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

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, Doudou Zhang, Ping Yang, Miaomiao Li, Yuncheng Li, Qinxue Hu, Sheng Ye, Peng Zheng, Hongxia Wei, Zhiwei Wu (), Linqi Zhang (), Yaxin Wang (), Yalan Liu () and Xilin Wu ()
Additional contact information
Linjing Zhu: Nanjing University
Bilian Huang: Nanjing University
Xiangyao Wang: Tianjin University
Fengfeng Ni: 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
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
Yuncheng Li: Chinese Academy of Sciences
Qinxue Hu: Chinese Academy of Sciences
Sheng Ye: Tianjin University
Peng Zheng: Nanjing University
Hongxia Wei: Nanjing Hospital Affiliated to Nanjing university of Chinese Medicine
Zhiwei Wu: Nanjing University
Linqi Zhang: Tsinghua University
Yaxin Wang: Tianjin University
Yalan Liu: Chinese Academy of Sciences
Xilin Wu: Nanjing University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51414-6

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