Lack of response to exogenous interferon-α in the liver of chimpanzees chronically infected with hepatitis C virus

The mechanism of the interferon-alpha (IFN alpha)-induced antiviral response is not completely understood. We recently examined the transcriptional response to IFNa in uninfected chimpanzees. The transcriptional response to IFNa in the liver and peripheral blood mononuclear cells (PBMCs) was rapidly induced but was also rapidly down-regulated, with most interferon-alpha-stimulated genes (ISGs) returning to the baseline within 24 hours. We have extended these observations to include chimpanzees chronically infected with hepatitis C virus (HCV). Remarkably, using total genome microarray analysis, we observed almost no induction of ISG transcripts in the livers of chronically infected animals following IFNa dosing, whereas the response in PBMCs was similar to that in uninfected animals. In agreement with this finding, no decrease in the viral load occurred with up to 12 weeks of pegylated IFN alpha therapy. The block in the response to exogenous IFN alpha appeared to be HCV-specific because the response in a hepatitis B virus-infected animal was similar to that of uninfected animals. The lack of a response to exogenous IFN alpha may be due to an already maximally induced ISG response because chronically HCV-infected chimpanzees already have a highly up-regulated hepatic ISG response. Alternatively, negative regulation may block the response to exogenous IFN alpha, yet it does not prevent the continued response to endogenous ISG stimuli. The IFNa alpha response in chronically HCV infected chimpanzees may be mechanistically similar to the null response in the human population. Conclusion: In chimpanzees infected with HCV, the highly elevated hepatic ISG expression may prevent the further induction of ISGs and antiviral efficacy following an IFNa treatment.