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Therapeutic Interfering Particles Exploiting Viral Replication and Assembly Mechanisms Show Promising Performance: A Modelling Study

Fatehi, Farzad, Bingham, Richard J., Dechant, Pierre-Philippe ORCID: https://orcid.org/0000-0002-4694-4010, Stockley, Pete G. and Twarock, Reidun (2021) Therapeutic Interfering Particles Exploiting Viral Replication and Assembly Mechanisms Show Promising Performance: A Modelling Study. arXive. (Submitted)

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Abstract

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 otherwise lack any genetic 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.

Item Type: Article
Status: Submitted
Subjects: Q Science > QA Mathematics
School/Department: School of Science, Technology and Health
URI: http://ray.yorksj.ac.uk/id/eprint/5457

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