Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized1. JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease2,3. Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 μg dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 angstrom and 4.6 angstrom resolution cryo-electron microscopy structures of JEV–2F2-Fab and JEV–2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV4, unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.
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Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies, Nat Microbiol, 3:287-294,29 Jan 2018
Nature Microbiology, 3: 287-294,29 January 2018，DOI: 10.1038/s41564-017-0099-x
Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies
Xiaodi Qiu, Yingfeng Lei, Pan Yang, Qiang Gao, Nan Wang, Lei Cao, Shuai Yuan, Xiaofang Huang, Yongqiang Deng, Wenyu Ma, Tianbing Ding, Fanglin Zhang, Xingan Wu, Junjie Hu, Shan-Lu Liu, Chengfeng Qin, Xiangxi Wang, Zhikai Xu & Zihe Rao
Abstract
Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized1. JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease2,3. Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 μg dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 angstrom and 4.6 angstrom resolution cryo-electron microscopy structures of JEV–2F2-Fab and JEV–2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV4, unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.
文章链接：https://www.nature.com/articles/s41564-017-0099-x
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