Determining the mechanism of miR-122 regulation of HCV translation

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HCV causes liver disease and cancer, and is a major cause of liver failure, and liver transplantation in North America. Cellular small RNAs, known as microRNAs (miRNA), regulate cellular gene expression. A liver specific miRNA, miR-122, regulates lipid and cholesterol metabolism, and cellular differentiation, and dis-regulation of miR-122 has been linked to liver cancer. Interestingly, miR-122 also modulates the efficiency by which HCV grows in infected cells. Antagonists of miR-122 inhibit HCV infections, and recent phase II trials showed that they are safe and effective in treating HCV infections in humans. However, we currently do not know how miR-122 promotes HCV replication. A direct interaction between miR-122 and the HCV genome is required, but how this promotes virus replication is unknown. In our research we are striving to determine the viral and cellular components that are involved in the activity of miR-122 so that we may learn more about the mechanism of miR-122 activity. We have found that an unconventional form of miR-122 may function to promote HCV, and suggests to us that different populations of miR-122 may exist in cells. We propose to confirm the identity and activity of the unique miR-122 form. We have also identified two host cellular proteins that are involved in miR-122 activity, Ago2 and DDX6. Both Ago2 and DDX6 are required for the mechanism by which normal miRNA regulate host genes, and our goals are to determine their specific roles in promoting HCV replication. With the completion of these studies we will construct a model for the mechanism of miR-122 activation of HCV infections. The information will also provide insight into the role of miR-122 in modulating translation in liver cells.