Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment.
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.
Indian Institute of Science, Department of Chemical Engineering, Bangalore 560012, India.
Pranesh
P
Padmanabhan
The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California 92037, USA.
Urtzi
U
Garaigorta
Indian Institute of Science, Department of Chemical Engineering, Bangalore 560012, India.
Narendra M
NM
Dixit
D000998:Antiviral Agents / Q000627:therapeutic use*; D003198:Computer Simulation; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons / Q000276:immunology*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D015398:Signal Transduction / Q000276:immunology*; D017211:Treatment Failure
D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012254:Ribavirin; D007372:Interferons