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

  1. Author:
    Zhang, Peng
    Gorman, Jason
    Geng, Hui
    Liu, Qingbo
    Lin, Yin
    Tsybovsky, Yaroslav
    Go, Eden P
    Dey, Barna
    Andine, Tsion
    Kwon, Alice
    Patel, Mit
    Gururani, Deepali
    Uddin, Ferzan
    Guzzo, Christina
    Cimbro, Raffaello
    Miao, Huiyi
    McKee, Krisha
    Chuang, Gwo-Yu
    Martin, Loïc
    Sironi, Francesca
    Malnati, Mauro S
    Desaire, Heather
    Berger, Edward A
    Mascola, John R
    Dolan, Michael A
    Kwong, Peter D
    Lusso, Paolo

  2. Author Address

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Department of Chemistry, University of Kansas, Lawrence, KS 66047, USA., Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., CEA, Joliot, Service d 39;Ing 233;nierie Mol 233;culaire des Prot 233;ines, 91191 Gif-sur-Yvette, France., Department of Biological and Technological Research, San Raffaele Scientific Institute, Milan 20122, Italy., Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: plusso@niaid.nih.gov.,
    1. Year: 2018
    2. Date: Jun 13
  2. Journal: Cell Host & Microbe
    1. 23
    2. 6
    3. Pages: 832-844.e6
  4. Type of Article: Article
  1. 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. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.chom.2018.05.002
  3. PMID: 29902444
  4. PMCID: PMC6007033
  5. View record in Web of Science®
  6. WOS: 000438408600021
  7. PII : S1931-3128(18)30256-7

Library Notes

  1. Fiscal Year: FY2017-2018
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