Dengue virus 3’ untranslated region regulates RNA genome translation

Viral antigenic burden drives the inflammation-driven pathophysiology of dengue in humans. Nonetheless, the control of dengue virus (DENV) antigen expression for pathogenicity in humans remain uncertain. Herein, we examined a clinical DENV-3 isolate (Sleman/78), along with its partially and fully attenuated derivatives through 30- (Δ30) as well as 30- and 31-nucleotide deletions (Δ30/31), respectively, in the 3’ untranslated region (3′UTR) of the RNA genome; the partially and fully attenuated phenotypes of these derivatives were demonstrated in clinical trials. We found, using infectious clone technology, protein and RNA pulldown approaches, that the wild-type 3’UTR bound host translation proteins, including non-canonical eukaryotic initiation factor-3D (EIF3D) to support viral protein expression. Both Δ30/31 mutation and EIF3D silencing attenuated viral protein expression and hence replication of Sleman/78. As DENV genome is cyclized through 5’ and 3’UTR interactions, our findings the role of 3′UTR in regulating translation for infection and pathogenesis in humans.