2. Academic Validation
  3. Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration

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

  • Nat Commun. 2024 Aug 13;15(1):6961. doi: 10.1038/s41467-024-51414-6.
Linjing Zhu # 1 2 3,  Bilian Huang # 1,  Xiangyao Wang # 4,  Fengfeng Ni # 5 6,  Mingjun Ao # 7,  Ruoke Wang 8,  Bin Zheng 7,  Chen Chen 9,  Jing Xue 10,  Lin Zhu 10,  Chenbo Yang 10,  Lingen Shi 1,  Shengya Geng 1 11,  Jiaqian Hu 1,  Mengshi Yang 5,  Doudou Zhang 1,  Ping Yang 5,  Miaomiao Li 5 6,  Yuncheng Li 5 6,  Qinxue Hu 5,  Sheng Ye 4 12,  Peng Zheng 7,  Hongxia Wei 9,  Zhiwei Wu 13 14 15 16,  Linqi Zhang 17,  Yaxin Wang 18,  Yalan Liu 19 20,  Xilin Wu 21 22 23
Affiliations

Affiliations

  • 1 Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China.
  • 2 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China.
  • 3 Abrev Biotechnology Co. Ltd., Nanjing, P.R. China.
  • 4 Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life sciences, Tianjin University, Tianjin, P.R. China.
  • 5 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China.
  • 6 Savaid Medical School, University of Chinese Academy of Sciences, Beijin, P.R. China.
  • 7 State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, P. R. China.
  • 8 Comprehensive AIDS Research Center, Center for Global Health and Infectious Diseases Research, NexVac Research Center, Center for Infectious Diseases Research, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, P.R. China.
  • 9 Department of Infection, Nanjing Hospital Affiliated to Nanjing university of Chinese Medicine, Nanjing, P.R. China.
  • 10 NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
  • 11 MOE Key Laboratory of Model Animals for Disease Study, Medical School, Nanjing University, Nanjing, P.R. China.
  • 12 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 13 Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China. wzhw@nju.edu.cn.
  • 14 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China. wzhw@nju.edu.cn.
  • 15 School of Life Sciences, Ningxia University, Yinchuan, Ningxia, P.R. China. wzhw@nju.edu.cn.
  • 16 State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, P.R. China. wzhw@nju.edu.cn.
  • 17 Comprehensive AIDS Research Center, Center for Global Health and Infectious Diseases Research, NexVac Research Center, Center for Infectious Diseases Research, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, P.R. China. zhanglinqi@tsinghua.edu.cn.
  • 18 Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life sciences, Tianjin University, Tianjin, P.R. China. wangyaxin@tju.edu.cn.
  • 19 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China. liuyl@wh.iov.cn.
  • 20 Hubei Jiangxia Laboratory, Wuhan, P.R. China. liuyl@wh.iov.cn.
  • 21 Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China. xilinwu@nju.edu.cn.
  • 22 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China. xilinwu@nju.edu.cn.
  • 23 State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, P.R. China. xilinwu@nju.edu.cn.
  • # Contributed equally.
PMID: 39138183 DOI: 10.1038/s41467-024-51414-6
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P99028
    99.91%, Anti-CD4 Monoclonal Antibody
    HIV