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Nat Struct Mol Biol. 2015 Jul;22(7):522-31. doi: 10.1038/nsmb.3051. Epub 2015 Jun 22.

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

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2
San Diego Biomedical Research Institute, San Diego, California, USA.
3
Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.
4
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
5
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, USA.
6
1] Department of Biochemistry &Molecular Biophysics, Columbia University, New York, New York, USA. [2] Department of Systems Biology, Columbia University, New York, New York, USA.
7
1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
8
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
9
New York University School of Medicine, New York, New York, USA.
10
1] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Chemistry, Duke University, Durham, North Carolina, USA. [3] Department of Computer Science, Duke University, Durham, North Carolina, USA.
11
Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
12
1] New York University School of Medicine, New York, New York, USA. [2] New York Veterans Affairs Harbor Healthcare System, New York, New York, USA.
13
Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.
14
1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] Department of Biochemistry &Molecular Biophysics, Columbia University, New York, New York, USA.
15
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
16
1] Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.

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.

PMID:
26098315
PMCID:
PMC4706170
DOI:
10.1038/nsmb.3051
[Indexed for MEDLINE]
Free PMC Article

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