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Updated: May 16, 2025
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Nucleocapsid Annealing-Mediated Electrophoresis NAME Assay Allows the Rapid Identification of HIV-1 Nucleocapsid Inhibitors
Published on: January 19, 2015
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Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice
Chenglei Li1, Ryan C Burdick1, Rokeya Siddiqui1
1Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
Summary
Lenacapavir stabilizes the HIV-1 capsid lattice while disrupting core integrity, unlike PF74 which affects both. This difference impacts nuclear import inhibition mechanisms for HIV-1 replication.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Lenacapavir is an HIV-1 capsid inhibitor for multidrug-resistant infections.
- Its precise effect on HIV-1 capsid structure and function remains incompletely understood.
Purpose of the Study:
- To investigate the impact of lenacapavir (LEN) on HIV-1 capsid integrity and lattice stability.
- To differentiate LEN's mechanism from other capsid inhibitors like PF-3450074 (PF74).
Main Methods:
- Utilized HIV-1 capsids labeled with GFP-CA (capsid lattice marker) and cmGFP (core integrity marker).
- Assessed LEN and PF74 effects using immunostaining, MX2 sensitivity assays, and electron microscopy.
- Monitored GFP-CA and cmGFP signal changes upon drug treatment.
Main Results:
- LEN dose-dependently decreased cmGFP signal (core integrity) but preserved GFP-CA signal (lattice stability).
- PF74 induced loss of both core integrity and capsid lattice.
- Electron microscopy showed capsid breakage with both inhibitors, but LEN did not prevent nuclear envelope docking, unlike PF74.
Conclusions:
- LEN disrupts HIV-1 core integrity while stabilizing the capsid lattice, leading to nuclear import inhibition.
- PF74 inhibits nuclear import by blocking viral core docking at the nuclear envelope.
- LEN and PF74 exhibit distinct mechanisms of action affecting HIV-1 nuclear import.
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