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Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding

Scheid, Johannes F. and Mouquet, Hugo and Ueberheide, Beatrix and Diskin, Ron and Klein, Florian and Oliveira, Thiago Y. K. and Pietzsch, John and Fenyo, David and Abadir, Alexander and Velinzon, Klara and Hurley, Arlene and Myung, Sunnie and Boulad, Farid and Poignard, Pascal and Burton, Dennis R. and Pereyra, Florencia and Ho, David D. and Walker, Bruce D. and Seaman, Michael S. and Bjorkman, Pamela J. and Chait, Brian T. and Nussenzweig, Michel C. (2011) Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science, 333 (6049). pp. 1633-1637. ISSN 0036-8075. PMCID PMC3351836.

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Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.

Item Type:Article
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URLURL TypeDescription CentralArticle
Diskin, Ron0000-0002-2837-5897
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:© 2011 American Association for the Advancement of Science. Received 19 April 2011; accepted 21 June 2011; Published online 14 July 2011. The data reported in this paper are tabulated in the supporting online material, and the coordinates for the 3BNC60 Fab as well as the antibody sequences have been deposited in the Protein Data Bank and the European Molecular Biology Laboratory–European Bioinformatics Institute database [accession codes: 3RPI (3BNC60 coordinates), HE584535 to HE584554 (antibody sequences)]. We thank the HIV-positive donors for their support. We thank M. Jankovic for discussions and help with cloning of HIV envelope constructs; R. Wyatt for the plasmid of YU2-gp140; J. Mascola for the plasmid of 2CC-core and YU2-gp120 mutants; and M. Connors for access to patient NIH45; C. Gaebler, M. Warncke, P. M. Marcovecchio, and H. Gao for help with protein expression; K. Moss for patient coordination. We thank F. McCutchan, G. Shaw, B. Hahn, J. Baalwa, D. Montefiori, F. Gao, M. Thomson, J. Overbaugh, R. Swanstrom, L. Morris, J. Kim, L. Zhang, D. Ellenberger, and C. Williamson for contributing the HIV-1 Envelope plasmids used in our neutralization panel. We thank M. Simek, F. Priddy, and all the study participants and research staff at each of the International AIDS Vaccine Initiative (IAVI) Protocol G project; clinical and site team members; and all of the Protocol G clinical investigators, specifically, G. Miiro, A. Pozniak, D. McPhee, O. Manigart, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L.-G. Bekker, P. Pitisuttithum, R. Paris, J. Serwanga, and S. Allen for samples from one broadly neutralizing serum donor from Protocol G. We thank L. Walker for providing data on the neutralizing specificity of the Protocol G donor. In connection with this work, M.C.N. and J.F.S. have a pending patent application with the U.S. Patent and Trademark Office, patent number U.S. 61/486,960, entitled “Human Immunodeficiency Virus Neutralizing Antibodies and Methods of Use Thereof.” The reagents are available with a Materials Transfer Agreement. The work was supported by NIH grants P01 AI081677, RR00862, and RR022220, and by the Bill & Melinda Gates Foundation’s Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody–Vaccine Immune Monitoring Consortium, grant numbers 38619s and 38660. We thank the Molecular Observatory at Caltech (supported by the Gordon and Betty Moore Foundation) and the Stanford Synchrotron Radiation Lightsource. F.K. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, KL 2389/1-1). M.C.N., P.J.B, and B.D.W. are Howard Hughes Medical Institute Investigators.
Funding AgencyGrant Number
NIHP01 AI081677
Bill and Melinda Gates Foundation’s Collaboration for AIDS Vaccine Discovery38619s
Bill and Melinda Gates Foundation’s Collaboration for AIDS Vaccine Discovery38660
Deutsche Forschungsgemeinschaft (DFG)KL 2389/1-1
Gordon and Betty Moore FoundationUNSPECIFIED
Stanford Synchrotron Radiation LightsourceUNSPECIFIED
Issue or Number:6049
PubMed Central ID:PMC3351836
Record Number:CaltechAUTHORS:20111010-101426546
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27138
Deposited By: Jason Perez
Deposited On:10 Oct 2011 22:33
Last Modified:03 Oct 2019 03:21

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