Work

The Central Pore of HIV-1 Capsomers Promotes Sustained Stability of the Viral Capsid

Year: 2026

Type: article

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.

Source: Journal of Molecular Biology

DOI: 10.1016/j.jmb.2026.169950