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Cell Host Microbe. 2018 Jun 13;23(6):832-844.e6. doi: 10.1016/j.chom.2018.05.002.

Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer.

Author information

1
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
2
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
3
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
4
Department of Chemistry, University of Kansas, Lawrence, KS 66047, USA.
5
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
6
CEA, Joliot, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France.
7
Department of Biological and Technological Research, San Raffaele Scientific Institute, Milan 20122, Italy.
8
Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
9
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: plusso@niaid.nih.gov.

Abstract

The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization provides a widely applicable template for the design of Env-based HIV-1 vaccines.

KEYWORDS:

HIV-1; conformational changes; immunogenicity; neutralizing antibodies; pre-clinical models; protein stabilization; protein structure; receptor binding; vaccine; viral envelope

Comment in

PMID:
29902444
PMCID:
PMC6007033
DOI:
10.1016/j.chom.2018.05.002
[Indexed for MEDLINE]
Free PMC Article

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