Journal article
A stable immature lattice packages IP6 for HIV capsid maturation
Science advances, Vol.7(11), eabe4716
03/01/2021
DOI: 10.1126/sciadv.abe4716
PMCID: PMC7946374
PMID: 33692109
Abstract
HIV immature lattice stability affects capsid maturation by altering IP
6
packaging.
HIV virion assembly begins with the construction of an immature lattice consisting of Gag hexamers. Upon virion release, protease-mediated Gag cleavage leads to a maturation event in which the immature lattice disassembles and the mature capsid assembles. The cellular metabolite inositiol hexakisphosphate (IP
6
) and maturation inhibitors (MIs) both bind and stabilize immature Gag hexamers, but whereas IP
6
promotes virus maturation, MIs inhibit it. Here we show that HIV is evolutionarily constrained to maintain an immature lattice stability that ensures IP
6
packaging without preventing maturation. Replication-deficient mutant viruses with reduced IP
6
recruitment display increased infectivity upon treatment with the MI PF46396 (PF96) or the acquisition of second-site compensatory mutations. Both PF96 and second-site mutations stabilise the immature lattice and restore IP
6
incorporation, suggesting that immature lattice stability and IP
6
binding are interdependent. This IP
6
dependence suggests that modifying MIs to compete with IP
6
for Gag hexamer binding could substantially improve MI antiviral potency.
Details
- Title: Subtitle
- A stable immature lattice packages IP6 for HIV capsid maturation
- Creators
- Donna L. Mallery - MRC Laboratory of Molecular BiologyAlex B. Kleinpeter - National Cancer InstituteNadine Renner - MRC Laboratory of Molecular BiologyK. M. Rifat Faysal - ARC Centre of Excellence in Advanced Molecular ImagingMariia Novikova - National Cancer InstituteLeo Kiss - MRC Laboratory of Molecular BiologyMiranda S. C. Wilson - MRC Laboratory for Molecular Cell Biology, University College London, London, UKBilal Ahsan - MRC Laboratory of Molecular BiologyZunlong Ke - MRC Laboratory of Molecular BiologyJohn A. G. Briggs - MRC Laboratory of Molecular BiologyAdolfo Saiardi - MRC Laboratory for Molecular Cell BiologyTill Böcking - EMBL AustraliaEric O. Freed - National Cancer InstituteLeo C. James - MRC Laboratory of Molecular Biology
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.7(11), eabe4716
- DOI
- 10.1126/sciadv.abe4716
- PMID
- 33692109
- PMCID
- PMC7946374
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Publisher
- American Association for the Advancement of Science
- Grant note
- APP1158338 / ; U105181010 / ; APP1100771 / ; 214344/A/18/Z / ;
- Language
- English
- Date published
- 03/01/2021
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984826361102771
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