag induces giant virions and causes protease-dependent inhibition of viral release.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Capsid stabilization reprograms the nuclear fate of the HIV genome.Science advances · 2026Article
- Capsid and integrase play essential apposing roles in viral ribonucleoprotein assembly during HIV-1 core morphogenesis.iScience · 2026Article
- HIV capsid inhibitors: Mechanisms, resistance, and therapeutic advances.PLoS pathogens · 2026Review
- A geometric criterion links HIV-1 capsid topography to its biophysical properties and function.Nature communications · 2026Article
- Damaging the conical morphology of HIV-1 capsid by targeting the FG-binding pocket and disfavoring pentameric subunits needed for core closure.bioRxiv : the preprint server for biology · 2026Article
- Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Recurrent and novel evolutionary pathways drive in vitro HIV-1 lenacapavir resistance with diverse phenotypic consequences.Nature communications · 2026Article
- A Scientometric Mapping of Global Lenacapavir and HIV Research: Dynamism, Visualization, and Emerging Patterns.International journal of preventive medicine · 2026Article
- Lenacapavir-induced capsid damage uncovers HIV-1 genomes emanating from nuclear speckles.The EMBO journal · 2026Article
- Emerging concepts in HIV pre-exposure prophylaxis: focus on twice-yearly lenacapavir.Drugs in context · 2026Review
- Use of the Split Luciferase Complementation Assay to Identify Novel Small Molecules That Disrupt Essential Protein-Protein Interactions of Viruses.Biomolecules · 2025Article
- Calicivirus assembly and stability are mediated by the N-terminal domain of the capsid protein with the involvement of the viral genome.PLoS pathogens · 2025Article
- Delineating Structural Functionalities of Lenacapavir Amenable to Modifications for Targeting Emerging Drug-Resistant HIV‑1 Capsid Variants.ACS medicinal chemistry letters · 2025Article
- Time-Resolved Fluorescence Imaging and Correlative Cryo-Electron Tomography to Study Structural Changes of the HIV-1 Capsid.ACS nano · 2025Article
- New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein.International journal of molecular sciences · 2025Review
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Abstract
Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during HIV-1 replication. Previous studies have mainly focused on elucidating LEN's mode of action during viral ingress. Additionally, the inhibitor has been shown to interfere with mature capsid assembly during viral egress. However, the mechanism for how LEN affects HIV-1 maturation is unknown. Here, we show that pharmacologically relevant LEN concentrations do not impair proteolytic processing of Gag in virions. Instead, we have elucidated the primary mechanism for highly potent inhibition of HIV-1 maturation by sub-stoichiometric LEN:CA ratios. The inhibitor exerts opposing effects on formation of CA pentamers versus hexamers, the key capsomere intermediates in mature capsid assembly. LEN impairs formation of pentamers, whereas it induces assembly of hexameric lattices by imposing an opened CA conformation and stabilizing a dimeric form of CA. Consequently, LEN treatment results in morphologically atypical virus particles containing malformed, hyper-stable CA assemblies, which fail to infect target cells. Moreover, we have uncovered an inverse correlation between inhibitor potency and CA levels in cell culture assays, which accounts for LEN's ability to potently (with picomolar EC50 values) inhibit HIV-1 maturation at clinically relevant drug concentrations.
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