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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment

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  • Pranesh Padmanabhan

    (Indian Institute of Science)

  • Urtzi Garaigorta

    (The Scripps Research Institute)

  • Narendra M. Dixit

    (Indian Institute of Science)

Abstract

Current interferon alpha-based treatment of hepatitis C virus (HCV) infection fails to cure a sizeable fraction of patients treated. The cause of this treatment failure remains unknown. Here using mathematical modelling, we predict treatment failure to be a consequence of the emergent properties of the interferon-signalling network. HCV induces bistability in the network, creating a new steady state where it can persist. Cells that admit the new steady state alone are refractory to interferon. Using a model of viral kinetics, we show that when the fraction of cells refractory to interferon in a patient exceeds a critical value, treatment fails. Direct-acting antivirals that suppress HCV replication can eliminate the new steady state, restoring interferon sensitivity and improving treatment response. Our study thus presents a new conceptual basis of HCV persistence and treatment response, elucidates the origin of the synergy between interferon and direct-acting antivirals, and facilitates rational treatment optimization.

Suggested Citation

  • Pranesh Padmanabhan & Urtzi Garaigorta & Narendra M. Dixit, 2014. "Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment," Nature Communications, Nature, vol. 5(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4872
    DOI: 10.1038/ncomms4872
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