Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins.

甲病毒引起严重的关节炎或脑炎疾病。E1 结构糖蛋白在这些病毒中高度保守，并介导病毒与宿主细胞融合。然而，对 E1 蛋白的抗体反应在免疫中的作用知之甚少。我们从自然 EEEV 感染的幸存者中分离出具有多种甲病毒识别模式（从东方马脑炎病毒 [EEEV] 特异性到甲病毒交叉反应）的 E1 特异性人单克隆抗体 (mAb)。抗体结合模式和表位作图实验确定了 E1 反应性的差异，这些差异基于通过 pH 依赖性机制暴露在糖蛋白上的表位或在病毒流出之前在细胞表面上的呈现。体内疗效这些 mAb 的数量与体外病毒出口抑制的效力相对应，并且不需要 Fc 介导的效应子功能来治疗皮下 EEEV 攻击。这些研究揭示了对甲病毒 E1 蛋白产生广泛保护性抗体反应的分子基础。