Evolution of a functionally intact but antigenically distinct DENV fusion loop.

Autor:	Meganck RM; Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, United States., Zhu D; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., Dong S; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., Snoderly-Foster LJ; Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, United States., Dalben YR; Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, United States., Thiono D; Department of Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., White LJ; Department of Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., DeSilva AM; Department of Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., Baric RS; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, United States., Tse LV; Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Sep 19; Vol. 12. Date of Electronic Publication: 2023 Sep 19.
DOI:	10.7554/eLife.87555
Abstrakt:	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. Competing Interests: RM inventor on a patent application (#63/320,922) filed on the subject matter of the manuscript, DZ, SD, LS, YD, DT, LW, AD No competing interests declared, RB member of the advisory board of VaxArt and Invivyd and has collaborations with Takeda, Pfizer, Moderna, Ridgeback Biosciences, Gilead, and Eli Lily. Inventor on a patent application (#63/320,922) filed on the subject matter of the manuscript, LT Inventor on a patent application (#63/320,922) filed on the subject matter of the manuscript (© 2023, Meganck et al.)
Databáze:	MEDLINE
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