Enhancement of antiviral activity against hepatitis C virus in vitro by interferon combination therapy

Abstract

Alpha, beta, and gamma interferons (IFN-alpha, IFN-beta, IFN-gamma) have been shown to be effective inhibitors of HCV replication in human cell lines carrying HCV replicons. To help define the divergent cellular processes involved in the control of intracellular HCV replication by these agents, we have characterized the activity of monotherapies and combination therapies with the major types of human interferons against HCV replication in the HCV replicon-containing cell line, AVA5. IFN-alpha, IFN-beta, and omega interferon (IFN-omega) were equally effective at inhibiting HCV replication, while IFN-gamma was approximately 10-fold more potent. In kinetic experiments, IFN-beta and IFN-gamma inhibited HCV replication more rapidly, and for a more prolonged period following the removal of treatment, than IFN-alpha. Combination interferon therapies produced enhanced anti-HCV activity in most cases, and displayed a diverse range of interactions. Mixtures of IFN-alpha and IFN-beta exhibited generally additive to slightly antagonistic interactions, IFN-alpha or IFN-beta combined with IFN-omega were strongly antagonistic, while IFN-alpha/IFN-gamma and IFN-beta/IFN-gamma combinations displayed the most enhanced and strongly synergistic antiviral effects. Simultaneous administration of interferons in the combination treatments was found to be superior to sequential administration. Ribavirin did not exhibit any selective anti-HCV activity in cell culture, consistent with in vivo monotherapies, and did not influence the effectiveness of IFN-alpha in combination treatments. A panel of human cytokines and immune response modifiers induced by interferon and ribavirin therapies in vivo did not demonstrate anti-HCV activity in HCV replicon-containing cultures. Combination therapy can be effectively modeled using HCV replicon technology yielding potentially more effective treatment regimens. HCV replicon technology has potential utility in designing combination therapies to significantly enhance the anti-HCV activity of IFN-alpha.