@article{102124657bf540d185e2bc203055bdc0,
title = "Convergent Evolution in Breadth of Two VH6-1-Encoded Influenza Antibody Clonotypes from a Single Donor",
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.",
keywords = "antibody, crystal structure, hemagglutinin, influenza, somatic hypermutation, stem, vaccine",
author = "Wu, {Nicholas C.} and Andrews, {Sarah F.} and Raab, {Julie E.} and Sarah O'Connell and Schramm, {Chaim A.} and Xintao Ding and Chambers, {Michael J.} and Kwanyee Leung and Lingshu Wang and Yi Zhang and Mascola, {John R.} and Douek, {Daniel C.} and Ledgerwood, {Julie E.} and McDermott, {Adrian B.} and Wilson, {Ian A.}",
note = "Funding Information: We thank Henry Tien for technical support with the crystalization robot. We acknowledge NIH R56 AI127371 (I.A.W.), NIH R01 AI132317 (I.A.W.), NIH K99 AI139445 (N.C.W.), NIH Collaborative Influenza Vaccine Innovation Center 75N93019C00051-0-9999-1 (I.A.W.), the Bill and Melinda Gates Foundation OPP1170236 (I.A.W.), and the Bill and Melinda Gates Foundation Post-Doctoral Fellowship in Global Health (N.C.W.). Support for this work was also provided by the Intramural Research Program of the Vaccine Research Center and Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (A.B.M.). Funding Information: We thank Henry Tien for technical support with the crystalization robot. We acknowledge NIH R56 AI127371 (I.A.W.), NIH R01 AI132317 (I.A.W.), NIH K99 AI139445 (N.C.W.), NIH Collaborative Influenza Vaccine Innovation Center 75N93019C00051-0-9999-1 (I.A.W.), the Bill and Melinda Gates Foundation OPP1170236 (I.A.W.), and the Bill and Melinda Gates Foundation Post-Doctoral Fellowship in Global Health (N.C.W.). Support for this work was also provided by the Intramural Research Program of the Vaccine Research Center and Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (A.B.M.). Conceptualization, N.C.W. and S.F.A.; Formal Analysis, C.A.S.; Investigation, N.C.W. S.F.A. J.E.R. S.O. M.J.C. K.L. L.W. Y.Z. and X.D.; Writing ? Original Draft, N.C.W. and S.F.A.; Writing ? Review & Editing, N.C.W. S.F.A, A.B.M. and I.A.W.; Supervision, J.R.M. D.C.D. J.E.L. A.B.M. and I.A.W.; Funding Acquisition, A.B.M. and I.A.W. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = sep,
day = "9",
doi = "10.1016/j.chom.2020.06.003",
language = "English (US)",
volume = "28",
pages = "434--444.e4",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "3",
}