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Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer.
- Source :
-
Cell host & microbe [Cell Host Microbe] 2018 Jun 13; Vol. 23 (6), pp. 832-844.e6. - Publication Year :
- 2018
-
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.<br /> (Published by Elsevier Inc.)
- Subjects :
- AIDS Vaccines immunology
Animals
Antibodies, Neutralizing immunology
Female
HEK293 Cells
HIV Antibodies immunology
HIV Antigens chemistry
HIV Antigens immunology
HIV Envelope Protein gp120 chemistry
HIV Envelope Protein gp120 genetics
HIV Envelope Protein gp120 immunology
HIV Envelope Protein gp120 metabolism
HIV Envelope Protein gp160 chemistry
HIV Envelope Protein gp160 immunology
HIV Envelope Protein gp160 metabolism
HIV-1 genetics
HIV-1 pathogenicity
Humans
Immunization
Models, Molecular
Protein Conformation
Rabbits
Virus Internalization
env Gene Products, Human Immunodeficiency Virus genetics
CD4 Antigens immunology
CD4 Antigens metabolism
HIV-1 immunology
Protein Binding immunology
Protein Domains immunology
Protein Stability
env Gene Products, Human Immunodeficiency Virus chemistry
env Gene Products, Human Immunodeficiency Virus immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1934-6069
- Volume :
- 23
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell host & microbe
- Publication Type :
- Academic Journal
- Accession number :
- 29902444
- Full Text :
- https://doi.org/10.1016/j.chom.2018.05.002