Among the hepatotropic viruses, hepatitis C virus (HCV) is considered to be the leading cause of liver disease in humans, comprising ~ 3 % of the world population. HCV infected individuals show a high risk of developing chronic infection (>80%) that may progress into cirrhosis and liver cancer. HCV is a positive-stranded RNA virus distantly related to the falviviruses and pestiviruses. The genome of HCV contains about 9600 nucleotides encoding at least three structural proteins and seven non-structural proteins. Immediately following the 5’ non-coding region (5'NCR), the gene order is as follows: C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B--3.

Research on HCV replication and pathogenesis as well as the development of therapeutic strategies has been severely hampered because of the lack of in vitro and and/or animal models for HCV infection and propagation.

Several epidemological studies have also established a strong correlation between the effect of alcohol intake and HCV infection during the progression of liver disease and associated hepatocellular carcinoma. The molecular details of the combined effects of alcohol and HCV are not understood. HCV encoded NS5A and C proteins have been implicated in regulating the transcription of certain cellular factors that may be involved in alcohol metabolism.

Our laboratory is interested in understanding the molecular details of synergism between HCV and alcohol. We have employed a wide variey of molecular and cell biological approches to assess the involvment of HCV proteins in progression of alcohol-induced liver disese. We found that HCV encoded NS5A protein increases the specific activity of alcohol dehydrogenase (ADH), a key enzyme in alcohol metabolism. Furthermore, we observed that protein levels of both ADH and cytochrome P4502E1 (CPY2E1) were increased in the presence of NS5A in a liver derived cell lines. We also initiated protein-protein interaction studies and found that NS5A functionally associated with the tumor suppressor protein p53.

It is widely acknowledged that the oxidative metabolism of ethanol mediated by ADH and CYP2E1 leads to the generation of reactive oxygen species (ROS) and the formation of acetaldehyde within hepatocytes. ROS and acetaldehyde are recognized to mediate some of the damaging effects in hepatocytes including DNA damage. In response to oxidative stress, p53 activates the key anti-oxidant pathways. We are invesitgating the potential mechanism(s) by which HCV may influence the oxidant and antioxidant balance in cultured hepatocytes in the context of NS5A's functional associations with p53.

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