Evolution of a functionally intact but antigenically distinct DENV fusion loop
© 2023, Meganck et al..
A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for naïve individuals and children.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
eLife - 12(2023) vom: 19. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meganck, Rita M [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal |
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| Anmerkungen: |
Date Completed 21.09.2023 Date Revised 26.09.2023 published: Electronic UpdateOf: bioRxiv. 2023 Aug 04;:. - PMID 37034784 Citation Status MEDLINE |
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| doi: |
10.7554/eLife.87555 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362219117 |
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| 245 | 1 | 0 | |a Evolution of a functionally intact but antigenically distinct DENV fusion loop |
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| 500 | |a UpdateOf: bioRxiv. 2023 Aug 04;:. - PMID 37034784 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023, Meganck et al. | ||
| 520 | |a A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for naïve individuals and children | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Dong, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Snoderly-Foster, Lisa J |e verfasserin |4 aut | |
| 700 | 1 | |a Dalben, Yago R |e verfasserin |4 aut | |
| 700 | 1 | |a Thiono, Devina |e verfasserin |4 aut | |
| 700 | 1 | |a White, Laura J |e verfasserin |4 aut | |
| 700 | 1 | |a DeSilva, Arivianda M |e verfasserin |4 aut | |
| 700 | 1 | |a Baric, Ralph S |e verfasserin |4 aut | |
| 700 | 1 | |a Tse, Longping V |e verfasserin |4 aut | |
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