Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.
Centre for BioImaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore 117557, Singapore.
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27637-27645. doi: 10.1073/pnas.2008051117. Epub 2020 Oct 21.
Chikungunya virus (CHIKV) is an emerging viral pathogen that causes both acute and chronic debilitating arthritis. Here, we describe the functional and structural basis as to how two anti-CHIKV monoclonal antibodies, CHK-124 and CHK-263, potently inhibit CHIKV infection in vitro and in vivo. Our in vitro studies show that CHK-124 and CHK-263 block CHIKV at multiple stages of viral infection. CHK-124 aggregates virus particles and blocks attachment. Also, due to antibody-induced virus aggregation, fusion with endosomes and egress are inhibited. CHK-263 neutralizes CHIKV infection mainly by blocking virus attachment and fusion. To determine the structural basis of neutralization, we generated cryogenic electron microscopy reconstructions of Fab:CHIKV complexes at 4- to 5-Å resolution. CHK-124 binds to the E2 domain B and overlaps with the Mxra8 receptor-binding site. CHK-263 blocks fusion by binding an epitope that spans across E1 and E2 and locks the heterodimer together, likely preventing structural rearrangements required for fusion. These results provide structural insight as to how neutralizing antibody engagement of CHIKV inhibits different stages of the viral life cycle, which could inform vaccine and therapeutic design.
基孔肯雅病毒（CHIKV）是一种新兴的病毒病原体，可引起急性和慢性衰弱性关节炎。在这里，我们描述了两种抗 CHIKV 单克隆抗体 CHK-124 和 CHK-263 如何在体外和体内有效抑制 CHIKV 感染的功能和结构基础。我们的体外研究表明，CHK-124 和 CHK-263 在病毒感染的多个阶段阻断 CHIKV。CHK-124 聚集病毒颗粒并阻断附着。此外，由于抗体诱导的病毒聚集，融合内体和出芽被抑制。CHK-263 通过阻断病毒附着和融合来中和 CHIKV 感染。为了确定中和的结构基础，我们生成了冷冻电子显微镜重建的 Fab：CHIKV 复合物，分辨率为 4-5Å。CHK-124 结合到 E2 结构域 B 并与 Mxra8 受体结合位点重叠。CHK-263 通过结合跨越 E1 和 E2 的表位来阻断融合，可能阻止融合所需的结构重排。这些结果提供了结构上的见解，即中和抗体与 CHIKV 的结合如何抑制病毒生命周期的不同阶段，这可能为疫苗和治疗设计提供信息。
