Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging

Yanan Zhu, Alex B. Kleinpeter, Juan S. Rey, Juan Shen, Yao Shen, Jialu Xu, Nathan Hardenbrook, Long Chen, Anka Lucic, Juan R. Perilla (), Eric O. Freed () and Peijun Zhang ()
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Yanan Zhu: University of Oxford
Alex B. Kleinpeter: National Cancer Institute
Juan S. Rey: University of Delaware
Juan Shen: University of Oxford
Yao Shen: University of Oxford
Jialu Xu: University of Oxford
Nathan Hardenbrook: University of Oxford
Long Chen: University of Oxford
Anka Lucic: University of Oxford
Juan R. Perilla: University of Delaware
Eric O. Freed: National Cancer Institute
Peijun Zhang: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Inositol hexakisphosphate (IP6) promotes HIV-1 assembly by stabilizing the immature Gag lattice and becomes enriched within virions, where it is required for mature capsid assembly. Previously, we identified Gag mutants that package little IP6 yet assemble particles, though they are non-infectious due to defective capsid formation. Here, we report a compensatory mutation, G225R, in the C-terminus of capsid protein (CA) that restores capsid assembly and infectivity in these IP6-deficient mutants. G225R also enhances in vitro assembly of CA into capsid-like particles at far lower IP6 concentrations than required for wild-type CA. CryoEM structures of G225R CA hexamers and lattices at 2.7 Å resolution reveal that the otherwise disordered C-terminus becomes structured, stabilizing hexamer-hexamer interfaces. Molecular dynamics simulations support this mechanism. These findings uncover how HIV-1 can adapt to IP6 deficiency and highlight a previously unrecognized structural role of the CA C-terminus, while offering tools for capsid-related studies.

Date: 2025
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DOI: 10.1038/s41467-025-63363-9

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