Human antibody recognition of antigenic site IV on Pneumovirus fusion proteins.

Mousa JJ, Binshtein E, Human S, Fong RH, Alvarado G, Doranz BJ, Moore ML, Ohi MD, Crowe JE
PLoS Pathog. 2018 14 (2): e1006837

PMID: 29470533 · PMCID: PMC5823459 · DOI:10.1371/journal.ppat.1006837

Respiratory syncytial virus (RSV) is a major human pathogen that infects the majority of children by two years of age. The RSV fusion (F) protein is a primary target of human antibodies, and it has several antigenic regions capable of inducing neutralizing antibodies. Antigenic site IV is preserved in both the pre-fusion and post-fusion conformations of RSV F. Antibodies to antigenic site IV have been described that bind and neutralize both RSV and human metapneumovirus (hMPV). To explore the diversity of binding modes at antigenic site IV, we generated a panel of four new human monoclonal antibodies (mAbs) and competition-binding suggested the mAbs bind at antigenic site IV. Mutagenesis experiments revealed that binding and neutralization of two mAbs (3M3 and 6F18) depended on arginine (R) residue R429. We discovered two R429-independent mAbs (17E10 and 2N6) at this site that neutralized an RSV R429A mutant strain, and one of these mAbs (17E10) neutralized both RSV and hMPV. To determine the mechanism of cross-reactivity, we performed competition-binding, recombinant protein mutagenesis, peptide binding, and electron microscopy experiments. It was determined that the human cross-reactive mAb 17E10 binds to RSV F with a binding pose similar to 101F, which may be indicative of cross-reactivity with hMPV F. The data presented provide new concepts in RSV immune recognition and vaccine design, as we describe the novel idea that binding pose may influence mAb cross-reactivity between RSV and hMPV. Characterization of the site IV epitope bound by human antibodies may inform the design of a pan-Pneumovirus vaccine.

MeSH Terms (19)

Amino Acid Sequence Amino Acid Substitution Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Antibody Specificity Binding, Competitive Binding Sites, Antibody Cross Reactions Epitope Mapping Epitopes Humans Kinetics Metapneumovirus Microscopy, Electron Mutation Recombinant Proteins Respiratory Syncytial Virus, Human Viral Fusion Proteins

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