Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

The mechanism of the interferon-alpha (IFN-α)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-α in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-α. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours post-inoculation, a time when high levels of circulating pegylated IFN-α were still present. The rapid downregulation of the IFN-α response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-α therapy in HCV-infected patients. The response to all three forms of IFN-α was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-α were not due to species specificity of IFN-α. The response to IFN-α was partially tissue-specific. A total of 1,778 genes were altered in expression by twofold or more by IFN-α, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-α and IFN-γ responses in primary chimpanzee and human hepatocytes were compared as well. IFN-α and IFN-γ induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-α is largely tissue-specific, and the response is rapidly down-regulated in vivo, which may have a significant influence on the kinetics of antiviral response. Supplementary material for this article can be found on the HEPATOLOGY website (http:// interscience.wiley.com/jpages/0270-9139/suppmat/ index.html).