Proteasome activator and antigen-processing aminopeptidases are regulated by virus-induced type I interferon in the hepatitis C virus-infected liver (44.39)

Abstract

Abstract Many components of the class I-antigen-processing pathway are thought to be regulated solely by IFN-γ. Recently, however, we reported type I IFN-mediated induction of immunoproteasomes in a viral infection of the liver (J Clin Invest 2006, 116:3006). In the present study, we extended this analysis to additional components of the MHC class I antigen-processing machinery. Specifically, we investigated type I IFN-mediated induction of the proteasome activator 28 (PA28) subunits α and β, the ER aminopeptidases-1 (ERAP1), -2 (ERAP2) and leucine aminopeptidase (LAP) in vitro and in vivo in a model of HCV infection. This mechanism was initiated by either synthetic or hepatitis C virus (HCV) RNA and abrogated by blocking of type I IFN. In the liver of chimpanzees with acute HCV infection, increased mRNA levels of PA28 subunits and all aminopeptidases occurred prior to IFN-γ responses and instead, coincided with type I IFN responses. Taken together, viral RNA-induced type I IFN regulates the antigen-processing machinery early during infection. Thus, viral RNA-induced type I IFN does not only exert direct antiviral functions but also enhances antigen processing in virus-infected cells to facilitate recognition by effector CD8+ T cells.