A naturally arising broad and potent CD4-binding site antibody with low somatic mutation

Creators: Barnes, Christopher O.; Schoofs, Till; Gnanapragasam, Priyanthi N. P.; Golijanin, Jovana; Huey-Tubman, Kathryn E.; Gruell, Henning; Schommers, Philipp; Suh-Toma, Nina; Lee, Yu Erica; Lorenzi, Julio C. Cetrulo; Piechocka-Trocha, Alicja; Scheid, Johannes F.; West, Anthony P., Jr.; Walker, Bruce D.; Seaman, Michael S.; Klein, Florian; Nussenzweig, Michel C.; Bjorkman, Pamela J.

Abstract

The induction of broadly neutralizing antibodies (bNAbs) is a potential strategy for a vaccine against HIV-1. However, most bNAbs exhibit features such as unusually high somatic hypermutation, including insertions and deletions, which make their induction challenging. VRC01-class bNAbs not only exhibit extraordinary breadth and potency but also rank among the most highly somatically mutated bNAbs. Here, we describe a VRC01-class antibody isolated from a viremic controller, BG24, that is much less mutated than most relatives of its class while achieving comparable breadth and potency. A 3.8-Å x-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach.

Additional Information

© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). Submitted 27 February 2022; Accepted 29 June 2022; Published 12 August 2022. We thank members of the Bjorkman, Nussenzweig, and Klein laboratories for helpful discussions. B cell sorting of donor 391370 was performed with help of K. Gordon and G. Breton. Neutralization fingerprinting analysis was performed by I. Georgiev. Sequencing analysis of antibody sequences and patient plasma env genes was supported by J. Pai. BG505 SOSIP.664-Avi, the CHO cell lines expressing the BG505 SOSIP.664 v4.1 trimer and DU422 SOSIP.664 v4.1 trimer, and the BG505.T332N gp160 expression plasmid were gifts of A. Cupo, J. P. Moore, and R. W. Sanders. We thank J. Vielmetter, P. Hoffman, and other members of the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. Structural studies were assisted by the Caltech Molecular Observatory (J. Kaiser, director) and the Biological and Cryogenic Transmission Electron Microscopy Center at Caltech (A. Malyutin and S. Chen, directors). Funding: This work was supported by National Institute of Allergy and Infectious Diseases of the NIH grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), NIH grant P50 AI150464 (to P.J.B.), Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery grants OPP1124068 (to M.C.N. and P.J.B.) and 1146996 (M.S.S.), NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.), the European Research Council (ERC-StG639961) (F.K.), and the German Center for Infection Research (DZIF) (F.K.). This work was supported, in part, by Bill & Melinda Gates Foundation grant no. INV-002143 (P.J.B.). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. C.O.B. was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. T.S. was supported by the Ernst Jung Career Advancement Award for Medical Research, grant UL1 TR001866 from the National Center for Advancing Translational Sciences [NCATS, NIH Clinical and Translational Science Award (CTSA) program], and DZIF grant TI 07.002. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory and electron microscopy. M.C.N. and B.D.W. are HHMI investigators. Author contributions: C.O.B., T.S., M.C.N., and P.J.B. conceived the study. T.S. and J.G. performed B cell sorting and antibody cloning of BG24 family members. C.O.B., Y.E.L., N.S.-T., and K.E.H.-T. performed protein purification and structural studies. P.N.P.G., K.E.H.-T., A.P.W., and C.O.B. performed in vitro 12-strain neutralization assays on engineered BG24 constructs and analyzed the data. C.O.B. and N.S.-T. conducted structural studies. T.S. and H.G. performed antibody in vivo experiments. P.S. conducted neutralization assays on viral mutants and envelope sequencing from mouse plasma. J.C.C.L. and T.S. conducted env sequencing from patient plasma. M.S.S. carried out neutralization testing on the 126-virus cross-clade panel. J.F.S. and M.S.S. conducted plasma screening of HIV controller cohort. A.P.-T. and B.D.W. collected and provided patient samples from the HIV controller cohort. C.O.B., T.S., M.C.N., and P.J.B. wrote the manuscript with contribution from all authors. Competing interests: The Rockefeller University has filed a provisional patent application in connection with this work on which C.O.B., T.S., M.C.N., and P.J.B. are inventors. H.G., P.S., and F.K. are all inventors on a patent application on HIV-1 neutralizing antibodies unrelated to this work filed by the University of Cologne. T.S. is currently an employee of the GSK group of companies and holds shares from the GSK group of companies as part of his current employee remuneration. M.C.N. is an inventor on a patent application on HIV-1 neutralizing antibodies that have been licensed to Gilead Sciences by Rockefeller University from which M.C.N. has received payments. M.C.N. is a member of the Scientific Advisory Boards of Aerium Therapeutics, Celldex Therapeutics, Walking Fish, and Frontier Biotechnologies. All other authors declare they have no competing interests. Data and materials availability: Nucleotide sequences of BG24 antibody family members and plasma env sequences from subject 391370 have been deposited in GenBank under accession numbers ON616415 - ON616492 and ON616493 - ON616516, respectively. The atomic models and cryo-EM maps generated from cryo-EM studies of the BG24CDR2-v2–DU422–10-1074 complex have been deposited at the PDB (www.rcsb.org/) and the Electron Microscopy Databank (EMDB, www.emdataresource.org/) under the accession numbers PDB 7UCG and EMD-26443, respectively. Coordinates for atomic models of the unliganded BG24S60A Fab and the BG24–BG505–10-1074 complex structure have been deposited in the Protein Data Bank under the accession numbers PDB 7UCE and PDB 7UCF, respectively. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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