1. Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.
- Author
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Do Kwon, Young, Pancera, Marie, Acharya, Priyamvada, Georgiev, Ivelin S, Crooks, Emma T, Gorman, Jason, Joyce, M Gordon, Guttman, Miklos, Ma, Xiaochu, Narpala, Sandeep, Soto, Cinque, Terry, Daniel S, Yang, Yongping, Zhou, Tongqing, Ahlsen, Goran, Bailer, Robert T, Chambers, Michael, Chuang, Gwo-Yu, Doria-Rose, Nicole A, and Druz, Aliaksandr
- Subjects
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CRYSTAL structure , *VACCINES , *CD4 antigen , *VIRAL receptors , *LIGANDS (Biochemistry) , *IMMUNOGLOBULINS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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