Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we extracted the native form of sNS1 from cells infected with either the DENV WT or T164S mutant whose appearance was associated with a dengue outbreak in Cuba. We determined the cryoEM structures of sNS1 and its complex with a monoclonal antibody/Fab and found that the major species of sNS1 is a 1:1 complex of the NS1 dimer embedded in a High Density Lipoprotein (HDL) particle. Cross-linking MS studies confirm NS1:ApoA1 dimer formation with most ApoA1 interaction sites mapped to the NS1 wing and hydrophobic domains. Our results shed fresh light on the molecular pathogenesis of dengue and may have broad implications for managing dengue infection.
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