Structural basis of lenacapavir-induced HIV-1 capsid defects during virion maturation.

Lenacapavir disrupts HIV-1 capsid maturation by altering interhexamer interactions, preventing functional cone-shaped capsid formation during virion assembly.

• Why it matters: Understanding how LEN affects late-stage HIV-1 replication is crucial for improving antiviral strategies and designing more effective inhibitors, as its impact during virion maturation was previously unclear.
• What they did: The study used cryo-electron microscopy to analyze the structure of HIV-1 capsids assembled with LEN, revealing changes in lattice curvature and interhexamer interactions, alongside biochemical tests on viral components.
• The result: LEN impairs capsid integrity, reduces reverse transcriptase activity, and significantly decreases viral infectivity, highlighting its potential as a powerful late-phase HIV inhibitor and guiding future drug development.