Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress

Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human mo...

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Bibliographic Details
Published in:Cell 2021-08, Vol.184 (17), p.4430-4446.e22
Main Authors: Williamson, Lauren E., Reeder, Kristen M., Bailey, Kevin, Tran, Minh H., Roy, Vicky, Fouch, Mallorie E., Kose, Nurgun, Trivette, Andrew, Nargi, Rachel S., Winkler, Emma S., Kim, Arthur S., Gainza, Christopher, Rodriguez, Jessica, Armstrong, Erica, Sutton, Rachel E., Reidy, Joseph, Carnahan, Robert H., McDonald, W. Hayes, Schoeder, Clara T., Klimstra, William B., Davidson, Edgar, Doranz, Benjamin J., Alter, Galit, Meiler, Jens, Schey, Kevin L., Julander, Justin G., Diamond, Michael S., Crowe, James E.
Format: Article
Language:English
Subjects:
alphavirus
Alphavirus - immunology
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - isolation & purification
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
Antigens, Viral - immunology
Cell Line
Chikungunya virus - immunology
Cross Reactions - immunology
cross-reactive antibodies
Encephalitis Virus, Eastern Equine - immunology
Encephalomyelitis, Equine - immunology
Encephalomyelitis, Equine - virology
Epitope Mapping
Female
Horses
human monoclonal antibodies
Humans
Hydrogen-Ion Concentration
Joints - pathology
Male
Mice
Mice, Inbred C57BL
Models, Biological
non-neutralizing antibodies
post-exposure prophylaxis
Protein Binding
Receptors, Fc - metabolism
RNA, Viral - metabolism
Temperature
Viral Proteins - immunology
Virion - metabolism
Virus Internalization
Virus Release - physiology
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Description
Summary:Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins. [Display omitted] •Human E1 mAbs recognize the conserved fusion loop for pan-alphavirus reactivity•Cryptic E1 epitopes depend on acidic pH for exposure•Human E1 mAbs can inhibit virus egress•Egress inhibition serves as a correlate of protection for EEEV-induced disease Broadly reactive alphavirus E1 antibodies obtained from survivors of natural Eastern equine encephalitis virus infection inhibit virus egress in vitro and protect against infection by encephalitic (Eastern equine encephalitis) and arthritogenic (chikungunya) alphaviruses in mice.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2021.07.033