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Viruses 2017, 9(11), 347; doi:10.3390/v9110347

RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance

1
Departments of Mathematics, University of York, York YO10 5DD, UK
2
Department of Biology, University of York, York YO10 5DD, UK
3
York Cross-disciplinary Centre for Systems Analysis, University of York, York YO10 5GE, UK
*
Author to whom correspondence should be addressed.
Received: 20 October 2017 / Revised: 14 November 2017 / Accepted: 16 November 2017 / Published: 17 November 2017
(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)
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Abstract

The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design. View Full-Text
Keywords: viral quasispecies; viral evolution; viral assembly; simulation viral quasispecies; viral evolution; viral assembly; simulation
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MDPI and ACS Style

Bingham, R.J.; Dykeman, E.C.; Twarock, R. RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance. Viruses 2017, 9, 347.

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