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

作者：Linjing Zhu, Bilian Huang, Xiangyao Wang, Fengfeng Ni, Mingjun Ao, Ruoke Wang, Bin Zheng, Chen Chen, Jing Xue, Lin Zhu, Chenbo Yang, Lingen Shi, Shengya Geng, Jia‐Qian Hu, Mengshi Yang, Doudou Zhang, Ping Yang, Miaomiao Li, Yuncheng Li, Qinxue Hu, Sheng Ye, Peng Zheng, Hongxia Wei, Zhiwei Wu, Linqi Zhang, Yaxin Wang, Yalan Liu, Xilin Wu · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-51414-6 · 被引用次数：22 · 研究领域：HIV Research and Treatment、Monoclonal and Polyclonal Antibodies Research、Immunotherapy and Immune Responses

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.