Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA.
Early and vigorous intrahepatic interferon-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection even though HCV inhibits the induction of type I interferons (IFNs) in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection type I and III IFN responses were studied in (i) serial liver biopsies and plasma samples obtained from six chimpanzees throughout acute HCV infection, and (ii) primary human hepatocyte cultures (PHH) upon HCV infection. Type I IFNs were minimally induced at the mRNA level in the liver and undetectable at the protein level in the plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular IL-29 mRNA and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatant of HCV-infected PHH mediated antiviral activity upon transfer to HCV-replicon containing cells, which was significantly blocked by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling, and was not enhanced by the presence of plasmacytoid dendritic cells (pDCs). CONCLUSION: Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity but are not the principal determinant of the outcome of HCV infection.