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Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration

Author

Listed:
  • Linjing Zhu

    (Nanjing University
    Nanjing University
    Abrev Biotechnology Co. Ltd.)

  • Bilian Huang

    (Nanjing University)

  • Xiangyao Wang

    (Tianjin University)

  • Fengfeng Ni

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Mingjun Ao

    (Nanjing University)

  • Ruoke Wang

    (Tsinghua University)

  • Bin Zheng

    (Nanjing University)

  • Chen Chen

    (Nanjing Hospital Affiliated to Nanjing university of Chinese Medicine)

  • Jing Xue

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Lin Zhu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Chenbo Yang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Lingen Shi

    (Nanjing University)

  • Shengya Geng

    (Nanjing University
    Nanjing University)

  • Jiaqian Hu

    (Nanjing University)

  • Mengshi Yang

    (Chinese Academy of Sciences)

  • Doudou Zhang

    (Nanjing University)

  • Ping Yang

    (Chinese Academy of Sciences)

  • Miaomiao Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yuncheng Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qinxue Hu

    (Chinese Academy of Sciences)

  • Sheng Ye

    (Tianjin University
    Zhejiang University)

  • Peng Zheng

    (Nanjing University)

  • Hongxia Wei

    (Nanjing Hospital Affiliated to Nanjing university of Chinese Medicine)

  • Zhiwei Wu

    (Nanjing University
    Nanjing University
    Ningxia University
    Nanjing University)

  • Linqi Zhang

    (Tsinghua University)

  • Yaxin Wang

    (Tianjin University)

  • Yalan Liu

    (Chinese Academy of Sciences
    Hubei Jiangxia Laboratory)

  • Xilin Wu

    (Nanjing University
    Nanjing University
    Nanjing University)

Abstract

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4’s potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab’s efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Suggested Citation

  • Linjing Zhu & Bilian Huang & Xiangyao Wang & Fengfeng Ni & Mingjun Ao & Ruoke Wang & Bin Zheng & Chen Chen & Jing Xue & Lin Zhu & Chenbo Yang & Lingen Shi & Shengya Geng & Jiaqian Hu & Mengshi Yang & , 2024. "Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51414-6
    DOI: 10.1038/s41467-024-51414-6
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    References listed on IDEAS

    as
    1. Peter D. Kwong & Richard Wyatt & James Robinson & Raymond W. Sweet & Joseph Sodroski & Wayne A. Hendrickson, 1998. "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody," Nature, Nature, vol. 393(6686), pages 648-659, June.
    2. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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