A flavivirus-inducible gene expression system that modulates broad-spectrum antiviral activity against dengue and Zika viruses

Incidence of dengue virus (DENV) and Zika virus (ZIKV), two mosquito-borne flaviviruses, is increasing in large parts of the world. Vaccination and medication for these diseases are unsatisfactory. Here, we developed a novel antiviral approach, using a virus-inducible gene expression system, to block virus replication and transmission. Constructs containing the smallest replication units of dengue virus serotype 2 (DENV2) with negative-stranded DENV2 artificial genomes and genes of interest were established in an Aedes aegypti cell line, resulting in expression of target genes after DENV2 infection. Green fluorescent protein (GFP) assays confirmed the system was virus-inducible. When we used one of two apoptosis-related genes, A. aegypti michelob_x (AaMx) and inhibitor of apoptosis (IAP)-antagonist michelob_x-like protein (AaIMP) instead of GFP, the production of viral RNA and proteins were inhibited for all five viruses tested (DENV1-4 and ZIKV), and effector caspase activity was induced. The system thus inhibited the production of infectious virus particles in vitro, and in mosquitoes it did so after DENV2 infection. This is a novel broad-spectrum antiviral approach using a flavivirus-inducible gene-expression system, which could lead to new avenues for mosquito-borne disease control.