Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.
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.
Duke Scholars
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- env Gene Products, Human Immunodeficiency Virus
- Virus Internalization
- Protein Multimerization
- Protein Conformation
- Models, Molecular
- Humans
- HIV-1
- HIV Infections
- HIV Antibodies
- HEK293 Cells
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- env Gene Products, Human Immunodeficiency Virus
- Virus Internalization
- Protein Multimerization
- Protein Conformation
- Models, Molecular
- Humans
- HIV-1
- HIV Infections
- HIV Antibodies
- HEK293 Cells