Transmission genetics of drug-resistant hepatitis C virus

Nicholas van Buuren; Timothy L. Tellinghuisen; Christopher D. Richardson; Karla Kirkegaard

doi:10.7554/eLife.32579

Transmission genetics of drug-resistant hepatitis C virus

Nicholas van Buuren, Timothy L. Tellinghuisen, Christopher D. Richardson, Karla Kirkegaard

Medicine

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Article number	e32579
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.32579
Publication status	Published - 2018

Bibliographical note

Funding Information:
We thank Drs. Yury Goltsev and Garry Nolan for advice on fluorescent cell sorting-based visualization of RNA, Drs. Michael Gale Jr. and Ralf Bartenschlager for the generous donation of reagents and Dr. Peter Sarnow for critical reading of the manuscript. We would like to acknowledge the work of Drs. Jeannie Spagnolo and Ernesto Mendez for initiating HCV research in our laboratory. This work was supported by funding to KK from NIH U19AI109662 (Jeffrey Glenn, PI), an NIH Director’s Pioneer Award and the Alison and Steve Krausz Innovation Fund. NvB was supported by the Canadian Institutes for Health Research NCRTP-HepC training program and the American Liver Foundation. Electron microscopy was performed in a facility supported in part by ARRA award number 1S10RR026780-01 from the National Center for Research Resources (NCRR). The Cell Sciences Imaging Facility used for confocal microscopy was supported by ARRA award number 1S10OD010580 from the NCRR. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health.

Publisher Copyright:
© van Buuren et al.

ASJC Scopus Subject Areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.32579

Cite this

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title = "Transmission genetics of drug-resistant hepatitis C virus",

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.",

author = "{van Buuren}, Nicholas and Tellinghuisen, {Timothy L.} and Richardson, {Christopher D.} and Karla Kirkegaard",

note = "Funding Information: We thank Drs. Yury Goltsev and Garry Nolan for advice on fluorescent cell sorting-based visualization of RNA, Drs. Michael Gale Jr. and Ralf Bartenschlager for the generous donation of reagents and Dr. Peter Sarnow for critical reading of the manuscript. We would like to acknowledge the work of Drs. Jeannie Spagnolo and Ernesto Mendez for initiating HCV research in our laboratory. This work was supported by funding to KK from NIH U19AI109662 (Jeffrey Glenn, PI), an NIH Director{\textquoteright}s Pioneer Award and the Alison and Steve Krausz Innovation Fund. NvB was supported by the Canadian Institutes for Health Research NCRTP-HepC training program and the American Liver Foundation. Electron microscopy was performed in a facility supported in part by ARRA award number 1S10RR026780-01 from the National Center for Research Resources (NCRR). The Cell Sciences Imaging Facility used for confocal microscopy was supported by ARRA award number 1S10OD010580 from the NCRR. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health. Publisher Copyright: {\textcopyright} van Buuren et al.",

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PY - 2018

Y1 - 2018

N2 - 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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Transmission genetics of drug-resistant hepatitis C virus

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

Access to Document

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