Interference of HCV with anti-infectious and inflammatory effector systems of the host

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The hepatitis C virus (HCV) develops persistent infections in over 60 % of cases implying that the virus has evolved strategies to influence the antiviral and inflammatory response of the host and to exploit the infrastructure of the host cell. During the current funding period we could show that HCV modifies Akt mediated growth factor signaling by NS3/4A dependent cleavage of the T-cell protein tyrosine phosphatase and that this as well as the tyrosine kinase c-Src is crucial for viral replication. Moreover, our data indicate that HCV or expression of the isolated NS3/4A protein influences basal and induced cytokine/chemokine expression in vitro and in vivo. This in turn might be responsible for the ameliorated course of LPS induced liver injury in NS3/4A transgenic animals. Based on these data the working hypothesis of the present project is that HCV disturbs NF-κB-, Akt- or p38MAPK dependent signal transduction of the host cell and hereby alters the basal as well as the inducible cytokine and chemokine expression pattern. This in turn would influence the surrounding liver tissue and in particular the differentiation state and number of immune competent cells such as monocytes, macrophages, dendritic cells, NK cells and the different T cell subtypes. The aim of the present project is to investigate the molecular mechanisms responsible for HCV dependent changes of basal and inducible chemokine expression and its impact on the migratory activity and differentiation of effector cells of the immune system, such as monocytes, macrophages and dendritic cells, the T cell subtypes and its influence on viral infectivity. In this context our observation that HCV induces degradation of different members of the inhibitor of kappa B family may be of particular relevance. The importance of these observations for HCV induced chemokine synthesis will be addressed as well as the underlying molecular mechanism responsible for HCV mediated degradation of the different IκB molecules. Furthermore the influence of HCV mediated TC-PTP suppression and enhancement of p38MAPK activity on the basal and cytokine induced chemokine production of hepatocytes will be assessed.