1. Genetics and Genomics
  2. Microbiology and Infectious Disease
Download icon

Transmission genetics of drug-resistant hepatitis C virus

  1. Nicholas van Buuren
  2. Timothy L Tellinghuisen
  3. Christopher C Richardson
  4. Karla Kirkegaard  Is a corresponding author
  1. Stanford University School of Medicine, United States
  2. The Scripps Research Institute, United States
  3. Dalhousie University, Canada
Research Article
  • Cited 3
  • Views 1,813
  • Annotations
Cite this article as: eLife 2018;7:e32579 doi: 10.7554/eLife.32579

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

  1. Nicholas van Buuren

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  2. Timothy L Tellinghuisen

    Department of Infectious Diseases, The Scripps Research Institute, Jupiter, United States
    Competing interests
    No competing interests declared.
  3. Christopher C Richardson

    Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada
    Competing interests
    No competing interests declared.
  4. 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.
    ORCID icon "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.

Reviewing Editor

  1. David M Knipe, Harvard Medical School, United States

Publication history

  1. Received: October 6, 2017
  2. Accepted: March 22, 2018
  3. Accepted Manuscript published: March 28, 2018 (version 1)
  4. Version of Record published: April 25, 2018 (version 2)
  5. Version of Record updated: November 29, 2018 (version 3)

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.

Metrics

  • 1,813
    Page views
  • 275
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease
    Gabriel Machado Matos et al.
    Research Article Updated

    Protozoa and fungi are known to have extraordinarily diverse mechanisms of genetic exchange. However, the presence and epidemiological relevance of genetic exchange in Trypanosoma cruzi, the agent of Chagas disease, has been controversial and debated for many years. Field studies have identified both predominantly clonal and sexually recombining natural populations. Two of six natural T. cruzi lineages (TcV and TcVI) show hybrid mosaicism, using analysis of single-gene locus markers. The formation of hybrid strains in vitro has been achieved and this provides a framework to study the mechanisms and adaptive significance of genetic exchange. Using whole genome sequencing of a set of experimental hybrids strains, we have confirmed that hybrid formation initially results in tetraploid parasites. The hybrid progeny showed novel mutations that were not attributable to either (diploid) parent showing an increase in amino acid changes. In long-term culture, up to 800 generations, there was a variable but gradual erosion of progeny genomes towards triploidy, yet retention of elevated copy number was observed at several core housekeeping loci. Our findings indicate hybrid formation by fusion of diploid T. cruzi, followed by sporadic genome erosion, but with substantial potential for adaptive evolution, as has been described as a genetic feature of other organisms, such as some fungi.

    1. Genetics and Genomics
    2. Neuroscience
    Xinrui L Zhang et al.
    Research Article Updated

    Assembly of transcriptomes encoding unique neuronal identities requires selective accessibility of transcription factors to cis-regulatory sequences in nucleosome-embedded postmitotic chromatin. Yet, the mechanisms controlling postmitotic neuronal chromatin accessibility are poorly understood. Here, we show that unique distal enhancers define the Pet1 neuron lineage that generates serotonin (5-HT) neurons in mice. Heterogeneous single-cell chromatin landscapes are established early in postmitotic Pet1 neurons and reveal the putative regulatory programs driving Pet1 neuron subtype identities. Distal enhancer accessibility is highly dynamic as Pet1 neurons mature, suggesting the existence of regulatory factors that reorganize postmitotic neuronal chromatin. We find that Pet1 and Lmx1b control chromatin accessibility to select Pet1-lineage-specific enhancers for 5-HT neurotransmission. Additionally, these factors are required to maintain chromatin accessibility during early maturation suggesting that postmitotic neuronal open chromatin is unstable and requires continuous regulatory input. Together, our findings reveal postmitotic transcription factors that reorganize accessible chromatin for neuron specialization.