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

Pranesh Padmanabhan, Urtzi Garaigorta and Narendra M. Dixit ()
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Pranesh Padmanabhan: Indian Institute of Science
Urtzi Garaigorta: The Scripps Research Institute
Narendra M. Dixit: Indian Institute of Science

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4872

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