Transmission genetics of drug-resistant hepatitis C virus

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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.

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Nicholas van Buuren

Department of Genetics, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Timothy L Tellinghuisen

Department of Infectious Diseases, The Scripps Research Institute, Jupiter, United States

Competing interests
No competing interests declared.
Christopher C Richardson

Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada

Competing interests
No competing interests declared.
Karla Kirkegaard

Department of Genetics, Stanford University School of Medicine, Stanford, United States

For correspondence
karlak@stanford.edu

Competing interests
Karla Kirkegaard, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-7628-3770

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.

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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.