Hepatitis C Virus Proteins Induce Cirrhosis Antigen Expression on Human Hepatoma Cells In Vitro: Implications for Viral Mechanisms in Hepatitis C Fibrogenesis

Hepatitis C virus (HCV), an RNA virus classified within the Flaviviridae (12), has a remarkable propensity for persistence in the human host following acute infection. Infections spontaneously resolve in 20-30% of infected individuals, while 70-80% of infections result in long-term persistent viremia. Chronically infected individuals are at an increased risk of developing hepatocellular injury compared to subjects with acute resolved infections (25), with manifestations progressing from mild to severe (bridging) fibrosis, and, ultimately cirrhosis, in 10-30% of chronic infections. Cirrhosis underlies life-threatening complications of end stage liver disease and/or hepatocellular carcinoma, after a long and extremely variable disease incubation period (25, 38). It is presently impossible to predict which persons with chronic hepatitis C are at greatest risk for disease progression, and, likewise, host-virus relationships are most important for driving chronic hepatitis C disease progression have not been defined. In vitro evidence supporting the concept of virusmediated liver injury has recently been reported, including isolation of cytopathic derivatives of HCV infectious clone JFH1 (27), and also in the chimeric mouse (immune deficient mouse with humanized liver) hepatitis C model (18). Based on experimental data from acute liver injury rodent model systems, where massive hepatic necrosis is experimentally induced by toxins such as carbon tetrachloride (29), the master mediators of hepatic fibrogenic processes are Transforming Growth Factor beta (TGFbeta) and Platelet Derived Growth factor (PDGF) (17). Hepatic Stellate Cells (HSCs) and macrophages appear to be the major cell types regulating hepatic fibrosis (17, 46). HSCs, normally quiescent in the liver, and potentially derived from hepatic oval cells (45), respond to injury by proliferation and secretion of large amounts of extracellular matrix proteins, in addition to pro-fibrogenic cytokines including TGFbeta. During the process, HSCs are transformed into fibrogenic myofibroblasts. A well characterized liver cirrhosis-