Journal Article

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

Lee, Kelly K, Zhang, Baoshan, Do Kwon, Young, Soto, Cinque, Munro, James B, Mascola, John R, Blanchard, Scott C, Yang, Yongping, Pancera, Marie, Osawa, Keiko, Stuckey, Jonathan, Druz, Aliaksandr, Acharya, Priyamvada, Gorman, Jason, Zhou, Zhou, Stewart-Jones, Guillaume B E, Narpala, Sandeep, Chambers, Michael, Sastry, Mallika, Crooks, Emma T, Zhao, Hong, Chuang, Gwo-Yu, Thomas, Paul V, Zhou, Tongqing, McDermott, Adrian B, Doria-Rose, Nicole A, Williams, Constance, Shapiro, Lawrence, Prabhakaran, Madhu, Lee, Lawrence K, Binley, James M, Kwong, Peter D, Hallen, Mark A, Kirys, Tatsiana, Guttman, Miklos, Ma, Xiaochu, Mothes, Walther, Freire, Ernesto, Joyce, M Gordon, Zolla-Pazner, Susan, O'Dell, Sijy, Georgiev, Ivelin S, Terry, Daniel S, Harned, Adam, Louder, Mark K, Ofek, Gilad, Donald, Bruce R, Tittley, Tishina, Bailer, Robert T, Baxa, Ulrich, Schön, Arne, Ahlsen, Goran, Arthos, James

2015

Overview

The structure of the ligand-free HIV-1–Env trimer allows conformational fixation of Env and generation of an antigen that binds CD4 with high affinity and is recognized by broadly neutralizing antibodies but not poorly neutralizing ones. As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/28 / 42/44 / 631/114 / 631/250 / 631/326/596/2116 / 631/535/1266 / 82/1 / 82/81 / 96/106 / AIDS vaccines / Antibodies, Neutralizing - immunology / Antigens / Biochemistry / Biological Microscopy / CD4 Antigens - immunology / Computational biology and bioinformatics / Crystal structure / Crystallography, X-Ray / env Gene Products, Human Immunodeficiency Virus - chemistry / env Gene Products, Human Immunodeficiency Virus - immunology / Epitopes - immunology / Health aspects / HEK293 Cells / HIV / HIV Antibodies - immunology / HIV Infections - immunology / HIV Infections - virology / HIV-1 - chemistry / HIV-1 - immunology / HIV-1 - physiology / Human immunodeficiency virus / Human immunodeficiency virus 1 / Humans / Immunology / Life Sciences / Membrane Biology / Models, Molecular / Molecular biology / Protein Conformation / Protein Multimerization / Protein Structure / Structural engineering / Vaccines / Viral antigens / Viral membrane fusion / Virus Internalization / X-ray crystallography