ArticleProceedings of the National Academy of Sciences of the United States of America2025
Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 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
- 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
- Lenacapavir allosterically remodels the HIV-1 capsid.Science advances · 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
- Article
- A geometric criterion links HIV-1 capsid topography to its biophysical properties and function.Nature communications · 2026Article
- Negative cooperativity drives activity of capsid-directed antivirals against hepatitis B virus.Science advances · 2026Article
- Non-integrase mechanisms for dolutegravir resistance.Retrovirology · 2026Review
- Mechanism of HIV-1 Capsid Rupture and Uncoating by Reverse Transcription.bioRxiv : the preprint server for biology · 2026Article
- Block-and-Lock Approaches for HIV Cure: Mechanistic Insights, Challenges, and Emerging Role of CPSF6.International journal of molecular sciences · 2026Review
- HIV-1 uncoating location dictates sites of integration.Nature communications · 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
- Lenacapavir at the Spatiotemporal Limit: Tissue Pharmacokinetics, Pharmacokinetic Tail Dynamics, and the Emergence of Capsid Resistance in Long-Acting HIV Prevention.Clinical pharmacology : advances and applications · 2026Review
- Lenacapavir-induced capsid damage uncovers HIV-1 genomes emanating from nuclear speckles.The EMBO journal · 2026Article
- Structural, biophysical, and virological mechanistic characterization of HIV-1 capsid-targeting antivirals.bioRxiv : the preprint server for biology · 2025Article
- Use of the Split Luciferase Complementation Assay to Identify Novel Small Molecules That Disrupt Essential Protein-Protein Interactions of Viruses.Biomolecules · 2025Article
- Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis.Journal of medicinal chemistry · 2025Article
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7 authors.
Funding
Abstract
Lenacapavir (GS-6207; LEN) is a potent HIV-1 capsid inhibitor approved for treating multidrug-resistant infection. LEN binds to a hydrophobic pocket between neighboring capsid (CA) proteins in hexamers and stabilizes the capsid lattice, but its effect on HIV-1 capsids is not fully understood. Here, we labeled HIV-1 capsids with green fluorescent protein fused to CA (GFP-CA) or a fluid-phase GFP content marker (cmGFP) to assess LEN's impact on HIV-1 capsids. HIV-1 cores labeled with GFP-CA, but not cmGFP, could be immunostained with an anti-GFP antibody and were less sensitive to the capsid-binding host restriction factor MX2, demonstrating that GFP-CA is incorporated into the capsid lattice and is a marker for capsid lattice stability, whereas cmGFP is an indicator of core integrity. LEN treatment of isolated HIV-1 cores resulted in a dose-dependent loss of cmGFP signal while preserving the GFP-CA signal, indicating that LEN disrupts core integrity but stabilizes the capsid lattice. In contrast, capsid inhibitor PF-3450074 (PF74) induced loss of core integrity and the capsid lattice. Electron microscopy of LEN- or PF74-treated viral cores revealed frequent breakage at the narrow end of the capsid and other morphological changes. Our results suggest that LEN treatment does not prevent nuclear envelope docking but inhibits nuclear import of cores with or without loss of core integrity. In contrast, PF74 treatment blocks nuclear import by inhibiting the nuclear envelope docking of viral cores, highlighting their different mechanisms of nuclear import inhibition.
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