Receptor mimicry by antibody F045-092 facilitates universal binding to the H3 subtype of influenza virus

By Peter S. Lee, Nobuko Ohshima, R. Stanfield, Wenli Yu, Y. Iba, Y. Okuno, Y. Kurosawa, Ian A. Wilson. 2014

204 citations recorded by the source corpus.

Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012–2013. Here we describe an antibody, F045–092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045–092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045–092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics. Influenza A H3 viruses circulate in humans and bind host cells using the haemagglutinin (HA) glycoprotein. Here, Lee et al.perform a structural analysis of antibody F045–092 with broadly neutralizing activity against the H3 subtype and reveal its interaction with the HA receptor binding site.

Subfields: Epidemiology, Radiology, Nuclear Medicine and Imaging

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Barney S. Graham
2. Nicholas C. Wu
3. M. Kanekiyo
4. Ian A. Wilson
5. Trevor Bedford
6. Jesse D. Bloom

In Radiology, Nuclear Medicine and Imaging

1. Barney S. Graham
2. M. Kanekiyo
3. Nicholas C. Wu
4. Dina Schneidman-Duhovny
5. Haim J. Wolfson

Citations in the corpus

• Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin (2019, background): “Protein structures The protein structures are all PDB 4O5N, which is the structure of HA from the A/Victoria/361/2011 (H3N2) strain (Lee et al., 2014).”
• ScanNet: an interpretable geometric deep learning model for structure-based protein binding site prediction (2021, background): “Additional B-cell conformational epitope predictions with ScanNet a) Hemagglutinin trimer of Influenza H3 (PDB ID: 4o5n [95] ) b) Hemagglutinin trimer of Influenza H1 (PDB ID: 1rvx [96]) c) HIV Envelope protein (PDB ID 5fyl [97]).”
• A perspective on the structural and functional constraints for immune evasion: insights from the influenza virus (2017, methodology): “In addition to 133a insertion, many isolates from subtypes H4, H6, H7, H10, H14, and H15 have single (158a) or double (156a/158b) amino-acid insertions in the 150-loop that can negatively influence the binding of C05 [69], 139/1[71], and F045–092 [58].”
• Next-Generation Influenza Vaccines. (2020, background): “Other conserved HA regions of vulnerability are also regarded as improved vaccine targets, inspired by highly neutralizing human nAbs targeting the receptor-binding site (Whittle et al. 2011; Ekiert et al. 2012; Lee et al. 2014; Schmidt et al. 2015; Shen et al. 2017) and the lateral patch or the ves”