Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Science translational medicine - 15(2023), 700 vom: 14. Juni, Seite eadg1855 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mittler, Eva [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Viral |
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| Anmerkungen: |
Date Completed 16.06.2023 Date Revised 28.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.adg1855 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358167477 |
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| 245 | 1 | 0 | |a Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody |
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| 500 | |a Date Completed 16.06.2023 | ||
| 500 | |a Date Revised 28.07.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antibodies, Viral |2 NLM | |
| 650 | 7 | |a Broadly Neutralizing Antibodies |2 NLM | |
| 700 | 1 | |a Serris, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Esterman, Emma S |e verfasserin |4 aut | |
| 700 | 1 | |a Florez, Catalina |e verfasserin |4 aut | |
| 700 | 1 | |a Polanco, Laura C |e verfasserin |4 aut | |
| 700 | 1 | |a O'Brien, Cecilia M |e verfasserin |4 aut | |
| 700 | 1 | |a Slough, Megan M |e verfasserin |4 aut | |
| 700 | 1 | |a Tynell, Janne |e verfasserin |4 aut | |
| 700 | 1 | |a Gröning, Remigius |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Abelson, Dafna M |e verfasserin |4 aut | |
| 700 | 1 | |a Wec, Anna Z |e verfasserin |4 aut | |
| 700 | 1 | |a Haslwanter, Denise |e verfasserin |4 aut | |
| 700 | 1 | |a Keller, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Chunyan |e verfasserin |4 aut | |
| 700 | 1 | |a Bakken, Russel R |e verfasserin |4 aut | |
| 700 | 1 | |a Jangra, Rohit K |e verfasserin |4 aut | |
| 700 | 1 | |a Dye, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Ahlm, Clas |e verfasserin |4 aut | |
| 700 | 1 | |a Rappazzo, C Garrett |e verfasserin |4 aut | |
| 700 | 1 | |a Ulrich, Rainer G |e verfasserin |4 aut | |
| 700 | 1 | |a Zeitlin, Larry |e verfasserin |4 aut | |
| 700 | 1 | |a Geoghegan, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Bradfute, Steven B |e verfasserin |4 aut | |
| 700 | 1 | |a Sidoli, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Forsell, Mattias N E |e verfasserin |4 aut | |
| 700 | 1 | |a Strandin, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Rey, Felix A |e verfasserin |4 aut | |
| 700 | 1 | |a Herbert, Andrew S |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Laura M |e verfasserin |4 aut | |
| 700 | 1 | |a Chandran, Kartik |e verfasserin |4 aut | |
| 700 | 1 | |a Guardado-Calvo, Pablo |e verfasserin |4 aut | |
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