Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging
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.
Authors
- Jialu Xu (ORCID: https://orcid.org/0000-0002-7825-9392)
- Alex B. Kleinpeter (ORCID: https://orcid.org/0000-0001-5630-1345)
- Yanan Zhu (ORCID: https://orcid.org/0000-0003-1025-7929)
- Eric O. Freed (ORCID: https://orcid.org/0000-0003-3345-022X)
- Yao Shen (ORCID: https://orcid.org/0000-0002-0278-0771)
- Juan S. Rey (ORCID: https://orcid.org/0000-0003-2274-3748)
- Juan R. Perilla (ORCID: https://orcid.org/0000-0003-1171-6816)
- Nathan Hardenbrook (ORCID: https://orcid.org/0000-0003-1539-6768)
- Long Chen (ORCID: https://orcid.org/0000-0001-5595-3026)
- Peijun Zhang (ORCID: https://orcid.org/0000-0003-1803-691X)
- Juan Shen (ORCID: https://orcid.org/0000-0002-2344-1971)
Institutions
- Centre for Human Genetics (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Diamond Light Source (GB)
- University of Oxford (GB)
- Institute for Advanced Study (DE)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- University of Delaware (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41467-025-63363-9
- Citations
- 1
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.04
Funders
- National Science Foundation
- Wellcome Trust
- National Institute for Health and Care Research
- National Institutes of Health
- Directorate for Biological Sciences
- National Cancer Institute
- Office of Advanced Cyberinfrastructure