Innate Immune Tolerance and the Role of Kupffer Cells in Differential Responses to Interferon Therapy Among Patients With HCV Genotype 1 Infection

BACKGROUND & AIMS: In patients with hepatitis C virus (HCV) infection, interferon alfa (IFN-alpha) alters expression of IFN-stimulated genes (ISGs), but little is understood about factors that determine outcomes of therapy. We used a systems biology approach to evaluate the acute response of patients with chronic hepatitis C to IFN-alpha therapy. METHODS: We collected liver biopsy samples from 8 treatment-naive patients with chronic HCV genotype 1 infection at baseline and 24 hours after treatment with IFN-alpha-2a (10 MU subcutaneously). Blood samples were collected before and up to 48 hours after administration of IFN-alpha-2a to measure HCV RNA levels and for gene expression analysis. Patients then received pegylated IFN-alpha-2a and ribavirin on day 5 of the study; therapy continued for up to 48 weeks. RESULTS: Based on the kinetics of HCV RNA during the first 12 weeks of therapy, 2 patients were rapid virologic responders, 4 were early virologic responders, and 2 did not respond to therapy (nonresponders). Nonresponders had high pretreatment levels of ISG expression in the liver but not in peripheral blood mononuclear cells. In responders, after administration of IFN-alpha, intrahepatic ISG expression increased significantly from baseline and was associated with a rapid phase 1 decrease in HCV. We identified distinct hepatic expression and tissue distribution patterns of ISGs that segregated with treatment outcome. Importantly, Kupffer cells were a local source of IFN that promoted basal expression of ISG in hepatocytes of nonresponders. This finding was validated in cultured THP1 human macrophages that expressed IFN-beta after exposure to viable HCV 2a. When Huh7 K2040 and Huh7 L2198S hepatoma cells were incubated with IFN-alpha-2a, expression of ISGs peaked by 4 hours and decreased by 72 hours, associated with an increase in level of HCV RNA. This indicates that constitutive exposure to IFN causes hepatoma cells to become tolerant of ISG function. CONCLUSIONS: In patients with chronic HCV infection, IFN production by Kupffer cells might promote innate immune tolerance, characterized by a lack of response to IFN therapy. Strategies to disrupt the virus-host interactions that induce innate immune tolerance should improve therapy.