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

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TitleCrystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.
Publication TypeJournal Article
Year of Publication2015
AuthorsKwon, YDo, Pancera, M, Acharya, P, Georgiev, IS, Crooks, ET, Gorman, J, M Joyce, G, Guttman, M, Ma, X, Narpala, S, Soto, C, Terry, DS, Yang, Y, Zhou, T, Ahlsen, G, Bailer, RT, Chambers, M, Chuang, G-Y, Doria-Rose, NA, Druz, A, Hallen, MA, Harned, A, Kirys, T, Louder, MK, O'Dell, S, Ofek, GA, Osawa, K, Prabhakaran, M, Sastry, M, Stewart-Jones, GBE, Stuckey, J, Thomas, PV, Tittley, T, Williams, C, Zhang, B, Zhao, H, Zhou, Z, Donald, BR, Lee, LK, Zolla-Pazner, S, Baxa, U, Schön, A, Freire, E, Shapiro, L, Lee, KK, Arthos, J, Munro, JB, Blanchard, SC, Mothes, W, Binley, JM, McDermott, AB, Mascola, JR, Kwong, PD
JournalNat Struct Mol Biol
Volume22
Issue7
Pagination522-31
Date Published2015 Jul
ISSN1545-9985
Abstract

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.

DOI10.1038/nsmb.3051
Alternate JournalNat. Struct. Mol. Biol.
PubMed ID26098315
Grant ListP01 AI104722 / AI / NIAID NIH HHS / United States