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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kwon, YD; Pancera, M; Acharya, P; Georgiev, IS; Crooks, ET; Gorman, J; Joyce, MG; 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, G; 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

Published Date

  • July 2015

Published In

Volume / Issue

  • 22 / 7

Start / End Page

  • 522 - 531

PubMed ID

  • 26098315

Pubmed Central ID

  • 26098315

Electronic International Standard Serial Number (EISSN)

  • 1545-9985

Digital Object Identifier (DOI)

  • 10.1038/nsmb.3051

Language

  • eng

Conference Location

  • United States