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Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis

Author

Listed:
  • Hang Zhang

    (The Hong Kong University of Science and Technology)

  • Ahmed Abdul Quadeer

    (The Hong Kong University of Science and Technology)

  • Matthew R. McKay

    (University of Melbourne
    University of Melbourne, at The Peter Doherty Institute for Infection and Immunity)

Abstract

Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Employing a sequence-based fitness landscape model whose predictions correlate highly with experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. Evolutionary modelling further supports that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs.

Suggested Citation

  • Hang Zhang & Ahmed Abdul Quadeer & Matthew R. McKay, 2023. "Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42550-6
    DOI: 10.1038/s41467-023-42550-6
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    References listed on IDEAS

    as
    1. Ahmed A. Quadeer & John P. Barton & Arup K. Chakraborty & Matthew R. McKay, 2020. "Deconvolving mutational patterns of poliovirus outbreaks reveals its intrinsic fitness landscape," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. John P. Barton & Nilu Goonetilleke & Thomas C. Butler & Bruce D. Walker & Andrew J. McMichael & Arup K. Chakraborty, 2016. "Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
    3. Ahmed Abdul Quadeer & David Morales-Jimenez & Matthew R McKay, 2018. "Co-evolution networks of HIV/HCV are modular with direct association to structure and function," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-29, September.
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    1. Ahmed Abdul Quadeer & David Morales-Jimenez & Matthew R McKay, 2018. "Co-evolution networks of HIV/HCV are modular with direct association to structure and function," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-29, September.
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