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Published June 27, 2019 | Supplemental Material + Accepted Version
Journal Article Open

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques

Abstract

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody–envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires.

Additional Information

© 2019 Springer Nature Publishing AG. Received 10 December 2018; Accepted 01 May 2019; Published 29 May 2019. Data availability: The atomic models and cryo-EM density maps generated during the current study have been deposited in the Protein Data Bank and Electron Microscopy Data Bank with accession numbers 6ORN and EMD-20175 (RC1–10-1074), 6ORQ and EMD-20178 (RC1–Ab275_(MUR)), 6ORO and EMD-20176 (RC1–Ab874_(NHP)), and 6ORP and EMD-20177 (RC1–Ab897_(NHP)). Sequence datasets generated and analysed during the current study are available from the corresponding authors upon reasonable request. We thank members of the Bjorkman, Martin and Nussenzweig laboratories for discussions, T. Eisenreich and S. Tittley for animal husbandry, K. Gordon for flow cytometry, S. Zolla-Pazner for providing the V3-consensus C peptide and anti-V3 monoclonal antibodies, M. Howarth for providing plasmids and advice for VLP expression and purification and A. Malyutin for help with cryo-EM data collection. Cryo-EM was done in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) Grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), NIH Grant P50 GM082545-06 (to P.J.B.), NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (to M.C.N.), the Intramural Research Program of the NIAID (to M.A.M.), the National Center for Biomedical Glycomics P41GM103490 and NIGMS R01GM130915 (to L.W.), Gates CAVD grant OPP1146996 (to M.S.S. and D.C.M.), NIH/NIAID P01 AI138212 (to L.S., A.T.M. and M.C.N.) and the Robertson Fund of the Rockefeller University (M.C.N.). Additional support included an NSF GRFP (to M.E.A.), an EMBO fellowship (to J.M.), the HHMI Hanna Gray Fellowship and the Postdoctoral Enrichment Program from the Burroughs Welcome Fund (to C.O.B.). M.C.N. and D.J.I. are HHMI investigators. Author Contributions: A.E., H.B.G., P.J.B. and M.C.N. designed the research. A.E., H.B.G., M.E.A., J.M., R.G., C.O.B., A.A.C., H.W., J.G., D.Y., J.R.K., Z.W., P.Z., L.N., K.-H.Y., J.B., H.G., A.V.V. and M.S. performed the research. A.E., H.B.G., M.E.A., J.M., R.G., T.Y.O., J.P., A.P.W., P.J.B. and M.C.N. analysed the data. D.C.M. and M.S.S. supervised in vitro neutralization assays. A.G. supervised antibody production. M.A.M. planned and supervised the immunization experiments in macaques. D.J.I. planned and supervised adjuvant production. A.T.M. and L.S. produced anti-idiotypic antibodies. L.W. planned and supervised mass spectrometry experiments. A.E., H.B.G., M.E.A., P.J.B. and M.C.N. wrote the manuscript. Competing interests: There are patents on 3BNC117 and 10-1074 on which M.C.N. and P.J.B. are inventors. M.C.N. is a member of the Scientific Advisory Boards of Celldex and Frontier Biosciences.

Attached Files

Accepted Version - nihms-1528399.pdf

Supplemental Material - 41586_2019_1250_Fig10_ESM.webp

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Additional details

Created:
August 19, 2023
Modified:
October 20, 2023