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Molecular insight into the neutralization mechanism of human-origin monoclonal antibody AH100 against Hantaan virus.
Wang, Feiran; Liu, Tiezhu; Liao, Liying; Chai, Yan; Qi, Jianxun; Gao, Feng; Liang, Mifang; Gao, George Fu; Wu, Yan.
Afiliação
  • Wang F; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
  • Liu T; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
  • Liao L; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.
  • Chai Y; Department of Pathogen Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • Qi J; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
  • Gao F; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
  • Liang M; Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, China.
  • Gao GF; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.
  • Wu Y; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
J Virol ; 98(8): e0088324, 2024 Aug 20.
Article em En | MEDLINE | ID: mdl-39078157
ABSTRACT
Both Old World and New World hantaviruses are transmitted through rodents and can lead to hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome in humans without the availability of specific therapeutics. The square-shaped surface spikes of hantaviruses consist of four Gn-Gc heterodimers that are pivotal for viral entry into host cells and serve as targets for the immune system. Previously, a human-derived neutralizing monoclonal antibody, AH100, demonstrated specific neutralization against the Old World hantavirus, Hantaan virus. However, the precise mode binding of this neutralizing monoclonal antibody remains unclear. In the present study, we determined the structure of the Hantaan virus Gn-AH100 antigen-binding fragment complex and identified its epitope. Crystallography revealed that AH100 targeted the epitopes on domain A and b-ribbon and E3-like domain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike revealed its localization between neighboring Gn protomers, distinguishing this epitope as a unique site compared to the previously reported monoclonal antibodies. This study provides crucial insights into the structural basis of hantavirus neutralizing antibody epitopes, thereby facilitating the development of therapeutic antibodies.IMPORTANCEHantaan virus (HTNV) poses a significant threat to humans by causing hemorrhagic fever with renal syndrome with high mortality rates. In the absence of FDA-approved drugs or vaccines, it is urgent to develop specific therapeutics. Here, we elucidated the epitope of a human-derived neutralizing antibody, AH100, by determining the HTNV glycoprotein Gn-AH100 antigen-binding fragment (Fab) complex structure. Our findings revealed that the epitopes situated on the domain A and b-ribbon and E3-like domain of the HTNV Gn head. By modeling the complex structure in the viral lattice, we propose that AH100 neutralizes the virus by impeding conformational changes of Gn protomer, which is crucial for viral entry. Additionally, sequence analysis of all reported natural isolates indicated the absence of mutations in epitope residues, suggesting the potential neutralization ability of AH100 in diverse isolates. Therefore, our results provide novel insights into the epitope and the molecular basis of AH100 neutralization.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vírus Hantaan / Mapeamento de Epitopos / Anticorpos Neutralizantes / Anticorpos Monoclonais / Anticorpos Antivirais / Epitopos Limite: Animals / Humans Idioma: En Revista: J Virol Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vírus Hantaan / Mapeamento de Epitopos / Anticorpos Neutralizantes / Anticorpos Monoclonais / Anticorpos Antivirais / Epitopos Limite: Animals / Humans Idioma: En Revista: J Virol Ano de publicação: 2024 Tipo de documento: Article