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

• Published in: Cell reports (Cambridge) 2023-11, Vol.42 (11), p.113410-113410, Article 113410
• Main Authors: Teo, Qi Wen, Wang, Yiquan, Lv, Huibin, Tan, Timothy J.C., Lei, Ruipeng, Mao, Kevin J., Wu, Nicholas C.
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing; Antibodies, Viral; antibody; Broadly Neutralizing Antibodies; Complementarity Determining Regions; CP: Immunology; hemagglutinin; Hemagglutinin Glycoproteins, Influenza Virus; Hemagglutinins; high-throughput experiments; Humans; Influenza Vaccines; influenza virus; Influenza, Human; next-generation sequencing; sequence motifs; yeast display
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113410

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. [Display omitted] •Compatibilities of CR9114 with diverse light chains and CDR H3s are probed•Light chain of CR9114, despite having no contact with the epitope, is important for binding•Most CDR H3s from other IGHV1-69 HA stem antibodies are incompatible with CR9114 Through high-throughput experiments, Teo et al. systematically analyze the sequence constraints of CR9114, which is the broadest influenza antibody known to date. This work provides molecular insights into broadly neutralizing antibody responses to influenza virus, which have important implications for universal influenza vaccine development.