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

• Published in: Nature communications 2024-08, Vol.15 (1), p.6961-18, Article 6961
• Main Authors: Zhu, Linjing, Huang, Bilian, Wang, Xiangyao, Ni, Fengfeng, Ao, Mingjun, Wang, Ruoke, Zheng, Bin, Chen, Chen, Xue, Jing, Zhu, Lin, Yang, Chenbo, Shi, Lingen, Geng, Shengya, Hu, Jiaqian, Yang, Mengshi, Zhang, Doudou, Yang, Ping, Li, Miaomiao, Li, Yuncheng, Hu, Qinxue, Ye, Sheng, Zheng, Peng, Wei, Hongxia, Wu, Zhiwei, Zhang, Linqi, Wang, Yaxin, Liu, Yalan, Wu, Xilin
• Format: Article
• Language: English
• Subjects: 101/1; 13/44; 42/109; 42/47; 49/1; 49/31; 631/154/51/2318; 631/1647/334/1874/345; 631/250/255/1901; 631/535/1266; 64/60; Animal models; Animals; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibodies; Antibodies, Monoclonal; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; Antiretroviral agents; Antiretroviral therapy; Antiviral agents; Camelids, New World - immunology; CD4 antigen; CD4 Antigens - immunology; CD4 Antigens - metabolism; Cloning; Cytotoxicity; Drug development; Drug resistance; Drug therapy; Effectiveness; Female; Global health; HEK293 Cells; HIV; HIV Antibodies - immunology; HIV Antibodies - pharmacology; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - immunology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Immunization; Infections; Libraries; Mice; multidisciplinary; Nanobodies; Neutralization; Protein Conformation; Proteins; Public health; Science; Science (multidisciplinary); Side effects; Single-Domain Antibodies - immunology; Single-Domain Antibodies - pharmacology; Structural analysis; Trimers; Virus Internalization - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51414-6

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. In this study, Zhu et al. report Nb457, an alpaca-derived nanobody with broad-spectrum anti-HIV1 activity and show that Nb457 induces conformational changes in CD4, blocking viral entry and completely inhibiting HIV-1 in its trimeric form.