Transmission genetics of drug-resistant hepatitis C virus
- Stanford University School of Medicine, United States
- The Scripps Research Institute, United States
- Dalhousie University, Canada
Abstract
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.
Article and author information
Author details
Funding
National Institutes of Health (U19-AI09662)
- Karla Kirkegaard
Canadian Institutes of Health Research (NCRTP-HepC Postdoctoral Fellowship)
- Nicholas van Buuren
American Liver Foundation (Postdoctoral Fellowship)
- Nicholas van Buuren
National Institutes of Health (NIH Director's Pioneer Award)
- Karla Kirkegaard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, van Buuren et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transmission genetics of drug-resistant hepatitis C virus
eLife 7:e32579.
https://doi.org/10.7554/eLife.32579
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