Division of Virology, Department of Pathology, University of Cambridge, UK.
Immunology-Vaccinology, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
J Gen Virol. 2012 Jun;93(Pt 6):1316-1327. doi: 10.1099/vir.0.040790-0. Epub 2012 Feb 29.
Herpesviruses consistently transmit from immunocompetent carriers, implying that their neutralization is hard to achieve. Murid herpesvirus-4 (MuHV-4) exploits host IgG Fc receptors to bypass blocks to cell binding, and pH-dependent protein conformation changes to unveil its fusion machinery only after endocytosis. Nevertheless, neutralization remains possible by targeting the virion glycoprotein H (gH)-gL heterodimer, and the neutralizing antibody responses of MuHV-4 carriers are improved by boosting with recombinant gH-gL. We analysed here how gH-gL-directed neutralization works. The MuHV-4 gH-gL binds to heparan sulfate. However, most gH-gL-specific neutralizing antibodies did not block this interaction; neither did they act directly on fusion. Instead, they blocked virion endocytosis and transport to the late endosomes, where membrane fusion normally occurs. The poor endocytosis of gH-gL-neutralized virions was recapitulated precisely by virions genetically lacking gL. Therefore, driving virion uptake appears to be an important function of gH-gL that provides a major target for antibody-mediated neutralization.
疱疹病毒通常在免疫功能正常的携带者中传播，这意味着它们的中和很难实现。鼠疱疹病毒-4（MuHV-4）利用宿主 IgG Fc 受体来绕过细胞结合的障碍，并且只有在细胞内吞作用后，依赖 pH 的蛋白构象变化才会揭示其融合机制。然而，通过靶向病毒糖蛋白 H（gH）-gL 异二聚体仍然可以实现中和，并且用重组 gH-gL 增强 MuHV-4 携带者的中和抗体反应。我们在这里分析了 gH-gL 定向中和的作用机制。MuHV-4 的 gH-gL 与肝素硫酸盐结合。然而，大多数 gH-gL 特异性中和抗体不能阻断这种相互作用；它们也没有直接作用于融合。相反，它们阻断了病毒粒子的内吞作用和向晚期内体的运输，正常情况下膜融合在此发生。缺乏 gL 的病毒粒子的内吞作用被很好地模拟，证明了 gH-gL 中和的病毒粒子的内吞作用很差。因此，驱动病毒粒子摄取似乎是 gH-gL 的一个重要功能，为抗体介导的中和提供了一个主要的靶标。
