title: Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env.
abstract: HIV's envelope glycoprotein (Env) is the sole target for neutralizing antibodies. The structures of many broadly neutralizing antibodies (bNAbs) in complex with truncated Env subunits or components have been reported. However, their interaction with the intact Env trimer, and the structural determinants that underlie neutralization resistance in this more native context are less well understood. Here we use hydrogen/deuterium exchange to examine the interactions between a panel of bNAbs and native-like Env trimers (SOSIP.664 trimers). Highly potent bNAbs cause only localized effects at their binding interface, while the binding of less potent antibodies is associated with elaborate changes throughout the trimer. In conjunction with binding kinetics, our results suggest that poorly neutralizing antibodies can only bind when the trimer transiently samples an open state. We propose that the kinetics of such opening motions varies among isolates, with Env from neutralization-sensitive viruses opening more frequently than Env from resistant viruses.
authors: Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, Washington 98195, USA.
authors: Miklos
authors: M
authors: Guttman
authors: Weill Cornell Medical College, New York, New York 10021, USA.
authors: Albert
authors: A
authors: Cupo
authors: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Jean-Philippe
authors: JP
authors: Julien
authors: 1] Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Rogier W
authors: RW
authors: Sanders
authors: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Ian A
authors: IA
authors: Wilson
authors: Weill Cornell Medical College, New York, New York 10021, USA.
authors: John P
authors: JP
authors: Moore
authors: Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, Washington 98195, USA.
authors: Kelly K
authors: KK
authors: Lee
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D041961:Deuterium Exchange Measurement; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics; D015870:Gene Expression; D057809:HEK293 Cells; D015497:HIV-1 / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054299:env Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus
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