Viral RNA-host protein interactions are critical for replication of 
flaviviruses, a genus of positive-strand RNA viruses comprising major 
vector-borne human pathogens including dengue viruses (DENV). We examined three 
conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue 
virus (DENV-2) infection and found them to be novel regulators of the interferon 
(IFN) response against DENV-2. The three RBPs were required for the accumulation 
of the protein products of several interferon stimulated genes (ISGs), and for 
efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and 
CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was 
antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), 
which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to 
profound inhibition of ISG mRNA translation. This work describes a new and 
unexpected level of regulation for interferon stimulated gene expression and 
presents the first mechanism of action for an sfRNA as a molecular sponge of 
anti-viral effectors in human cells.