Journal article
The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid
Journal of molecular biology, Vol.438(21), 169950
11/01/2026
DOI: 10.1016/j.jmb.2026.169950
PMID: 42462964
Abstract
The HIV-1 capsid, which orchestrates several key post-entry events to facilitate infection, is composed of hexamers and pentamers (capsomers) of the capsid (CA) protein. The capsomers are arranged in a closed, conical structure - 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 N21K substitution 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 substitution 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.The HIV-1 capsid, which orchestrates several key post-entry events to facilitate infection, is composed of hexamers and pentamers (capsomers) of the capsid (CA) protein. The capsomers are arranged in a closed, conical structure - 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 N21K substitution 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 substitution 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 - National Cancer InstituteDonna L Mallery - MRC Laboratory of Molecular BiologyAnna Albecka - MRC Laboratory of Molecular BiologyRyan C Burdick - Frederick National Laboratory for Cancer ResearchNadine Renner - MRC Laboratory of Molecular BiologyJ Ole Klarhof - MRC Laboratory of Molecular BiologyBoglarka Vamos - MRC Laboratory of Molecular BiologyVinay K Pathak - Frederick National Laboratory for Cancer ResearchLeo C James - MRC Laboratory of Molecular BiologyEric O Freed - National Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Journal of molecular biology, Vol.438(21), 169950
- DOI
- 10.1016/j.jmb.2026.169950
- PMID
- 42462964
- NLM abbreviation
- J Mol Biol
- ISSN
- 1089-8638
- eISSN
- 1089-8638
- Publisher
- Elsevier
- Grant note
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health NIH Office of AIDS Research Intramural AIDS Research Fellowship National Institute of Allergy and Infectious Diseases: K99AI174891-01, U54AI170791, U54AI170855 MRC (UK): U105181010 Wellcome Trust Investigator Award: 200594/Z/16/Z Wellcome Trust Collaborator Award: 214344/A/18/Z
Research in the Freed and Pathak laboratories is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and by funding from the NIH Office of AIDS Research. The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. ABK was supported in part by an Intramural AIDS Research Fellowship and the National Institute of Allergy and Infectious Diseases (K99AI174891-01) . We acknowledge our collaborative interactions with the Pittsburgh Center for HIV Protein Interactions (U54AI170791) and the Behavior of HIV in Viral Environments Center (U54AI170855) . Research in the James lab is supported by the MRC (UK; U105181010) , a Wellcome Trust Investigator Award (200594/Z/16/Z) , and a Wellcome Trust Collaborator Award (214344/A/18/Z) .
- Language
- English
- Electronic publication date
- 07/16/2026
- Date published
- 11/01/2026
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9985183121302771
Metrics
4 Record Views