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Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability

Author

Listed:
  • Leopold Kong

    (The Scripps Research Institute
    International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute)

  • Linling He

    (The Scripps Research Institute)

  • Natalia de Val

    (The Scripps Research Institute
    International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute)

  • Nemil Vora

    (The Scripps Research Institute)

  • Charles D. Morris

    (The Scripps Research Institute)

  • Parisa Azadnia

    (The Scripps Research Institute)

  • Devin Sok

    (International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

  • Bin Zhou

    (The Scripps Research Institute)

  • Dennis R. Burton

    (International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute
    Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard)

  • Andrew B. Ward

    (The Scripps Research Institute
    International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute)

  • Ian A. Wilson

    (The Scripps Research Institute
    International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute
    The Joint Center for Structural Genomics, The Scripps Research Institute)

  • Jiang Zhu

    (The Scripps Research Institute
    Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute
    The Scripps Research Institute)

Abstract

The trimeric HIV-1 envelope glycoprotein (Env) is critical for host immune recognition and neutralization. Despite advances in trimer design, the roots of Env trimer metastability remain elusive. Here we investigate the contribution of two Env regions to metastability. First, we computationally redesign a largely disordered bend in heptad region 1 (HR1) of SOSIP trimers that connects the long, central HR1 helix to the fusion peptide, substantially improving the yield of soluble, well-folded trimers. Structural and antigenic analyses of two distinct HR1 redesigns confirm that redesigned Env closely mimics the native, prefusion trimer with a more stable gp41. Next, we replace the cleavage site between gp120 and gp41 with various linkers in the context of an HR1 redesign. Electron microscopy reveals a potential fusion intermediate state for uncleaved trimers containing short but not long linkers. Together, these results outline a general approach for stabilization of Env trimers from diverse HIV-1 strains.

Suggested Citation

  • Leopold Kong & Linling He & Natalia de Val & Nemil Vora & Charles D. Morris & Parisa Azadnia & Devin Sok & Bin Zhou & Dennis R. Burton & Andrew B. Ward & Ian A. Wilson & Jiang Zhu, 2016. "Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12040
    DOI: 10.1038/ncomms12040
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    Cited by:

    1. Timothy J. C. Tan & Zongjun Mou & Ruipeng Lei & Wenhao O. Ouyang & Meng Yuan & Ge Song & Raiees Andrabi & Ian A. Wilson & Collin Kieffer & Xinghong Dai & Kenneth A. Matreyek & Nicholas C. Wu, 2023. "High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Yi-Zong Lee & Yi-Nan Zhang & Maddy L. Newby & Garrett Ward & Keegan Braz Gomes & Sarah Auclair & Connor DesRoberts & Joel D. Allen & Andrew B. Ward & Robyn L. Stanfield & Linling He & Max Crispin & Ia, 2025. "Rational design of next-generation filovirus vaccines combining glycoprotein stabilization and nanoparticle display with glycan modification," Nature Communications, Nature, vol. 16(1), pages 1-30, December.
    3. Rory Henderson & Kara Anasti & Kartik Manne & Victoria Stalls & Carrie Saunders & Yishak Bililign & Ashliegh Williams & Pimthada Bubphamala & Maya Montani & Sangita Kachhap & Jingjing Li & Chuancang J, 2024. "Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Jun Niu & Qi Wang & Wenwen Zhao & Bing Meng & Youwei Xu & Xianfang Zhang & Yi Feng & Qilian Qi & Yanling Hao & Xuan Zhang & Ying Liu & Jiangchao Xiang & Yiming Shao & Bei Yang, 2023. "Structures and immune recognition of Env trimers from two Asia prevalent HIV-1 CRFs," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Yi-Zong Lee & Jerome Han & Yi-Nan Zhang & Garrett Ward & Keegan Braz Gomes & Sarah Auclair & Robyn L. Stanfield & Linling He & Ian A. Wilson & Jiang Zhu, 2024. "Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    6. Yi-Nan Zhang & Jennifer Paynter & Aleksandar Antanasijevic & Joel D. Allen & Mor Eldad & Yi-Zong Lee & Jeffrey Copps & Maddy L. Newby & Linling He & Deborah Chavez & Pat Frost & Anna Goodroe & John Du, 2023. "Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates," Nature Communications, Nature, vol. 14(1), pages 1-29, December.

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