RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance
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 ef...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-11-01
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| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/9/11/347 |
| _version_ | 1818903736985059328 |
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| author | Richard J. Bingham Eric C. Dykeman Reidun Twarock |
| author_facet | Richard J. Bingham Eric C. Dykeman Reidun Twarock |
| author_sort | Richard J. Bingham |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T20:56:17Z |
| format | Article |
| id | doaj.art-8d2b5221659546c6b0948713d986e4bb |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-19T20:56:17Z |
| publishDate | 2017-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-8d2b5221659546c6b0948713d986e4bb2022-12-21T20:05:57ZengMDPI AGViruses1999-49152017-11-0191134710.3390/v9110347v9110347RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to ResistanceRichard J. Bingham0Eric C. Dykeman1Reidun Twarock2Departments of Mathematics, University of York, York YO10 5DD, UKDepartments of Mathematics, University of York, York YO10 5DD, UKDepartments of Mathematics, University of York, York YO10 5DD, UKThe 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.https://www.mdpi.com/1999-4915/9/11/347viral quasispeciesviral evolutionviral assemblysimulation |
| spellingShingle | Richard J. Bingham Eric C. Dykeman Reidun Twarock RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance Viruses viral quasispecies viral evolution viral assembly simulation |
| title | RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance |
| title_full | RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance |
| title_fullStr | RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance |
| title_full_unstemmed | RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance |
| title_short | RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance |
| title_sort | rna virus evolution via a quasispecies based model reveals a drug target with a high barrier to resistance |
| topic | viral quasispecies viral evolution viral assembly simulation |
| url | https://www.mdpi.com/1999-4915/9/11/347 |
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