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Published March 28, 2013 | Accepted Version + Supplemental Material
Journal Article Open

Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization

Abstract

Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design.

Additional Information

© 2013 Elsevier Inc. Received: April 6, 2012. Revised: January 7, 2013. Accepted: March 11, 2013. Published: March 28, 2013. We thank Louise Scharf for her help on generating structural images and Kai-Hui Yao for technical assistance. We thank Paola Marchovecchio and Han Gan for preparation of 3BNC60P61A as well as the members of the Nussenzweig and Bjorkman laboratory for helpful discussions. We also thank R. Wyatt for the YU2-gp140 plasmid; Davide Corti and Antonio Lanzavecchia for the HJ16 plasmids, and Francine McCutchan, Beatrice Hahn, David Montefiori, Michael Thomson, Ronald Swanstrom, Lynn Morris, Jerome Kim, Linqi Zhang, Dennis Ellenberger, and Carolyn Williamson for contributing HIV-1 envelope plasmids used in neutralization assays. F.K. was supported by the German Research Foundation (DFG, KL 2389/1-1), the Stavros Niarchos Foundation and the Robert Mapplethorpe Foundation. C.G. and R.-B.I. were supported by The German National Academic Foundation. I.G., M.P., T.Z., and P.D.K. were supported by intramural funding to the Vaccine Research Center, NIAID, NIH. M.S.S., P.J.B., and M.C.N. were supported by the Bill and Melinda Gates Foundation (M.S.S., Comprehensive Antibody Vaccine Immune Monitoring Consortium grant 1032144; P.J.B. and M.C.N., Collaboration for AIDS Vaccine Discovery grants 38660 [P.J.B.] and OPP1033115 [M.C.N.]). M.C.N is supported by the CHAVI-ID Award UM1AI100663 and The NIH grant AI081677. M.C.N. and P.J.B. are HHMI investigators.

Attached Files

Accepted Version - nihms513655.pdf

Supplemental Material - mmc1.xlsx

Supplemental Material - mmc2.xlsx

Supplemental Material - mmc3.pdf

Supplemental Material - mmc4.pdf

Supplemental Material - mmc5.pdf

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Additional details

Created:
August 19, 2023
Modified:
October 23, 2023