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

KMR Faysal; JC Walsh; N Renner; CL Márquez; VB Shah; AJ Tuckwell; MP Christie; MW Parker; SG Turville; GJ Towers; LC James; DA Jacques; T Böcking

Journal article

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

KMR Faysal, JC Walsh, N Renner, CL Márquez, VB Shah, AJ Tuckwell, MP Christie, MW Parker, SG Turville, GJ Towers, LC James, DA Jacques, T Böcking

eLife | eLIFE SCIENCES PUBL LTD | Published : 2024

DOI: 10.7554/eLife.83605

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.

University of Melbourne Researchers

Michelle Christie Author

Michael Parker Author

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Grants

Awarded by National Health and Medical Research Council

Awarded by NHMRC

Awarded by Wellcome Trust Collaborator Award

Awarded by Wellcome Trust

Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by NHMRC Ideas Grant APP1182212 (DAJ, TB), Wellcome Trust Collaborator Award 214344/Z/18/Z (GJT, LJ, DAJ, TB), NHMRC Investigator Grant APP1194263 (MWP), Australian Research Council Grants DP160101874 and DP200102871 (MWP) and a UNSW Scientia Award (KMRF). CM received an Australian Government Research Training Program Scholarship. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Program to St. Vincent's Institute are gratefully acknowledged. MWP is an NHMRC Leadership Fellow. We thank Sara Lawrence (St. Vincent's Institute) for expression and purification of recombinant DLY, Claire Dickson and Prabhjeet Phalora for critical feedback on the manuscript.