Hepatitis C virus (HCV) is a major cause of liver disease and mortality, affecting approximately 170 million people worldwide. Chronic infection with HCV leads to liver fibrosis, cirrhosis and hepatocellular carcinoma. HCV must use the host gene expression machinery to facilitate viral replication. The mechanisms involved in the replication are incompletely understood. It has been found that the HCV nonstructural protein NS5A is essential to the replication machinery of the virus and critical in the assembly of infectious viral particles, however its specific role remains unclear. Recent preliminary data from the Bohjanen's laboratory indicates that the HCV NS5A protein binds to host GRE-containing transcripts and mediates their stabilization in hepatoma cell lines. This data suggest that HCV could manipulate host cellular mRNA decay through NS5A- mediated stabilization of GRE-containing transcripts. Stabilization of these transcripts would prevent cell death and promote growth of virus -infected cells allowing the virus to establish chronic infection in the host. In this study, we aim to identify host cellular transcripts that bind to the hepatitis C virus non-structural protein and to determine if the NS5A inhibitor BMS 790052 blocks HCV replication through interference with the binding of NS5A to GRE-containing host cellular transcripts. Further understanding of the critical genes involved in RNA regulation of HCV in human cell lines, will help characterize the virus replication cycle. In addition, it will expose genes of critical importance, thus unveiling potential targets for treatment. Moreover, dissection of the downstream effects of NS5A inhibitors will expose additional weak spots in the HCV replication machinery, expanding our understanding of the virus and facilitating innovation of new therapies.
Hepatitis C affects 170 millon people in the world, leading to liver cirrhosis, cancer and death. Our study, aimed to understand HCV replication and define the role of potential therapies is of major significance.
