Anti–influenza H7 human antibody targets antigenic site in hemagglutinin head domain interface
Jinhui Dong, … , Robert H. Carnahan, James E. Crowe Jr.
Jinhui Dong, … , Robert H. Carnahan, James E. Crowe Jr.
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(9):4734-4739. https://doi.org/10.1172/JCI136032.
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Anti–influenza H7 human antibody targets antigenic site in hemagglutinin head domain interface

Abstract

Although broadly protective, stem-targeted Abs against the influenza A virus hemagglutinin (HA) have been well studied, very limited information is available on Abs that broadly recognize the head domain. We determined the crystal structure of the HA protein of the avian H7N9 influenza virus in complex with a pan-H7, non-neutralizing, protective human Ab. The structure revealed a B cell epitope in the HA head domain trimer interface (TI). This discovery of a second major protective TI epitope supports a model in which uncleaved HA trimers exist on the surface of infected cells in a highly dynamic state that exposes hidden HA head domain features.

Authors

Jinhui Dong, Iuliia Gilchuk, Sheng Li, Ryan Irving, Matthew T. Goff, Hannah L. Turner, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.

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Figure 1

H7-200 is a heterosubtypic HA head domain–specific Ab that disrupts the HA trimer upon binding.

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H7-200 is a heterosubtypic HA head domain–specific Ab that disrupts the ...
(A) H7-200, H7.5, or FluA-20, in serial dilutions, was tested for binding to recombinant soluble proteins from A/Shanghai/02/2013 (H7 SH13), A/British Columbia/1/2015 (H7 BC15), A/Hunan/02650/2016 (H7 HN16), A/Guangdong/17SF003/2016 (H7 GD16), A/England/268/1996 (H7 EN96), A/Netherlands/219/2003 (H7 NL03), A/Canada/rv504/2004 (H7 rCA04), A/New York/107/2003 (H7 NY03), and A/shearwater/Western Australia/2576/1979 (H15 wts/WA79) strains, and detection of binding with a conjugate and colorimetric signal read for optical density at 405 nm was measured. Data points indicate the mean optical density of 3 replicates, and error bars indicate the SD. (B) Competition-binding assays were performed using biolayer interferometry. A His-tagged H7 SH13 HA1 protein was loaded onto Anti-Penta-HIS biosensors (FortéBio, Sartorius), and the binding of 2 successively applied IgG Abs was tested. (C) Representative 2D class averages of H7-200 bound to H7 SH13 HA. The majority of the particles were composed of Fab-HA complexes, in which the Fab bound at the trimer interface, thereby disrupting the protomer-protomer interactions and resulting in a splayed open conformation of the HA trimer. We also observed a small minority of intact HA trimers that were not Fab bound (red boxes). (D) Colored class averages showing H7.167 Fab (yellow) or H7-200 Fab (teal) bound to HA protomers (white). The box size for each 2D class average is 295 x 295 Å. (E) Cartoon showing 2 models of the mechanism of Ab-induced trimer dissociation, either principally separation of the head domains or coordinated separation of the full protomer including the head and stem domains.