Stringent and complex sequence constraints of an IGHV1-69 broadly neutralizing antibody to influenza HA stem
Qi Wen Teo,
Yiquan Wang,
Huibin Lv,
Timothy J.C. Tan,
Ruipeng Lei,
Kevin J. Mao,
Nicholas C. Wu
Affiliations
Qi Wen Teo
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
Yiquan Wang
Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
Huibin Lv
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
Timothy J.C. Tan
Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
Ruipeng Lei
Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
Kevin J. Mao
Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
Nicholas C. Wu
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; Corresponding author
Summary: 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.
