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Design of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation

  1. Author:
    Zhang, Peng
    Gorman, Jason
    Tsybovsky,Yaroslav
    Lu, Maolin
    Liu, Qingbo
    Gopan, Vinay
    Singh, Mamta
    Lin, Yin
    Miao, Huiyi
    Seo, Yuna
    Kwon, Alice
    Olia, Adam S
    Chuang, Gwo-Yu
    Geng, Hui
    Lai, Yen-Ting
    Zhou, Tongqing
    Mascola, John R
    Mothes, Walther
    Kwong, Peter D
    Lusso, Paolo

  2. Author Address

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: zhangp@ihm.ac.cn., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Cellular and Molecular Biology, School of Medicine, University of Texas at Tyler Health Science Center, Tyler, TX 75708, USA., Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; School of Life Science and Technology, Southeast University, Nanjing 210096, China., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; ModeX Therapeutics, 20 Riverside Road, Weston, MA 02493, USA., Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA., Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: plusso@niaid.nih.gov.,
    1. Year: 2024
    2. Date: Jul 18
    3. Epub Date: 2024 07 18
  2. Journal: Cell Reports
    1. 43
    2. 8
    3. Pages: 114518
  4. Type of Article: Article
  5. Article Number: 114518
  1. Abstract:

    Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.celrep.2024.114518
  3. PMID: 39028623
  4. PII : S2211-1247(24)00847-7

Library Notes

  1. Fiscal Year: FY2023-2024
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