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Nature. 2019 Apr;568(7752):415-419. doi: 10.1038/s41586-019-1101-y. Epub 2019 Apr 10.

Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET.

Author information

1
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
4
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
5
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
6
Centre de Recherche du CHUM (CRCHUM), Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
7
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
8
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.
9
Werner Reichardt Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany.
10
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
11
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
12
Departments of Biology and Chemistry, Pharmacy and Geosciences, Johannes Gutenberg University Mainz, Mainz, Germany.
13
Institute of Molecular Biology (IMB), Johannes Gutenberg University Mainz, Mainz, Germany.
14
Structural and Computational Biology Unit and Cell Biology and Biophysics Unit, EMBL, Heidelberg, Germany.
15
Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA, USA.
16
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
17
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. scb2005@med.cornell.edu.
18
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Joseph_Sodroski@dfci.harvard.edu.
19
Department of Microbiology, Harvard Medical School, Boston, MA, USA. Joseph_Sodroski@dfci.harvard.edu.
20
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. walther.mothes@yale.edu.

Abstract

The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic1-8. Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3)8-10. It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers)5,11-18. Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1JR-FL strain in complex with the antibody PGT15119. Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pre-triggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies-and thus of interest for the design of immunogens-remains unknown.

PMID:
30971821
PMCID:
PMC6655592
[Available on 2019-10-10]
DOI:
10.1038/s41586-019-1101-y

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