Structural basis for cross-group recognition of an influenza virus hemagglutinin antibody that targets postfusion stabilized epitope

Plasticity of influenza virus hemagglutinin (HA) conformation increases an opportunity to generate conserved non-native epitopes with unknown functionality. Here, we have performed an in-depth analysis of human monoclonal antibodies against a stem-helix region that is occluded in native prefusion ye...

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Bibliographic Details
Published in:PLoS pathogens 2023-08, Vol.19 (8), p.e1011554-e1011554
Main Authors: Tonouchi, Keisuke, Adachi, Yu, Suzuki, Tateki, Kuroda, Daisuke, Nishiyama, Ayae, Yumoto, Kohei, Takeyama, Haruko, Suzuki, Tadaki, Hashiguchi, Takao, Takahashi, Yoshimasa
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Antibodies, Neutralizing
Antibodies, Viral
Antigenic determinants
Antigens
Binding sites
Biology and Life Sciences
Cell surface
Conformation
Control
Dosage and administration
Epitopes
Hemagglutinin Glycoproteins, Influenza Virus
Hemagglutinins
Humans
Identification and classification
Immunity
Immunoglobulin G
Infections
Influenza
Influenza viruses
Influenza, Human
Medicine and Health Sciences
Molecular modelling
Monoclonal antibodies
Mutation
Orthomyxoviridae
Physical Sciences
Prevention
Protective antigen
Research and Analysis Methods
Risk factors
Structural analysis
Viral infections
Viruses
Zoonoses
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Summary:Plasticity of influenza virus hemagglutinin (HA) conformation increases an opportunity to generate conserved non-native epitopes with unknown functionality. Here, we have performed an in-depth analysis of human monoclonal antibodies against a stem-helix region that is occluded in native prefusion yet exposed in postfusion HA. A stem-helix antibody, LAH31, provided IgG Fc-dependent cross-group protection by targeting a stem-helix kinked loop epitope, with a unique structure emerging in the postfusion state. The structural analysis and molecular modeling revealed key contact sites responsible for the epitope specificity and cross-group breadth that relies on somatically mutated light chain. LAH31 was inaccessible to the native prefusion HA expressed on cell surface; however, it bound to the HA structure present on infected cells with functional linkage to the Fc-mediated clearance. Our study uncovers a novel non-native epitope that emerges in the postfusion HA state, highlighting the utility of this epitope for a broadly protective antigen design.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1011554