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

Nicholas C. Wu, Sarah F. Andrews, Julie E. Raab, Sarah O'Connell, Chaim A. Schramm, Xintao Ding, Michael J. Chambers, Kwanyee Leung, Lingshu Wang, Yi Zhang, John R. Mascola, Daniel C. Douek, Julie E. Ledgerwood, Adrian B. McDermott, Ian A. Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)434-444.e4
JournalCell Host and Microbe
Volume28
Issue number3
DOIs
StateAccepted/In press - 2020
Externally publishedYes

Keywords

  • antibody
  • crystal structure
  • hemagglutinin
  • influenza
  • somatic hypermutation
  • stem
  • vaccine

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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