A capsid hinge region in European hepatitis E virus links mutations to genotype, virion surface properties, and environmental circulation
Abstract
Hepatitis E virus (HEV) exhibits genetic diversity associated with distinct public health outcomes and circulation patterns across interconnected human and environmental reservoirs. Most studies have focused on genome-wide diversity, revealing relationships between genotype, virulence, and dissemination routes. However, the role of localized mutations in the capsid protein (ORF2), which may influence the extracellular fate and ecology of HEV through changes in surface biological and physicochemical properties of virions, received limited attention. Here, we combined large-scale analysis of European HEV sequences, structural modeling, and physicochemical characterization to investigate such variations in ORF2. Analysis of ORF2 sequences on a genomic segment highly reported in GenBank, derived from patients and the environment, revealed recurrent mutation motifs (single H354Y and triple H354Y–G357S–V364I motifs) located in a conserved capsid hinge region connecting the middle (M) and protruding (P) domains of the protein. These motifs displayed distinct frequency patterns according to sequence sources and were associated with genotypes 3 and 1, respectively. AlphaFold-based modeling identified this region as a flexible interface between the M and P domains and indicated that mutations reduce predicted alignment error of the P domain relative to the overall protein model, consistent with altered exposure at the virion surface. In vitro analyses of synthetic peptides encompassing this critical region revealed increased hydrophobicity and structural rearrangements, supporting local modulation of capsid surface properties. Together, these results identify a structurally and physicochemically sensitive hinge region in the HEV capsid, suggesting a link between ORF2 sequence variations, genotype, virion surface properties, and environmental circulation. IMPORTANCE: Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide, which is transmitted through complex, genotype-linked dissemination routes between humans, animals, and environmental waters. Understanding the circulation dynamics of HEV virions is essential for improving environmental surveillance, risk assessment, and public health strategies within a One Health approach. By combining genetic, structural, and physicochemical analyses, this study highlights specific mutation motifs in a hinge region of the ORF2 capsid protein likely to link distinct distribution patterns of HEV across environmental reservoirs to potential changes in virion surface properties. Such mutation motifs may serve as molecular signatures for exploring virus persistence and dissemination in environmental contexts. Overall, this work provides a new framework for connecting viral genetic variation to environmental behavior beyond traditional genotype classification.
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BibTeX
@article{kasmi2026capsid,
title = {{A capsid hinge region in European hepatitis E virus links mutations to genotype, virion surface properties, and environmental circulation}},
author = {Samy Kasmi and Guillaume Sautrey and Cédric Hartard and Fabienne Quilès and Jean-Luc Bailly and Alexis de Rougemont and Hélène Jeulin and Raphael Duval and Christophe Gantzer and Evelyne Schvoerer},
journal = {Applied and Environmental Microbiology},
year = {2026},
month = aug,
doi = {10.1128/aem.01445-26},
url = {https://hal.science/hal-05732819v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A capsid hinge region in European hepatitis E virus links mutations to genotype, virion surface properties, and environmental circulation
AU - Samy Kasmi
AU - Guillaume Sautrey
AU - Cédric Hartard
AU - Fabienne Quilès
AU - Jean-Luc Bailly
AU - Alexis de Rougemont
AU - Hélène Jeulin
AU - Raphael Duval
AU - Christophe Gantzer
AU - Evelyne Schvoerer
PY - 2026
DA - 2026/08/28
JO - Applied and Environmental Microbiology
DO - 10.1128/aem.01445-26
UR - https://hal.science/hal-05732819v1
AB - Hepatitis E virus (HEV) exhibits genetic diversity associated with distinct public health outcomes and circulation patterns across interconnected human and environmental reservoirs. Most studies have focused on genome-wide diversity, revealing relationships between genotype, virulence, and dissemination routes. However, the role of localized mutations in the capsid protein (ORF2), which may influence the extracellular fate and ecology of HEV through changes in surface biological and physicochemical properties of virions, received limited attention. Here, we combined large-scale analysis of European HEV sequences, structural modeling, and physicochemical characterization to investigate such variations in ORF2. Analysis of ORF2 sequences on a genomic segment highly reported in GenBank, derived from patients and the environment, revealed recurrent mutation motifs (single H354Y and triple H354Y–G357S–V364I motifs) located in a conserved capsid hinge region connecting the middle (M) and protruding (P) domains of the protein. These motifs displayed distinct frequency patterns according to sequence sources and were associated with genotypes 3 and 1, respectively. AlphaFold-based modeling identified this region as a flexible interface between the M and P domains and indicated that mutations reduce predicted alignment error of the P domain relative to the overall protein model, consistent with altered exposure at the virion surface. In vitro analyses of synthetic peptides encompassing this critical region revealed increased hydrophobicity and structural rearrangements, supporting local modulation of capsid surface properties. Together, these results identify a structurally and physicochemically sensitive hinge region in the HEV capsid, suggesting a link between ORF2 sequence variations, genotype, virion surface properties, and environmental circulation. IMPORTANCE: Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide, which is transmitted through complex, genotype-linked dissemination routes between humans, animals, and environmental waters. Understanding the circulation dynamics of HEV virions is essential for improving environmental surveillance, risk assessment, and public health strategies within a One Health approach. By combining genetic, structural, and physicochemical analyses, this study highlights specific mutation motifs in a hinge region of the ORF2 capsid protein likely to link distinct distribution patterns of HEV across environmental reservoirs to potential changes in virion surface properties. Such mutation motifs may serve as molecular signatures for exploring virus persistence and dissemination in environmental contexts. Overall, this work provides a new framework for connecting viral genetic variation to environmental behavior beyond traditional genotype classification.
SN - 0099-2240
SN - 1098-5336
ER -