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- Title
Evolution of a functionally intact but antigenically distinct DENV fusion loop.
- Authors
Meganck, Rita M.; Zhu, Deanna; Dong, Stephanie; Snoderly-Foster, Lisa J.; Dalben, Yago R.; Thiono, Devina; White, Laura J.; DeSilva, Arivianda M.; Baric, Ralph S.; Tse, Longping V.
- Abstract
A hallmark of dengue virus (DENV) pathogenesis is the potential for antibodydependent 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 prMand 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 liveattenuated DENV vaccines suitable for naïve individuals and children.
- Subjects
MONOCLONAL antibodies; DENGUE viruses; DENGUE; VACCINE effectiveness; FLAVIVIRUSES; MUTAGENESIS; TITERS; IMMUNOGLOBULINS
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.87555