Gammaherpesvirus is a subfamily of herpesvirus, distinct phylogenetically from alpha- and betaherpesvirus and featured by its oncogenic subtypes, including Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus1. It broadly infects humans and other vertebrate animals and causes various diseases and malignancies2,3. However, no specific antiviral agents are available for each type or the whole family. gB is the common fusion protein vital for herpesvirus infection and an ideal target for broad vaccine development, while the lack of basis for gB as a universal antigen hinders such effort4. Here, we report the molecular basis for broad gB binding and cross-genus virus neutralization by an antibody Fab5 for the first time. This antibody confers effective protection against authentic virus challenges in immune-competent mice, non-human primates, and humanized mice with murine, rhesus, and human gammaherpesvirus. Cryo-EM structures revealed that Fab5 targeted a conservative and vulnerable epitope of gammaherpesvirus gB and antigenically exposed across pre- or post-fusion status. This finding not only demonstrates Fab5 as cross-genus antibody broadly reactive against gammaherpesvirus infection and pathogenesis progression, but offers insights into potential common mechanisms for herpesvirus infection and facilitates the development of broad-spectrum vaccines against the gammaherpesvirus.
γ疱疹病毒是疱疹病毒的一个亚科，在系统发育上与α和β疱疹病毒存在差异，其特征在于其致癌亚型，包括EB病毒和卡波西肉瘤相关疱疹病毒1。它广泛感染人类和其他脊椎动物，并引起多种疾病和恶性肿瘤2,3。然而，目前尚无针对每种类型或整个病毒家族的特异性抗病毒药物。gB是疱疹病毒感染中至关重要的通用融合蛋白，也是广谱疫苗开发的理想靶点，但缺乏gB作为通用抗原的基础阻碍了此类努力4。在此，我们首次报道了抗体Fab5广泛结合gB并实现跨属病毒中和的分子基础。该抗体在具有免疫能力的小鼠、非人灵长类动物以及携带小鼠、恒河猴和人类γ疱疹病毒的人源化小鼠中，能有效抵抗真实病毒的攻击。冷冻电镜结构揭示，Fab5靶向γ疱疹病毒gB上一个保守且脆弱的表位，该表位在融合前或融合后状态均具有抗原暴露性。这一发现不仅证明了Fab5作为一种可广泛反应对抗γ疱疹病毒感染和病程进展的跨属抗体，还为理解疱疹病毒感染的潜在通用机制提供了见解，并促进了针对γ疱疹病毒的广谱疫苗的开发。
肿瘤(癌症)患者之家