Preprint
The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid
bioRxiv
Cold Spring Harbor Laboratory, 1.1
05/19/2025
DOI: 10.1101/2025.05.19.654868
PMCID: PMC12139970
PMID: 40475674
Abstract
The HIV-1 capsid, which orchestrates several key post-entry events to facilitate infection in target cells, is composed of hexamers and pentamers (capsomers) of the capsid (CA) protein arranged in a closed, conical structure known as the capsid that protects the viral RNA genome and replicative enzymes reverse transcriptase (RT) and integrase (IN). Each capsomer contains a central pore lined with rings of positively charged amino acid side chains – Arg-18 (R18) and Lys-25 (K25). The R18 and K25 rings drive capsid assembly by binding the host polyanion inositol hexakisphosphate (IP6) and are proposed to mediate the import of dNTPs into the capsid to facilitate reverse transcription. Here we demonstrate that the R18 ring can be functionally replaced by the introduction of a mutation (N21K) that establishes a new electropositive ring within the central pore. In contrast with previous studies in which R18 mutants were unable to adapt in culture, the N21K mutation facilitated the acquisition of second-site compensatory mutations that restored near-WT fitness to viral mutants lacking the R18 ring. Comparative analysis of several central pore mutants lacking the R18 ring revealed that particle infectivity was not correlated with IP6 binding or capsid assembly, but rather with capsid stability and key post-entry events including reverse transcription and nuclear entry. Our results indicate that the central pore plays critical roles in both the assembly of capsids and their sustained stability post-entry.
Details
- Title: Subtitle
- The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid
- Creators
- Alex B. Kleinpeter - InterActionDonna L. Mallery - Medical Research Council Laboratory of Molecular BiologyAnna Albecka - Medical Research Council Laboratory of Molecular BiologyRyan C. Burdick - Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer InstituteNadine Renner - Medical Research Council Laboratory of Molecular BiologyJ Ole Klarhof - Medical Research Council Laboratory of Molecular BiologyBoglarka Vamos - Medical Research Council Laboratory of Molecular BiologyVinay K. Pathak - Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer InstituteLeo C. James - Medical Research Council Laboratory of Molecular BiologyEric O. Freed - InterAction
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Edition
- 1.1
- DOI
- 10.1101/2025.05.19.654868
- PMID
- 40475674
- PMCID
- PMC12139970
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory
- Number of pages
- 28
- Language
- English
- Date posted
- 05/19/2025
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984827498002771
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