title: Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design.
abstract: Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity. Here we report x-ray structures of lipid complexes with 10E8 and a scaffolded MPER construct and mutagenesis studies that provide evidence that the 10E8 epitope is composed of both MPER and lipid. 10E8 engages lipids through a specific lipid head group interaction site and a basic and polar surface on the light chain. In the model that we constructed, the MPER would then be essentially perpendicular to the virion membrane during 10E8 neutralization of HIV-1. As the viral membrane likely also plays a role in selecting for the germline antibody as well as size and residue composition of MPER antibody complementarity determining regions, the identification of lipid interaction sites and the MPER orientation with regard to the viral membrane surface during 10E8 engagement can be of great utility for immunogen and therapeutic design.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Irimia
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Andreia M
authors.identifier: 0000-0002-6738-303X
authors.initials: AM
authors.lastname: Serra
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.|Applied Physics Laboratory, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Ronald
authors.identifier: 0000-0002-2896-3453
authors.initials: R
authors.lastname: Jacak
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Oleksandr
authors.identifier: 0000-0002-5273-1951
authors.initials: O
authors.lastname: Kalyuzhniy
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Devin
authors.identifier: 0000-0002-9354-1740
authors.initials: D
authors.lastname: Sok
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Karen L
authors.identifier: 0000-0003-4404-5393
authors.initials: KL
authors.lastname: Saye-Francisco
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Torben
authors.initials: T
authors.lastname: Schiffner
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Tingle
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Michael
authors.identifier: 0000-0002-3917-453X
authors.initials: M
authors.lastname: Kubitz
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Robyn L
authors.identifier: 0000-0001-9521-9184
authors.initials: RL
authors.lastname: Stanfield
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Deller
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.|Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.|Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: William R
authors.identifier: 0000-0002-1120-0150
authors.initials: WR
authors.lastname: Schief
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.|International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.|Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, California, United States of America.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Ian A
authors.identifier: 0000-0002-6469-2419
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D019138:Antibodies, Blocking / Q000737:chemistry / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology*; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D014961:X-Ray Diffraction
chemical_list: D019138:Antibodies, Blocking; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41