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

Authors :
KM Rifat Faysal
James C Walsh
Nadine Renner
Chantal L Márquez
Vaibhav B Shah
Andrew J Tuckwell
Michelle P Christie
Michael W Parker
Stuart G Turville
Greg J Towers
Leo C James
David A Jacques
Till Böcking
Source :
eLife, Vol 13 (2024)
Publication Year :
2024
Publisher :
eLife Sciences Publications Ltd, 2024.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
13
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.08ba42401fe84baebde255dedc84b832
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.83605