PNNL

Abstract

The dengue viruses (DENV) exist as numerous genetic strains that are grouped into four antigenically distinct serotypes. DENV strains from each serotype can cause severe disease and threaten public health in tropical and subtropical regions worldwide. No licensed antiviral to treat DENV infections is currently available and there is an acute need for the development of novel therapeutics. We found that a synthetic siRNA (DC-3) targeting the highly conserved 5’ cyclization sequence (5’CS) region of the DENV genome reduced, by more than 100-fold, the titer of representative strains from each DENV serotype in vitro. To determine if DC-3 siRNA could inhibit DENV in vivo, an “In Vivo Ready” version of DC-3 was synthesized and administered to AG129 mice 1 day before and 1 and 3 days after infection with DENV-2 using a model of antibody-dependent enhancement of infection (ADE)-induced disease. When compared with the rapid weight loss and 5 days average survival time of the control groups, mice receiving DC-3 siRNA had an average survival time of 15 days and showed little weight loss for approximately 12 days. DC-3-treated mice also contained significantly less virus than control groups in several tissues at various time points post-infection. These results suggest that exogenously introduced siRNA combined with the endogenous RNA interference processing machinery has the capacity to thwart severe dengue-mediated disease. Overall, the data indicate that DC-3 siRNA represents a useful research reagent and has potential as a novel approach to therapeutic intervention against the genetically diverse dengue viruses.