Hepatitis C virus is known for its propensity to establish persistent infection and a state of biological balance with the host immune response, which requires viral escape from multiple phases of the host immune response. ? ? The direct, not inverse, correlation between HCV RNA titer and expression of IFN-response genes in the acute phase of infection and the description of multiple viral escape mechanisms in transfection and replication systems indicate that type I IFN responses are induced but not efficient in acute hepatitis C.? ? Type I IFN responses are also an important link to adaptive immune responses, because they regulate antigen processing. One of the major antigen-processing enzymes is the proteasome. If three subunits of this enzyme are exchanged by immunosubunits, the proteasome converts to an immunoproteasome with qualitatively and quantitatively altered antigen-processing function. Interestingly, as we have shown in other studies, intrahepatic synthesis of immunoproteasome subunits is induced by type I IFN in acute HCV infection rather than by the well-known immunproteasome inducer IFN-gamma, and occurs much earlier than CD8 T cell infiltration. Studying primary human hepatocyte and hepatoma cell lines, we now demonstrate that type I IFN not only induces transcription and translation of immunoproteasome subunits, but also their incorporation into the proteasome complex and the generation of immunoproteasome-dependent CD8 T-cell epitopes. Furthermore, transfection of human hepatoma cells with hepatitis C virus (HCV) RNA induced the expression of the three immunoproteasome subunits in an IFN-beta?dependent manner. Treatment with exogenous IFN-alpha may therefore enhance and extend induction of immunoproteasomes to the time point of CD8 T cell infiltration, a possible explanation for the high HCV clearance rates if IFN-treatment is initiated during acute hepatitis C.? ? After the first 1-2 months, the course of HCV infection is highly variable in patients with ALT and HCV RNA levels peaking more than once during this phase. Vigorous HCV-specific T cell responses are often detectable at precisely those time points at which viral RNA titers are transiently controlled. One of the major viral escape strategies during this phase of infection is viral sequence mutation which has been shown to affect T cell responses at the level of antigen processing, MHC binding and TCR stimulation. ? ? Finally, if spontaneous recovery from hepatitis C is achieved, HCV-specific T cell responses remain detectable for decades. In contrast, our recent data demonstrate that cellular immune responses decline if recovery is induced by treatment with pegylated IFN and ribavirin. Even decades after spontaneous and treatment-induced recovery, all assessed functions of HCV-specific T cells (proliferation, IFN-gamma-production in response to proteins and peptides) are considerably weaker in treatment-recovered than in spontaneously recovered patients. These results suggest differences in function and/or differentiation of HCV-specific memory T cells between treatment-recovered than in spontaneously recovered patients, which may affect the degree of long-term immune protection.
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