Defective interfering (DI) RNAs are truncated forms of viral genomes that naturally occur in most RNA viruses. These RNAs emerge during viral replication and contain deletions and mutations that distinguish them from complete viral genomes. While these RNAs are termed "defective" due to their inability to independently generate complete viruses or replicate efficiently, DI RNAs significantly impact on viral pathogenesis through mechanisms such as viral interference, persistence and immune stimulation. With the help of a helper virus, DI RNAs can be incorporated into virions to form defective interfering particles (DIPs).
Our research focuses on DI290 RNA, a 290-nucleotide RNA identified in dengue virus (DENV)-infected laboratory cultures and human patients. We demonstrate that delivering DI290 RNA via DIPs and lipid nanoparticles (termed LNP-DI290) effectively activates innate immune responses and suppresses DENV infection in human primary monocyte-derived macrophages, THP-1 macrophages and human fibroblasts, which are cell types naturally targeted by DENV. Furthermore, our current studies show that LNP-DI290 can strongly inhibit DENV replication in vivo using two mouse models of DENV infection.
In addition to inhibiting DENV, DENV DIP and LNP-DI290 also inhibit the replication of several viruses in vitro, including respiratory syncytial virus, yellow fever virus, zika virus, Japanese encephalitis virus and SARS-CoV-2. Our findings indicate that DI290 RNA exhibits broad-spectrum antiviral activity. This presentation will detail our in vitro and in vivo studies, emphasising the potential of DI290 RNA as a novel, broadly acting antiviral agent against various RNA virus infections.