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Title: 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. In this paper, 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. Finally, 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.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [1] ;  [1] ;  [5] ;  [1] ; ORCiD logo [1] ;  [6] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] more »;  [7] ;  [8] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [9] ;  [1] ;  [5] ;  [5] ;  [10] ;  [11] ;  [12] ;  [8] ;  [13] ;  [13] ;  [14] ;  [3] ;  [15] ;  [16] ;  [5] ;  [4] ;  [2] ;  [1] ;  [1] ;  [1] « less
  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Vaccine Research Center
  2. San Diego Biomedical Research Inst., San Diego, CA (United States)
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Medicinal Chemistry
  4. Yale Univ., New Haven, CT (United States). School of Medicine. Dept. of Microbial Pathogenesis
  5. Weill Cornell Medical College of Cornell Univ., New York, NY (United States). Dept. of Physiology and Biophysics
  6. Columbia Univ., New York, NY (United States). Dept. of Biochemistry & Molecular Biophysics. Dept. of Systems Biology
  7. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Vaccine Research Center; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Biochemistry
  8. Frederick National Lab. for Cancer Research, Frederick, MD (United States). Leidos Biomedical Research. Cancer Research Technology Program. Electron Microscopy Lab.
  9. New York Univ. (NYU), NY (United States). School of Medicine
  10. Duke Univ., Durham, NC (United States). Medical Center. Dept. of Biochemistry. Dept. of Chemistry. Dept. of Computer Science
  11. Victor Chang Cardiac Research Inst., Darlinghurst, NSW (Australia). Structural and Computational Biology Division
  12. New York Univ. (NYU), NY (United States). School of Medicine; New York Veterans Affairs Harbor Healthcare System, New York, NY (United States)
  13. Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biology
  14. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Vaccine Research Center; Columbia Univ., New York, NY (United States). Dept. of Biochemistry & Molecular Biophysics
  15. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Lab. of Immunoregulation
  16. Yale Univ., New Haven, CT (United States). School of Medicine. Dept. of Microbial Pathogenesis; Tufts Univ., Boston, MA (United States). School of Medicine. Dept. of Molecular Biology and Microbiology
Publication Date:
OSTI Identifier:
1245840
Grant/Contract Number:
W-31-109-Eng-38; HHSN261200800001E; P01-AI100151; P01-AI104722; R01-AI93278; R21-AI100696; R21-AI112389; R33-AI84714; P01-GM56550; R01-GM78031; R01-GM98859; PO1-HL59725; MCB-1157506; OPP1033102; DP130102219
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 7; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
National Inst. of Health (NIH), Bethesda, MD (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); National Science Foundation (NSF); Bill and Melinda Gates Foundation (United States); Australian Research Council (Australia)
Contributing Orgs:
San Diego Biomedical Research Inst., San Diego, CA (United States); Univ. of Washington, Seattle, WA (United States); Yale Univ., New Haven, CT (United States); Weill Cornell Medical College of Cornell Univ., New York, NY (United States); Columbia Univ., New York, NY (United States); Duke Univ., Durham, NC (United States); Frederick National Lab. for Cancer Research, Frederick, MD (United States); New York Univ. (NYU), NY (United States); Victor Chang Cardiac Research Inst., Darlinghurst, NSW (Australia); New York Veterans Affairs Harbor Healthcare System, New York, NY (United States); Johns Hopkins Univ., Baltimore, MD (United States); Tufts Univ., Boston, MA (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Computational biology and bioinformatics; Immunology; Viral membrane fusion; X-ray crystallography