Convergent Evolution in Breadth of Two VH6-1-Encoded Influenza Antibody Clonotypes from a Single Donor

• Published in: Cell host & microbe Vol. 28; no. 3; pp. 434 - 444.e4
• Main Authors: Wu, Nicholas C., Andrews, Sarah F., Raab, Julie E., O’Connell, Sarah, Schramm, Chaim A., Ding, Xintao, Chambers, Michael J., Leung, Kwanyee, Wang, Lingshu, Zhang, Yi, Mascola, John R., Douek, Daniel C., Ledgerwood, Julie E., McDermott, Adrian B., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2020; Elsevier; Cell Press
• Subjects: antibody; BASIC BIOLOGICAL SCIENCES; crystal structure; hemagglutinin; influenza; somatic hypermutation; stem; vaccine; influenza; vaccine; antibody; somatic hypermutation; hemagglutinin; crystal structure; stem
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2020.06.003

Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain VH6-1. We describe two genetically similar VH6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutralization activity. One clonotype evolved from a germline precursor recognizing influenza group 1 subtypes to gain breadth to group 2 subtypes. The other clonotype recognized group 2 subtypes and developed binding to group 1 subtypes through somatic hypermutation. Crystal structures reveal that the specificity differences are primarily mediated by complementarity-determining region H3 (CDR H3). Thus, while VH6-1 provides a framework for development of HA stem-directed bnAbs, sequence differences in CDR H3 junctional regions during VDJ recombination can alter reactivity and evolutionary pathways toward increased breadth. [Display omitted] •Two VH6-1 influenza HA stem-specific clonotypes are isolated from one individual•Precursors for these two VH6-1 clonotypes bind different influenza A HA groups•Differences in the CDRH3 conformation mediate the distinctive binding profiles•Somatic hypermutation leads to similar binding breadth between the two clonotypes Wu et al. describes two genetically similar influenza antibody clonotypes from the same individual. Clonotype precursors recognize different influenza A HA groups, but both develop cross-group neutralizing capability through affinity maturation. Structural characterization reveals that the specificity difference between clonotypes is mainly due to conformational variation in CDR H3.