[Source: Proceedings of the National Academy of the Sciences of the United States of America, full text: (LINK). Abstract, edited.]
Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody
Aaron G. Schmidta,1, Huafeng Xub,1, Amir R. Khana,2, Timothy O’Donnellb, Surender Khuranac, Lisa R. Kingc, Jody Manischewitzc, Hana Goldingc, Pirada Suphaphiphatd, Andrea Carfid, Ethan C. Settembred, Philip R. Dormitzerd, Thomas B. Keplere, Ruijun Zhangf, M. Anthony Moodyf, Barton F. Haynesf, Hua-Xin Liaof, David E. Shawb,g, and Stephen C. Harrisona,3
Author Affiliations: aLaboratory of Molecular Medicine, Children’s Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115; bD. E. Shaw Research, New York, NY 10036; cDivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; dNovartis Vaccines and Diagnostics, Cambridge, MA 02139; eDepartment of Microbiology, Boston University School of Medicine, Boston, MA 02118; fDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710; and gCenter for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032
Contributed by Stephen C. Harrison, October 19, 2012 (sent for review August 30, 2012)
Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.
immunity - antigen recognition - X-ray crystallography
1A.G.S. and H.X. contributed equally to this work.
2Present address: School of Biochemistry and Immunology, Trinity College, Dublin, Republic of Ireland.
3To whom correspondence should be addressed. E-mail: email@example.com.
Author contributions: A.G.S., H.X., A.R.K., S.K., H.G., P.S., D.E.S., and S.C.H. designed research; A.G.S., H.X., A.R.K., T.O., S.K., L.R.K., J.M., P.S., and R.Z. performed research; A.G.S., H.X., A.R.K., T.O., S.K., H.G., A.C., E.C.S., P.R.D., T.B.K., M.A.M., B.F.H., H.-X.L., D.E.S., and S.C.H. analyzed data; and A.G.S., H.X., D.E.S., and S.C.H. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The crystallography, atomic coordinates, and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4HK0, 4HK3, 4HKB, and 4HKX). The sequences reported in this paper have been deposited in the GenBank database (accession nos. JX477156, JX477157, JX477158, JX477159, JX477160, JX477161, JX477162, JX477163, and JX477164).
See Commentary on page 7.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1218256109/-/DCSupplemental.
Freely available online through the PNAS open access option.