Journal Article

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

Yang, Mengshi, Geng, Shengya, Zheng, Bin, Huang, Bilian, Ni, Fengfeng, Liu, Yalan, Zheng, Peng, Wu, Xilin, Wang, Xiangyao, Ao, Mingjun, Chen, Chen, Zhu, Lin, Wu, Zhiwei, Yang, Chenbo, Li, Yuncheng, Wei, Hongxia, Hu, Qinxue, Yang, Ping, Li, Miaomiao, Wang, Yaxin, Zhu, Linjing, Zhang, Doudou, Shi, Lingen, Xue, Jing, Zhang, Linqi, Hu, Jiaqian, Ye, Sheng, Wang, Ruoke

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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 / Antibodies / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Antiviral agents / Antiviral drugs / Broadly Neutralizing Antibodies - immunology / Camelids, New World / CD4 antigen / CD4 Antigens - chemistry / CD4 Antigens - genetics / CD4 Antigens - immunology / CD4-Positive T-Lymphocytes - immunology / Cloning / Cytotoxicity / Drug development / Drug resistance / Drug therapy / Effectiveness / Global health / HIV / HIV Infections - immunology / HIV-1 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Immunization / Infections / Libraries / Models, Molecular / Monoclonal antibodies / multidisciplinary / Nanobodies / Neutralization / Protein Multimerization / Protein Structure, Quaternary / Protein Structure, Tertiary / Proteins / Public health / Science / Science (multidisciplinary) / Side effects / Single-Domain Antibodies - immunology / Structural analysis / Trimers