title: Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system.
abstract: The use of type I interferon (IFN), in combination with ribvirin, to treat chronic hepatitis C virus (HCV) infection has many drawbacks that prevent widespread application, ultimately leading to a significant unmet clinical need. Potential improvements in IFN therapy through targeted delivery, molecular alteration, and combination with other agents are ongoing in an attempt to decrease adverse effects and increase efficacy. In this report, the HCV replicon cell culture system was used to assess potential synergistic antiviral effects of multiple IFN species when administered in combination. Quantitative analysis of HCV replicon RNA by TaqMan (PE Applied Biosystems, Foster City, CA) and qualitative analysis of HCV protein expression were used to measure the antiviral efficacy of individual and combination IFN treatments, and synergistic responses of IFN combinations were determined through statistical analysis of the TaqMan results. We found that when administered simultaneously, type I/II IFN combinations (IFN-alpha2b + IFN-gamma or IFN-beta + IFN-gamma) resulted in dramatic antiviral synergy, whereas a type I/I combination (IFN-alpha2b + IFN-beta) demonstrated a slightly antagonistic profile. The synergistic effect is likely due to differential cell surface receptors and signaling pathways employed by types I and II IFNs. Conversely, all type I IFN species bind the same receptor and signal through similar pathways, possibly accounting for the nearly additive response observed. In support of this hypothesis, IFN treatment resulted in differential induction of Stat1 phosphorylation at Tyr 701. In conclusion, simultaneous type I/II IFN combination treatment may allow an overall decreased effective IFN dose, which may reduce the side effect profiles that hinder current therapy.
authors.affiliation: Infectious Diseases Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. jolarkin@iupui.edu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Larkin
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.forename: Mark
authors.initials: M
authors.lastname: Farmen
authors.forename: Daryl
authors.initials: D
authors.lastname: Venable
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
authors.forename: John I
authors.initials: JI
authors.lastname: Glass
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D001483:Base Sequence; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D005814:Genes, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000008:administration & dosage; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007371:Interferon-gamma / Q000008:administration & dosage; D007372:Interferons / Q000008:administration & dosage*; D011994:Recombinant Proteins; D012093:Replicon / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D007371:Interferon-gamma; D007372:Interferons