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

• Published in: PLoS pathogens Vol. 19; no. 8; p. e1011554
• Main Authors: Tonouchi, Keisuke, Adachi, Yu, Suzuki, Tateki, Kuroda, Daisuke, Nishiyama, Ayae, Yumoto, Kohei, Takeyama, Haruko, Suzuki, Tadaki, Hashiguchi, Takao, Takahashi, Yoshimasa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.08.2023
• Subjects: Analysis; Antibodies; Antibodies, Neutralizing; Antibodies, Viral - chemistry; Antibodies, Viral - metabolism; Antigenic determinants; Antigens; Binding sites; Biology and Life Sciences; Cell surface; Conformation; Control; Dosage and administration; Epitopes; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Hemagglutinins; Humans; Identification and classification; 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; Japan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011554

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.