Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 7, Pages 522-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3051
Keywords
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Funding
- Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH)
- Division of AIDS, NIAID, NIH [P01-AI100151, P01-AI104722, R01-AI93278, R21-AI100696, R21-AI112389, R33-AI84714]
- US National Institutes of General Medical Sciences [P01-GM56550, R01-GM78031, R01-GM98859]
- US National Institute of Heart, Lung and Blood [PO1-HL59725]
- US National Science Foundation [MCB-1157506]
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery [OPP1033102]
- Australian Research Council [DP130102219]
- Irvington Fellows Program of the Cancer Research Program
- Department of Veterans Affairs
- China Scholarship Council-Yale World Scholars
- Federal funds from the Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]
- US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1157506] Funding Source: National Science Foundation
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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.
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