Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope
Abstract Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can cause severe encephalitis in humans and horses with a high case fatality rate. There are no licensed EEEV vaccines or therapeutics for human use, warranting the need to better understand the human immune...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60505-x |
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| author | Abhishek Bandyopadhyay Lauren E. Williamson Devika Sirohi Kevin Bailey Theron Gilliland Thomas Klose Geeta Buda Andrew Trivette Chengqun Sun Justin G. Julander William B. Klimstra James E. Crowe Richard J. Kuhn |
| author_facet | Abhishek Bandyopadhyay Lauren E. Williamson Devika Sirohi Kevin Bailey Theron Gilliland Thomas Klose Geeta Buda Andrew Trivette Chengqun Sun Justin G. Julander William B. Klimstra James E. Crowe Richard J. Kuhn |
| author_sort | Abhishek Bandyopadhyay |
| collection | DOAJ |
| description | Abstract Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can cause severe encephalitis in humans and horses with a high case fatality rate. There are no licensed EEEV vaccines or therapeutics for human use, warranting the need to better understand the human immune response against EEEV. Here we present a cryo-EM reconstruction of the chimeric virus, Sindbis (SINV)/EEEV, in complex with a potently neutralizing and efficacious intact human IgG1 antibody in a mouse model of infection and disease. This antibody requires bivalency to recognize a quaternary epitope on the E2 glycoprotein and cross-links two virus spikes across the icosahedral two-fold axis through a unique binding mode. Kinetic analysis of the binding interaction provides insights into this distinguishing feature. Mechanistically, the antibody inhibits viral entry into cells through blockade of receptor binding and early fusion events but does not block egress, thereby, exclusively targeting an epitope found on intact virions. The discovery of the quaternary epitope and unique binding mode recognized by this antibody together advance our understanding of the complexity of antibody-antigen interactions and can aid in vaccine design to elicit recognition of distinct epitopes of clinically relevant alphaviruses. |
| format | Article |
| id | doaj-art-11d87986ff1443408aac10316e5facfb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-11d87986ff1443408aac10316e5facfb2025-08-24T11:37:59ZengNature PortfolioNature Communications2041-17232025-08-0116111710.1038/s41467-025-60505-xStructural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitopeAbhishek Bandyopadhyay0Lauren E. Williamson1Devika Sirohi2Kevin Bailey3Theron Gilliland4Thomas Klose5Geeta Buda6Andrew Trivette7Chengqun Sun8Justin G. Julander9William B. Klimstra10James E. Crowe11Richard J. Kuhn12Department of Biological Sciences, Purdue UniversityThe Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical CenterDepartment of Biological Sciences, Purdue UniversityInstitute for Antiviral Research, Utah State UniversityThe Center for Vaccine Research, University of PittsburghDepartment of Biological Sciences, Purdue UniversityDepartment of Biological Sciences, Purdue UniversityThe Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical CenterThe Center for Vaccine Research, University of PittsburghInstitute for Antiviral Research, Utah State UniversityThe Center for Vaccine Research, University of PittsburghThe Vanderbilt Center for Antibody Therapeutics, Vanderbilt University Medical CenterDepartment of Biological Sciences, Purdue UniversityAbstract Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can cause severe encephalitis in humans and horses with a high case fatality rate. There are no licensed EEEV vaccines or therapeutics for human use, warranting the need to better understand the human immune response against EEEV. Here we present a cryo-EM reconstruction of the chimeric virus, Sindbis (SINV)/EEEV, in complex with a potently neutralizing and efficacious intact human IgG1 antibody in a mouse model of infection and disease. This antibody requires bivalency to recognize a quaternary epitope on the E2 glycoprotein and cross-links two virus spikes across the icosahedral two-fold axis through a unique binding mode. Kinetic analysis of the binding interaction provides insights into this distinguishing feature. Mechanistically, the antibody inhibits viral entry into cells through blockade of receptor binding and early fusion events but does not block egress, thereby, exclusively targeting an epitope found on intact virions. The discovery of the quaternary epitope and unique binding mode recognized by this antibody together advance our understanding of the complexity of antibody-antigen interactions and can aid in vaccine design to elicit recognition of distinct epitopes of clinically relevant alphaviruses.https://doi.org/10.1038/s41467-025-60505-x |
| spellingShingle | Abhishek Bandyopadhyay Lauren E. Williamson Devika Sirohi Kevin Bailey Theron Gilliland Thomas Klose Geeta Buda Andrew Trivette Chengqun Sun Justin G. Julander William B. Klimstra James E. Crowe Richard J. Kuhn Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope Nature Communications |
| title | Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope |
| title_full | Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope |
| title_fullStr | Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope |
| title_full_unstemmed | Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope |
| title_short | Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope |
| title_sort | structural elucidation of a unique binding mode by an intact alphavirus human igg molecule to a quaternary epitope |
| url | https://doi.org/10.1038/s41467-025-60505-x |
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