Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface
Seth J. Zost, … , Andrew B. Ward, James E. Crowe Jr.
Seth J. Zost, … , Andrew B. Ward, James E. Crowe Jr.
Published June 22, 2021
Citation Information: J Clin Invest. 2021;131(15):e146791. https://doi.org/10.1172/JCI146791.
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Research Article Immunology

Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface

Abstract

Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of protective human antibodies from several individuals recognizing the trimer interface (TI) of the influenza A HA head, a recently identified site of vulnerability. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody–antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza A HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody–antigen interaction suggests that the TI epitope might serve as an important target for structure-based vaccine design.

Authors

Seth J. Zost, Jinhui Dong, Iuliia M. Gilchuk, Pavlo Gilchuk, Natalie J. Thornburg, Sandhya Bangaru, Nurgun Kose, Jessica A. Finn, Robin Bombardi, Cinque Soto, Elaine C. Chen, Rachel S. Nargi, Rachel E. Sutton, Ryan P. Irving, Naveenchandra Suryadevara, Jonna B. Westover, Robert H. Carnahan, Hannah L. Turner, Sheng Li, Andrew B. Ward, James E. Crowe Jr.

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Figure 4

Structural and sequence alignments of TI mAbs reveal common features of epitope recognition.

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Structural and sequence alignments of TI mAbs reveal common features of ...
(A–C) Structural alignment of the Fab/HA head domain complexes of FluA-20, S5V2-29, and H5.31, with the HA head domains aligned to one another. (A) View of the structural alignment from the side (upper image) and top (lower image). (B) Despite differences in HCDR3 length, FluA-20, S5V2-29, and H5.31 all contact HA R229 using a D or E at heavy chain position 98. (C) FluA-20, S5V2-29, and H5.31 germline-encoded light chain residue Y49 makes hydrophobic contacts and a hydrogen bond with D98 or E98 of the heavy chain, while germline-encoded Q55 makes hydrogen bond contacts with the main chain amide and carbonyl groups of HA residue 222. The shared somatic mutation S53N introduces an additional hydrogen bond with the main chain amide of HA residue 224. The interaction between HCDR3 D/E98 and LCDR2 Y49 is shown with blue dashes. (D) Sequence alignment of previously reported and newly reported TI mAbs identifies common recognition motifs, including a shared acidic residue at position 98 in the HCDR3, a common light chain (IGKV1-39), germline-encoded light chain contact residues shared by all mAbs, as well as a common light chain S53N somatic mutation. (E) Biolayer interferometry-based competition data demonstrate TI mAbs strongly compete with one another for binding to A/California/04/2009 HA trimer, but do not compete with the RBS mAb 5J8.