Chronic hepatitis C virus (HCV) infection has become a major cause of liver related morbidity and mortality in the USA and Europe. Progression of chronic hepatitis C to advanced liver fibrosis and finally cirrhosis is the key predictor of liver failure and the development of primary liver cancer. However, cirrhosis develops in only 20-30% of patients after a mean of 20 years of infection, while others progress more slowly or not at all. Hepatic stellate cells and myofibroblasts, the effector cells of liver fibrosis that are responsible for excess deposition of extracellular matrix components during progression, seem to respond uniformly to fibrogenic stimuli. On the contrary, HCV infected hepatocytes and the host's immune response to HCV appear to be major factors that determine the activation state of hepatic stellate cells and myofibroblasts (collectively termed hepatic stellate cells), most likely via release of profibrogenic factors. In addition, viral genotype and variants (quasispecies) may indirectly (via interaction with the immune system) or directly (via alterations within the infected hepatocytes) stimulate hepatic stellate cell activation and thus fibrogenesis and progression. Furthermore, the mechanistic role of well established cofactors of progression in HCV liver disease, such as hepatic steatosis and enhanced oxidative stress is largely unexplored. To mimic the extracellular environment of hepatic stellate cells, we will use conditioned media from a spectrum of HCV replicating hepatocytic cell lines and from CD4+, CD8+ and NK T cell subsets derived from slow and rapid progressor patients to test the hypothesis that 1. hepatocytic cell lines with replicating HCV release profibrogenic factors that drive activation of hepatic stellate cells, and that a major profibrogenic factor thus released is TGFbeta1. 2. different HCV genotypes (type 1b vs. 2b) and certain quasispecies, defined as mutations in sequence regions of importance, namely in Core, NS4B and NS5A, elicit different levels of profibrogenic factors in the replicon cells or in Core, NS4B/NS5A transfected hepatocytic cells. 3. HCV induced hepatocyte alterations in lipid metabolism and oxidative stress lead to enhanced release of TGF-beta1 and other profibrogenic factors. 4. the cytokine profile released by key inflammatory cells in chronic HCV infection (CD4+, CD8+ and NK T cells) is more fibrogenic in patients with rapid vs. slow progression, and identify the key fibrogenic factors released by these T cell subsets. It is expected that a better understanding of the HCV-induced fibrogenic response in the liver and its cooperation or interaction with other extrinsic and intrinsic profibrogenic triggers and pathways will lead to a better understanding of HCV liver disease progression and to novel antifibrotic treatments tailored to chronic hepatitis C.
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