Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance
Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.
Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.
View: Text | PDF
Research Article Immunology Infectious disease Virology

Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance

Abstract

H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at a high dose in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective, broadly reactive anti-H7 antibodies, informing the rational design of therapeutics and vaccines against H7N9 influenza virus.

Authors

Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.

×

Figure 1

Crystal structure and detailed interactions between Fab H7-235 and H7N9 SH13 HA1.

Options: View larger image (or click on image) Download as PowerPoint
Crystal structure and detailed interactions between Fab H7-235 and H7N9 ...
(A) Cartoon representation of the structure of the antigen-antibody complex. The HA1 domain is colored light blue, the receptor binding site (RBS) is indicated as a yellow circle, the H7-235 Fab heavy chain is red, and the light chain is brown. Individual CDRs of Fab H7-235 are labeled. Left or right panels show side or top views of the complex structure. See also Supplemental Figure 1, B and C and Supplemental Table 1. (B) Cartoon representation of H7-235 binding site. The HA1 domain is colored light blue, the RBS is yellow, and H7-235 Fab contact residues on HA1 are indicated with side chains and cyan color. See also Supplemental Figure 1A. (C) The H7-235 paratope. The footprint of H7-235 on the H7 HA surface is labeled in cyan color. The H7-235 Fab heavy chain is red, and the light chain is brown. H7-235 heavy or light chain contact residues are indicated with side chains in red or brown, respectively. The heavy chain and light chain interactions are shown in detail in D and E, with slightly reoriented views. Yellow dash lines represent hydrogen bonds in heavy or light chains.