A broadly neutralizing antibody confers cross-genus protection against alphaherpesviruses by inhibiting gB-mediated membrane fusion
Guosong Wang, Yu Li, Chongxin Wu, Tian Chen, Mengxuan Gui, Yue Zeng, Hui Sun, Kaiyun Chen, Xiangfeng Xi, Yanbo Yang, Yuchen Jiang, Yanan Jiang, Liqin Liu, Chengyu Yang, Jiarui Xin, Caihong Liu, Yiyi Li, Ningning Huo, Yang Huang, Lina Lin, Hai Yu, Chenghao Huang, Quan Yuan, Shaowei Li, Kegong Tian, Qingbing Zheng, Ningshao Xia, Yixin Chen
Abstract
The global prevalence and disease burden of alphaherpesviruses infections, including human-infecting viruses such as HSV-1, HSV-2, and VZV, as well as animal-infecting viruses like PRV, BHV, CHV, and FHV, highlight the unmet need for more effective and universal antiviral strategies. However, there has been no significant progress in developing broad-spectrum interventions against herpesvirus. Here we report the identification of a broadly neutralizing antibody against alphaherpesviruses, 16F9, which targets the glycoprotein B (gB) of alphaherpesviruses and offers cross-protection against multiple viruses such as HSV-1, HSV-2, and PRV in mice. 16F9 demonstrated robust therapeutic efficacy in various female mouse models of herpesvirus diseases including PRV-induced viral encephalitis, HSV-1-induced viral encephalitis, viral keratitis, cutaneous herpes, and neonatal herpesvirus infections. High-resolution cryo-electron microscopy structures revealed that 16F9 binds a conserved site of vulnerability on Domain I of gB. The binding of 16F9 disrupts the interaction between pre-gB and gHgL complex, thereby preventing viral membrane fusion and blocking viral infection. This study provides a foundation for advancing antiviral strategies and underscores the potential of gB-targeted interventions for combating herpesvirus infections. Alphaherpesvirus infections pose a health challenge due to the lack of effective broad-spectrum antiviral strategies. Here, the authors identify a broadly neutralizing antibody, 16F9, which targets glycoprotein B, offering cross-protection against multiple viruses and demonstrating robust efficacy in mouse models, paving the way for antiviral interventions.