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- Title
Structural basis for cross-group recognition of an influenza virus hemagglutinin antibody that targets postfusion stabilized epitope.
- Authors
Tonouchi, Keisuke; Adachi, Yu; Suzuki, Tateki; Kuroda, Daisuke; Nishiyama, Ayae; Yumoto, Kohei; Takeyama, Haruko; Suzuki, Tadaki; Hashiguchi, Takao; Takahashi, Yoshimasa
- Abstract
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. Author summary: Induction of broadly protective antibodies is a clue to combat the antigenic variation of influenza virus. In this context, directing the antibody specificity toward the conserved hemagglutinin (HA) epitopes is a rational approach; however, it is hampered by virus strategies to hide the vulnerable sites. Here, we show a novel non-native epitope that emerges in the postfusion HA state with unique structure, denoted as kinked loop-helix. Antibody toward this epitope is accessible to HA on infected cells, demonstrating an exposure of the vulnerable sites during viral replication. In-depth structural analysis uncovers how antibody adapts to the conserved non-native epitope and provide cross-group protection, with an implication to rational design of broadly protective immunogens.
- Subjects
VIRAL antibodies; INFLUENZA viruses; MONOCLONAL antibodies; IMMUNOGLOBULINS; AVIAN influenza; ANTIGENIC variation; ANTIBODY specificity; VIRAL variation
- Publication
PLoS Pathogens, 2023, Vol 19, Issue 8, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011554