Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration PMID: 39138183

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
14. Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China. [email protected].
15. School of Life Sciences, Ningxia University, Yinchuan, Ningxia, P.R. China. [email protected].
16. State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, P.R. China. [email protected].
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. [email protected].
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. [email protected].
19. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China. [email protected].
20. Hubei Jiangxia Laboratory, Wuhan, P.R. China. [email protected].
21. Center for Public Health Research, Medical School, Nanjing University, Nanjing, P.R. China. [email protected].
22. Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, P.R. China. [email protected].
23. State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, P.R. China. [email protected].
# Contributed equally.

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.