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Published June 4, 2015 | Accepted Version + Supplemental Material
Journal Article Open

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Abstract

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V_H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V_H-gene-restricted ontogenies.

Additional Information

© 2015 Elsevier Inc. Received 24 December 2014, Revised 19 March 2015, Accepted 25 March 2015, Available online 21 May 2015. Published: May 21, 2015. We thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript and B. Honig for structural biology mentorship. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel. The authors acknowledge the contributions of the Center for HIV/AIDS Vaccine Discovery (CHAVI) Clinical Core Team. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, by the Howard Hughes Medical Institute (M.C.N. and P.J.B. are investigators), and by grants from the Division of AIDS, NIAID, National Institutes of Health (AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, and 1UM1 AI100663 and UM1 AI100645), from the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery Grant IDs 38637 and 1040753), and from the International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors, including: the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the UK Department for International Development (DFID); and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. Author Contributions: T.Z., R.M.L, L.C., P.A., L. Shapiro, J.R.M., and P.D.K. designed research, analyzed data, and assembled and wrote the paper, on which all principal investigators commented. R.M.L., X.W., and N.A.D.-R. isolated and characterized VRC13, VRC16, VRC18, and VRC27 antibodies with assistance from M.J.E., L.T., and Z.Y. and with R.T.B, M.K.L., K.M., S.O., and S.D.S. performing neutralization assays. T.Z., L.C., and P.A. led the structure determination and analysis with assistance from T.S.L., S.M., S.S., and A.Z. and with A.D., Y.Y., and B.Z. expressing HIV-1 gp120 cores and antibodies for crystallization and binding and T.Z. and M.P. performing trimer modeling. L.C., M.G.J., M.D.G., and L. Stamatatos produced germline antibodies and assessed binding to HIV-1 gp120. R.M.L. and X.W. prepared samples for 454 pyrosequencing; NISC and J.C.M. performed next-generation sequencing; C.S., L. Shapiro, and P.D.K. carried out bioinformatics. N.S.L. contributed to repertoire analysis, and A.P.W. and P.J.B. contributed to ontogeny analysis. I.S.G. performed neutralization fingerprinting, and T.K. and I.S.G. defined the CD4 supersite by antibody potency. T.G., H.-P.P., A.-S.Y., and L. Shapiro analyzed antibody paratope chemistry. D.L. and R.K. performed B cell activation experiments. R.M.L. analyzed donor sera potency and breadth, with D.R.B., W.C.K., M.S.C., B.F.H., J.P.C., M.C., J.F.S., and M.C.N. contributing donor samples. D.C., A.L, Q.J.S., and R.A.W. provided antibody HJ16; J.F.S. and M.C.N. provided antibodies 1B2530, 8ANC131, and 8ANC134.

Attached Files

Accepted Version - nihms735732.pdf

Supplemental Material - mmc1.pdf

Supplemental Material - mmc2.xlsx

Supplemental Material - mmc3.xlsx

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Created:
August 20, 2023
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October 23, 2023