Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration
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.
Authors
- Lin Zhu (ORCID: https://orcid.org/0000-0001-5772-9482)
- Peng Zheng (ORCID: https://orcid.org/0000-0003-4792-6364)
- Linqi Zhang (ORCID: https://orcid.org/0000-0003-4931-509X)
- Jing Xue (ORCID: https://orcid.org/0000-0002-9113-2433)
- Ping Yang (ORCID: https://orcid.org/0000-0003-1689-6588)
- Hongxia Wei (ORCID: https://orcid.org/0000-0002-2253-9950)
- Yalan Liu (ORCID: https://orcid.org/0000-0003-0464-0964)
- Doudou Zhang (ORCID: https://orcid.org/0000-0001-8784-5599)
- Xiangyao Wang
- Jia‐Qian Hu (ORCID: https://orcid.org/0000-0002-0142-6498)
- Ruoke Wang (ORCID: https://orcid.org/0000-0002-8040-7913)
- Yuncheng Li (ORCID: https://orcid.org/0000-0002-8819-5169)
- Qinxue Hu (ORCID: https://orcid.org/0000-0002-4594-9215)
- Chenbo Yang
- Zhiwei Wu (ORCID: https://orcid.org/0000-0002-0672-948X)
- Mengshi Yang
- Fengfeng Ni
- Lingen Shi (ORCID: https://orcid.org/0000-0002-8145-4631)
- Xilin Wu (ORCID: https://orcid.org/0000-0002-2829-6654)
- Yaxin Wang (ORCID: https://orcid.org/0000-0002-3507-3969)
- Chen Chen (ORCID: https://orcid.org/0000-0003-2104-534X)
- Miaomiao Li (ORCID: https://orcid.org/0000-0003-2132-6168)
- Bin Zheng (ORCID: https://orcid.org/0000-0002-0721-7099)
- Sheng Ye (ORCID: https://orcid.org/0000-0001-9300-6257)
- Shengya Geng (ORCID: https://orcid.org/0009-0009-7136-5529)
- Mingjun Ao (ORCID: https://orcid.org/0009-0007-4831-7532)
- Linjing Zhu (ORCID: https://orcid.org/0009-0005-2071-9770)
- Bilian Huang
Institutions
- Nanjing University of Chinese Medicine (CN)
- Tianjin University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Ningxia University (CN)
- Jianghan University (CN)
- Wuhan Institute of Virology (CN)
- Beike Biotechnology (China) (CN)
- Model Animal Research Center (CN)
- Institute of Laboratory Animal Science (CN)
- China Academy of Chinese Medical Sciences (CN)
- Zhejiang University (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1038/s41467-024-51414-6
- Citations
- 18
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.29
Funders
- National Science Foundation
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Key Research and Development Program of China