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; Peijun Zhang

doi:10.1038/s41467-025-63363-9

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

Journal article

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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, …

Nature communications, Vol.16(1), 8152

09/01/2025

DOI: 10.1038/s41467-025-63363-9

PMCID: PMC12402280

PMID: 40890096

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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.

Mutation

Capsid - chemistry

Capsid - metabolism

Capsid - ultrastructure

Capsid Proteins - chemistry

Capsid Proteins - genetics

Capsid Proteins - metabolism

Cryoelectron Microscopy

gag Gene Products, Human Immunodeficiency Virus - chemistry

gag Gene Products, Human Immunodeficiency Virus - genetics

gag Gene Products, Human Immunodeficiency Virus - metabolism

HIV-1 - genetics

HIV-1 - metabolism

HIV-1 - physiology

Humans

Molecular Dynamics Simulation

Phytic Acid - metabolism

Virion - metabolism

Virus Assembly - genetics

Details

Title: Subtitle: Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging
Creators: Yanan Zhu - Centre for Human Genetics
Alex B Kleinpeter - Center for Cancer Research
Juan S Rey - University of Delaware
Juan Shen - University of Oxford
Yao Shen - University of Oxford
Jialu Xu - University of Oxford
Nathan Hardenbrook - Centre for Human Genetics
Long Chen - Centre for Human Genetics
Anka Lucic - University of Oxford
Juan R Perilla - University of Delaware
Eric O Freed - Center for Cancer Research
Peijun Zhang - University of Oxford
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 8152
DOI: 10.1038/s41467-025-63363-9
PMID: 40890096
PMCID: PMC12402280
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: Springer Nature
Grant note: BB/S003339/1 / RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) 101021133 / EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) 206422/Z/17/Z / Wellcome Trust (Wellcome) Wellcome Trust K99 AI174891 / NIAID NIH HHS P50AI150481 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) U54 AI170791 / NIAID NIH HHS 311427/Z/24/Z / Wellcome Trust (Wellcome) P50 AI150481 / NIAID NIH HHS R01 AI178846 / NIAID NIH HHS
Language: English
Date published: 09/01/2025
Academic Unit: Microbiology and Immunology
Record Identifier: 9984963147702771

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