James Crowe
Faculty Member
Last active: 3/31/2019

Influenza human monoclonal antibody 1F1 interacts with three major antigenic sites and residues mediating human receptor specificity in H1N1 viruses.

Tsibane T, Ekiert DC, Krause JC, Martinez O, Crowe JE, Wilson IA, Basler CF
PLoS Pathog. 2012 8 (12): e1003067

PMID: 23236279 · PMCID: PMC3516549 · DOI:10.1371/journal.ppat.1003067

Most monoclonal antibodies (mAbs) to the influenza A virus hemagglutinin (HA) head domain exhibit very limited breadth of inhibitory activity due to antigenic drift in field strains. However, mAb 1F1, isolated from a 1918 influenza pandemic survivor, inhibits select human H1 viruses (1918, 1943, 1947, and 1977 isolates). The crystal structure of 1F1 in complex with the 1918 HA shows that 1F1 contacts residues that are classically defined as belonging to three distinct antigenic sites, Sa, Sb and Ca(2). The 1F1 heavy chain also reaches into the receptor binding site (RBS) and interacts with residues that contact sialoglycan receptors and determine HA receptor specificity. The 1F1 epitope is remarkably similar to the previously described murine HC63 H3 epitope, despite significant sequence differences between H1 and H3 HAs. Both antibodies potently inhibit receptor binding, but only HC63 can block the pH-induced conformational changes in HA that drive membrane fusion. Contacts within the RBS suggested that 1F1 may be sensitive to changes that alter HA receptor binding activity. Affinity assays confirmed that sequence changes that switch the HA to avian receptor specificity affect binding of 1F1 and a mAb possessing a closely related heavy chain, 1I20. To characterize 1F1 cross-reactivity, additional escape mutant selection and site-directed mutagenesis were performed. Residues 190 and 227 in the 1F1 epitope were found to be critical for 1F1 reactivity towards 1918, 1943 and 1977 HAs, as well as for 1I20 reactivity towards the 1918 HA. Therefore, 1F1 heavy-chain interactions with conserved RBS residues likely contribute to its ability to inhibit divergent HAs.

MeSH Terms (14)

Animals Antibodies, Monoclonal Antibodies, Viral Antibody Affinity Binding Sites, Antibody Crystallography, X-Ray Epitopes Hemagglutinin Glycoproteins, Influenza Virus Humans Immunoglobulin Heavy Chains Influenza A Virus, H1N1 Subtype Mice Mutagenesis, Site-Directed Protein Structure, Quaternary

Connections (1)

This publication is referenced by other Labnodes entities:

Links