Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
J Exp Med. 2022 Apr 4;219(4). doi: 10.1084/jem.20212532. Epub 2022 Mar 17.
Venezuelan equine encephalitis virus (VEEV) remains a risk for epidemic emergence or use as an aerosolized bioweapon. To develop possible countermeasures, we isolated VEEV-specific neutralizing monoclonal antibodies (mAbs) from mice and a human immunized with attenuated VEEV strains. Functional assays and epitope mapping established that potently inhibitory anti-VEEV mAbs bind distinct antigenic sites in the A or B domains of the E2 glycoprotein and block multiple steps in the viral replication cycle including attachment, fusion, and egress. A 3.2-Å cryo-electron microscopy reconstruction of VEEV virus-like particles bound by a human Fab suggests that antibody engagement of the B domain may result in cross-linking of neighboring spikes to prevent conformational requirements for viral fusion. Prophylaxis or postexposure therapy with these mAbs protected mice against lethal aerosol challenge with VEEV. Our study defines functional and structural mechanisms of mAb protection and suggests that multiple antigenic determinants on VEEV can be targeted for vaccine or antibody-based therapeutic development.
委内瑞拉马脑炎病毒（VEEV）仍然存在流行爆发的风险，或被用作气溶胶化生物武器。为了开发可能的对策，我们从感染减毒 VEEV 株的小鼠和人类中分离出了 VEEV 特异性中和单克隆抗体（mAb）。功能分析和表位作图表明，具有强抑制作用的抗 VEEV mAb 结合 E2 糖蛋白的 A 或 B 结构域中的不同抗原位点，并阻断病毒复制周期中的多个步骤，包括附着、融合和出芽。与人类 Fab 结合的 VEEV 病毒样颗粒的 3.2Å 冷冻电镜重建表明，B 结构域的抗体结合可能导致相邻刺突的交联，从而阻止病毒融合的构象要求。用这些 mAb 进行预防或暴露后治疗可保护小鼠免受致死性气溶胶 VEEV 攻击。我们的研究定义了 mAb 保护的功能和结构机制，并表明 VEEV 上的多个抗原决定簇可作为疫苗或基于抗体的治疗开发的靶标。
