title: Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site.
abstract: Hepatitis A virus (HAV) infects ∼1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High-resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention.
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China; xiangxi@ibp.ac.cn liz@strubi.ox.ac.uk dave@strubi.ox.ac.uk raozh@xtal.tsinghua.edu.cn.
authors.forename: Xiangxi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Dang
authors.affiliation: National Institutes for Food and Drug Control, Beijing 100050, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Hu
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.|Sinovac Biotech Co., Ltd., Beijing 100085, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Sinovac Biotech Co., Ltd., Beijing 100085, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Abhay
authors.initials: A
authors.lastname: Kotecha
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Walter
authors.affiliation: National Institutes for Food and Drug Control, Beijing 100050, China.
authors.forename: Junzhi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom; xiangxi@ibp.ac.cn liz@strubi.ox.ac.uk dave@strubi.ox.ac.uk raozh@xtal.tsinghua.edu.cn.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Fry
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford OX3 7BN, United Kingdom; xiangxi@ibp.ac.cn liz@strubi.ox.ac.uk dave@strubi.ox.ac.uk raozh@xtal.tsinghua.edu.cn.|Diamond Light Sources, Didcot OX11 0DE, United Kingdom.
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China; xiangxi@ibp.ac.cn liz@strubi.ox.ac.uk dave@strubi.ox.ac.uk raozh@xtal.tsinghua.edu.cn.|Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001665:Binding Sites / Q000276:immunology; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D005260:Female; D030041:Hepatitis A virus / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D007140:Immunoglobulin Fab Fragments
keywords: entry; neutralizing mechanism; picornavirus; receptor recognition; uncoating