Stringent and complex sequence constraints of an IGHV1-69 broadly neutralizing antibody to influenza HA stem.

Cell Rep

Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. Electronic address:

Published: November 2023

IGHV1-69 is frequently utilized by broadly neutralizing influenza antibodies to the hemagglutinin (HA) stem. These IGHV1-69 HA stem antibodies have diverse complementarity-determining region (CDR) H3 sequences. Besides, their light chains have minimal to no contact with the epitope. Consequently, sequence determinants that confer IGHV1-69 antibodies with HA stem specificity remain largely elusive. Using high-throughput experiments, this study reveals the importance of light-chain sequence for the IGHV1-69 HA stem antibody CR9114, which is the broadest influenza antibody known to date. Moreover, we demonstrate that the CDR H3 sequences from many other IGHV1-69 antibodies, including those to the HA stem, are incompatible with CR9114. Along with mutagenesis and structural analysis, our results indicate that light-chain and CDR H3 sequences coordinately determine the HA stem specificity of IGHV1-69 antibodies. Overall, this work provides molecular insights into broadly neutralizing antibody responses to influenza virus, which have important implications for universal influenza vaccine development.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872586PMC
http://dx.doi.org/10.1016/j.celrep.2023.113410DOI Listing

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