  Defective interfering particles arise spontaneously during a viral infection
as mutants lacking essential parts of the viral genome. Their ability to
replicate in the presence of the wild-type (WT) virus (at the expense of viable
viral particles) is mimicked and exploited by therapeutic interfering
particles. We propose a strategy for the design of therapeutic interfering RNAs
(tiRNAs) against positive-sense single-stranded RNA viruses that assemble via
packaging signal-mediated assembly. These tiRNAs contain both an optimised
version of the virus assembly manual that is encoded by multiple dispersed RNA
packaging signals and a replication signal for viral polymerase, but lack any
protein coding information. We use an intracellular model for hepatitis C viral
(HCV) infection that captures key aspects of the competition dynamics between
tiRNAs and viral genomes for virally produced capsid protein and polymerase. We
show that only a small increase in the assembly and replication efficiency of
the tiRNAs compared with WT virus is required in order to achieve a treatment
efficacy greater than 99%. This demonstrates that the proposed tiRNA design
could be a promising treatment option for RNA viral infections.
