Logo image
Back
The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid
Journal article   Open access   Peer reviewed

The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid

Alex B Kleinpeter, Donna L Mallery, Anna Albecka, Ryan C Burdick, Nadine Renner, J Ole Klarhof, Boglarka Vamos, Vinay K Pathak, Leo C James and Eric O Freed
Journal of molecular biology, 169950
07/16/2026
DOI: 10.1016/j.jmb.2026.169950
PMID: 42462964
url
https://doi.org/10.1016/j.jmb.2026.169950View
Published (Version of record) Open Access

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

Metrics

1 Record Views
Logo image