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Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency
Yanan Zhu1,2, Alex B Kleinpeter3, Juan S Rey4
1Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Biorxiv : the Preprint Server for Biology
|February 20, 2025
Summary
A new mutation, G225R, restores HIV-1 capsid assembly and infectivity in the absence of inositol hexakisphosphate (IP6). This discovery offers insights into viral adaptation and provides a tool for studying capsid formation.
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- Inositol hexakisphosphate (IP6) is crucial for Human Immunodeficiency Virus type 1 (HIV-1) assembly, promoting Gag lattice formation and subsequent capsid shell assembly.
- HIV-1 protease cleaves Gag polyproteins during maturation, releasing IP6 to facilitate mature capsid formation, essential for viral infectivity.
- Previously identified IP6-independent HIV-1 Gag mutants were non-infectious and failed to form stable capsids.
Purpose of the Study:
- To identify mutations that restore capsid formation and infectivity in IP6-packaging-deficient HIV-1 mutants.
- To elucidate the structural mechanism by which a novel mutation compensates for IP6 deficiency in HIV-1 capsid assembly.
- To investigate the role of the C-terminus of the capsid (CA) protein in mature capsid formation.
Main Methods:
- Genetic screening to identify mutations restoring infectivity in IP6-independent HIV-1 mutants.
- Single-particle cryo-electron microscopy (cryo-EM) to determine the structure of mutant capsid-like particles (CLPs).
- Molecular dynamics simulations to analyze the structural impact of the mutation on capsid stability.
Main Results:
- The G225R mutation in the CA C-terminus restored capsid formation and infectivity to IP6-packaging-deficient HIV-1 mutants.
- G225R facilitated *in vitro* assembly of purified CA into CLPs at significantly lower IP6 concentrations than wild-type.
- High-resolution cryo-EM structures revealed that the G225R mutation restructures the CA C-terminus, stabilizing the hexamer-hexamer interface in the mature capsid.
Conclusions:
- The G225R mutation provides a structural mechanism for HIV-1 to adapt to IP6 packaging deficiencies by stabilizing the mature capsid.
- The study highlights a previously unrecognized role for the unstructured CA C-terminus in HIV-1 capsid assembly.
- The G225R mutation serves as a valuable tool for further research into HIV-1 capsid structure, assembly, and function.
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