State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2202371119. doi: 10.1073/pnas.2202371119. Epub 2022 Aug 2.
Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.
爱泼斯坦-巴尔病毒（EBV）感染了世界上超过 90%的成年人，是上皮细胞和 B 细胞起源的重要癌症负担。糖蛋白 B（gB）是 EBV 进入宿主细胞所必需的主要融合蛋白。在这里，我们分离了两种 EBV gB 特异性中和抗体 3A3 和 3A5；两者均能有效中和双嗜性 EBV 对 B 细胞和上皮细胞的感染。在人源化小鼠中，两种抗体均能有效预防 EBV 诱导的淋巴增殖性疾病。冷冻电镜分析鉴定出 3A3 和 3A5 分别结合在 D-II 和 D-IV 结构域上的非重叠位点。基于结构的突变分析表明，3A3 和 3A5 通过不同的机制抑制膜融合，涉及干扰 gB-细胞相互作用和 gB 激活。重要的是，3A3 和 3A5 表位是人类自然 EBV 感染引起的保护性 gB 特异性中和抗体的主要靶标，为抗病毒治疗和疫苗提供了潜在的靶点。
