In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28504265.
- Also identified by DOI 10.1038/ncomms15371 and PMC identifier 5440694.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The relatively recent discovery and characterization of human broadly neutralizing antibodies (bnAbs) against influenza virus provide valuable insights into antiviral and vaccine development. However, the factors that influence the evolution of high-affinity bnAbs remain elusive. We therefore explore the functional sequence space of bnAb C05, which targets the receptor-binding site (RBS) of influenza haemagglutinin (HA) via a long CDR H3. We combine saturation mutagenesis with yeast display to enrich for C05 variants of CDR H3 that bind to H1 and H3 HAs. The C05 variants evolve up to 20-fold higher affinity but increase specificity to each HA subtype used in the selection. Structural analysis reveals that the fine specificity is strongly influenced by a highly conserved substitution that regulates receptor binding in different subtypes. Overall, this study suggests that subtle natural variations in the HA RBS between subtypes and species may differentially influence the evolution of high-affinity bnAbs.
Medical subject headings
- Antibodies, Neutralizing
- Hemagglutinin Glycoproteins, Influenza Virus
- Influenza A virus
- Influenza, Human
- Receptors, Virus