Kwon, Young Do and Pancera, Marie and Acharya, Priyamvada and Georgiev, Ivelin S and Crooks, Emma T and Gorman, Jason and Joyce, M Gordon and Guttman, Miklos and Ma, Xiaochu and Narpala, Sandeep and Soto, Cinque and Terry, Daniel S and Yang, Yongping and Zhou, Tongqing and Ahlsen, Goran and Bailer, Robert T and Chambers, Michael and Chuang, Gwo-Yu and Doria-Rose, Nicole A and Druz, Aliaksandr and Hallen, Mark A and Harned, Adam and Kirys, Tatsiana and Louder, Mark K and O'Dell, Sijy and Ofek, Gilad and Osawa, Keiko and Prabhakaran, Madhu and Sastry, Mallika and Stewart-Jones, Guillaume B E and Stuckey, Jonathan and Thomas, Paul V and Tittley, Tishina and Williams, Constance and Zhang, Baoshan and Zhao, Hong and Zhou, Zhou and Donald, Bruce R and Lee, Lawrence K and Zolla-Pazner, Susan and Baxa, Ulrich and Schön, Arne and Freire, Ernesto and Shapiro, Lawrence and Lee, Kelly K and Arthos, James and Munro, James B and Blanchard, Scott C and Mothes, Walther and Binley, James M and McDermott, Adrian B and Mascola, John R and Kwong, Peter D (2015) Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nature Structural & Molecular Biology, 22 (7). pp.522-31. ISSN 1545-9985 (PMC OA)
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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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 Feb 2016 23:10 |
| Last Modified: | 29 Apr 2016 01:04 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/301 |
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