Transmission genetics of drug-resistant hepatitis C virus
Antiviral development is plagued by drug resistance and genetic barriers to resistance are needed. For HIV and hepatitis C virus (HCV), combination therapy has proved life-saving. The targets of direct-acting antivirals for HCV infection are NS3/4A protease, NS5A phosphoprotein and NS5B polymerase....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/32579 |
| _version_ | 1818024990601117696 |
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| author | Nicholas van Buuren Timothy L Tellinghuisen Christopher D Richardson Karla Kirkegaard |
| author_facet | Nicholas van Buuren Timothy L Tellinghuisen Christopher D Richardson Karla Kirkegaard |
| author_sort | Nicholas van Buuren |
| collection | DOAJ |
| description | Antiviral development is plagued by drug resistance and genetic barriers to resistance are needed. For HIV and hepatitis C virus (HCV), combination therapy has proved life-saving. The targets of direct-acting antivirals for HCV infection are NS3/4A protease, NS5A phosphoprotein and NS5B polymerase. Differential visualization of drug-resistant and -susceptible RNA genomes within cells revealed that resistant variants of NS3/4A protease and NS5A phosphoprotein are cis-dominant, ensuring their direct selection from complex environments. Confocal microscopy revealed that RNA replication complexes are genome-specific, rationalizing the non-interaction of wild-type and variant products. No HCV antivirals yet display the dominance of drug susceptibility shown for capsid proteins of other viruses. However, effective inhibitors of HCV polymerase exact such high fitness costs for drug resistance that stable genome selection is not observed. Barriers to drug resistance vary with target biochemistry and detailed analysis of these barriers should lead to the use of fewer drugs. |
| first_indexed | 2024-12-10T04:09:00Z |
| format | Article |
| id | doaj.art-224a2a5a9e4b4353b3c93e2ea499bc25 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:09:00Z |
| publishDate | 2018-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-224a2a5a9e4b4353b3c93e2ea499bc252022-12-22T02:02:47ZengeLife Sciences Publications LtdeLife2050-084X2018-03-01710.7554/eLife.32579Transmission genetics of drug-resistant hepatitis C virusNicholas van Buuren0Timothy L Tellinghuisen1Christopher D Richardson2Karla Kirkegaard3https://orcid.org/0000-0001-7628-3770Department of Genetics, Stanford University School of Medicine, Stanford, United StatesDepartment of Infectious Diseases, The Scripps Research Institute, Jupiter, United StatesDepartment of Microbiology and Immunology, Dalhousie University, Nova Scotia, CanadaDepartment of Genetics, Stanford University School of Medicine, Stanford, United StatesAntiviral development is plagued by drug resistance and genetic barriers to resistance are needed. For HIV and hepatitis C virus (HCV), combination therapy has proved life-saving. The targets of direct-acting antivirals for HCV infection are NS3/4A protease, NS5A phosphoprotein and NS5B polymerase. Differential visualization of drug-resistant and -susceptible RNA genomes within cells revealed that resistant variants of NS3/4A protease and NS5A phosphoprotein are cis-dominant, ensuring their direct selection from complex environments. Confocal microscopy revealed that RNA replication complexes are genome-specific, rationalizing the non-interaction of wild-type and variant products. No HCV antivirals yet display the dominance of drug susceptibility shown for capsid proteins of other viruses. However, effective inhibitors of HCV polymerase exact such high fitness costs for drug resistance that stable genome selection is not observed. Barriers to drug resistance vary with target biochemistry and detailed analysis of these barriers should lead to the use of fewer drugs.https://elifesciences.org/articles/32579hepatitis C virusdrug resistanceantiviral drugsviral evolutionRNA replication |
| spellingShingle | Nicholas van Buuren Timothy L Tellinghuisen Christopher D Richardson Karla Kirkegaard Transmission genetics of drug-resistant hepatitis C virus eLife hepatitis C virus drug resistance antiviral drugs viral evolution RNA replication |
| title | Transmission genetics of drug-resistant hepatitis C virus |
| title_full | Transmission genetics of drug-resistant hepatitis C virus |
| title_fullStr | Transmission genetics of drug-resistant hepatitis C virus |
| title_full_unstemmed | Transmission genetics of drug-resistant hepatitis C virus |
| title_short | Transmission genetics of drug-resistant hepatitis C virus |
| title_sort | transmission genetics of drug resistant hepatitis c virus |
| topic | hepatitis C virus drug resistance antiviral drugs viral evolution RNA replication |
| url | https://elifesciences.org/articles/32579 |
| work_keys_str_mv | AT nicholasvanbuuren transmissiongeneticsofdrugresistanthepatitiscvirus AT timothyltellinghuisen transmissiongeneticsofdrugresistanthepatitiscvirus AT christopherdrichardson transmissiongeneticsofdrugresistanthepatitiscvirus AT karlakirkegaard transmissiongeneticsofdrugresistanthepatitiscvirus |