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Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

ABSTRACT: The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.

SUBMITTER: Faysal KMR

PROVIDER: S-EPMC10863983 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

Faysal K M Rifat KMR Walsh James C JC Renner Nadine N Márquez Chantal L CL Shah Vaibhav B VB Tuckwell Andrew J AJ Christie Michelle P MP Parker Michael W MW Turville Stuart G SG Towers Greg J GJ James Leo C LC Jacques David A DA Böcking Till T

eLife 20240213

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the ...[more]

PMID: 38347802

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