Lack of Response to Exogenous Interferon-α in the Liver of HCV Chronically Infected Chimpanzees

• Published in: Hepatology (Baltimore, Md.) Vol. 46; no. 4; pp. 999 - 1008
• Main Authors: Lanford, Robert E., Guerra, Bernadette, Bigger, Catherine B., Lee, Helen, Chavez, Deborah, Brasky, Kathleen M.
• Format: Journal Article
• Language: English
• Published: 01.10.2007
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.21776

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