State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, 361102, China.
School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
Antiviral Res. 2022 May;201:105298. doi: 10.1016/j.antiviral.2022.105298. Epub 2022 Mar 24.
Infections caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) remain a serious global health issue, and the medical countermeasures available thus far are limited. Virus-neutralizing monoclonal antibodies (NAbs) are crucial tools for studying host-virus interactions and designing effective vaccines, and the discovery and development of these NAbs could be one approach to treat or prevent HSV infection. Here, we report the isolation of five HSV NAbs from mice immunized with both HSV-1 and HSV-2. Among these were two antibodies that potently cross-neutralized both HSV-1 and HSV-2 with the 50% virus-inhibitory concentrations (IC) below 200 ng/ml, one of which (4A3) exhibited high potency against HSV-2, with an IC of 59.88 ng/ml. 4A3 neutralized HSV at the prebinding stage and prevented HSV infection and cell-to-cell spread. Significantly, administration of 4A3 completely prevented weight loss and improved survival of mice challenged with a lethal dose of HSV-2. Using structure-guided molecular modeling combined with alanine-scanning mutagenesis, we observed that 4A3 bound to a highly conserved continuous epitope (residues 216 to 220) within the receptor-binding domain of glycoprotein D (gD) that is essential for viral infection and the triggering of membrane fusion. Our results provide guidance for developing NAb drugs and vaccines against HSV.
单纯疱疹病毒 1 型（HSV-1）和 2 型（HSV-2）感染仍然是一个严重的全球健康问题，迄今为止可用的医疗对策有限。病毒中和单克隆抗体（NAb）是研究宿主-病毒相互作用和设计有效疫苗的重要工具，发现和开发这些 NAb 可能是治疗或预防 HSV 感染的一种方法。在这里，我们报告了从用 HSV-1 和 HSV-2 免疫的小鼠中分离出的五种 HSV NAb。其中有两种抗体能够强烈中和 HSV-1 和 HSV-2，其 50%病毒抑制浓度（IC）低于 200ng/ml，其中一种（4A3）对 HSV-2 具有很高的效力，IC 为 59.88ng/ml。4A3 在预结合阶段中和 HSV，防止 HSV 感染和细胞间传播。值得注意的是，4A3 的给药完全阻止了接受致死剂量 HSV-2 攻击的小鼠的体重减轻并提高了其存活率。通过结构引导的分子建模结合丙氨酸扫描诱变，我们观察到 4A3 结合到 gD 糖蛋白受体结合域内的一个高度保守的连续表位（残基 216 至 220），该表位对于病毒感染和膜融合的触发至关重要。我们的结果为开发针对 HSV 的 NAb 药物和疫苗提供了指导。
