Hu Jing, Tan Haoyuan, Wang Meihua, Deng Shasha, Liu Mengyao, Zheng Peiyi, Wang Anmin, Guo Meng, Wang Jin, Li Jiayin, Qiu Huanwen, Yao Chengbing, Zhu Zhongliang, Hasi Chaolu, Pan Dongli, He Hongliang, Huang Chenghao, Shang Yuhua, Zhu Shu, Jin Tengchuan
Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.
National Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
Nat Commun. 2025 May 6;16(1):4196. doi: 10.1038/s41467-025-58669-7.
Herpes simplex virus (HSV) causes significant health burden worldwide. Currently used antiviral drugs are effective but resistance can occur. Here, we report two high-affinity neutralizing nanobodies, namely Nb14 and Nb32, that target non-overlapping epitopes in HSV gD. Nb14 binds a neutralization epitope located in the N-A' interloop, which prevents the interaction between gD and gH/gL during the second step of conformational changes during membrane fusion after virus attachment. The bispecific nanobody dimer (Nb14-32-Fc) exhibits high potency in vitro and in vivo. Mechanistically, Nb14-32-Fc neutralizes HSVs at both the pre-and post-attachment stages and prevents cell-to-cell spread in vitro. Administration of Nb14-32-Fc at low dosage of 1 mg/kg provides 100% protection in an HSV-1 infection male mouse model and an HSV-2 infection female mouse model. Our results demonstrate that Nb14-32-Fc could serve as a promising drug candidate for treatment of HSV infection, especially in the cases of antiviral drug resistance and severe herpes encephalitis.
单纯疱疹病毒（HSV）在全球范围内造成了巨大的健康负担。目前使用的抗病毒药物是有效的，但可能会产生耐药性。在此，我们报告了两种高亲和力的中和纳米抗体，即Nb14和Nb32，它们靶向HSV gD中不重叠的表位。Nb14结合位于N-A'内环的一个中和表位，在病毒附着后膜融合的构象变化第二步中，该表位可阻止gD与gH/gL之间的相互作用。双特异性纳米抗体二聚体（Nb14-32-Fc）在体外和体内均表现出高效力。从机制上讲，Nb14-32-Fc在附着前和附着后阶段均可中和HSV，并在体外阻止细胞间传播。以1 mg/kg的低剂量给药Nb14-32-Fc，在HSV-1感染的雄性小鼠模型和HSV-2感染的雌性小鼠模型中可提供100%的保护。我们的结果表明，Nb14-32-Fc有望成为治疗HSV感染的候选药物，尤其是在抗病毒药物耐药和严重疱疹性脑炎的情况下。
