Modulation of the host cell signaling pathways and protein synthesis by hepatitis C virus nonstructural 5A protein

Hepatitis C virus (HCV) is the global leading cause of chronic liver disease, sets up persistent infection in the great majority of patients, and is resistant to the only available, interferon (IFN)-based therapies in a great portion of patients. The nonstructural 5A (NS5A) protein of HCV became the focus of much attention and extensive study due to its involvement in regulating IFN-resistance and virus replication. This dissertation includes studies aimed at understanding three important aspects of the interaction between HCV and the host cells, focusing on the role of the NS5A protein: (i) molecular mechanisms of viral perturbation of the IFN antiviral pathway and viral resistance to IFN treatment, (ii) regulation of the PI3K-AKT cell survival pathway to allow viral persistence, and (iii) regulation of cellular and viral protein synthesis pathways to facilitate viral life cycle. A major host cell innate antiviral system is the IFN pathway, and numerous viruses encode strategies to block IFN-induced antiviral responses. In addition of our previous studies showing that NS5A interacts with and inhibits a major IFN-induced antiviral function, PKR (IFN-induced, dsRNA-dependent protein kinase), NS5A also directly perturbs the intracellular IFN signaling pathway through inhibition of the MAPK pathway. On the other hand, NS5A upregulates the PI3K-AKT cell survival pathway, which is a popular target of persistent, oncogenic viruses, through direct interaction with the p85 subunit of PI3K, suggesting a molecular mechanism that allows HCV persistence and oncogenesis. In addition, through differential regulation of pivotal translational control factors such as eIF2α and eIF4E via PKR and MAPK-dependent pathways respectively, NS5A may maintain global protein synthesis while specifically interfering with cellular cap-dependent translation. Furthermore, this study found that NS5A is capable of specifically enhancing viral IRES (internal ribosome-entry site)-directed translation through a still-unclear mechanism. This study highlights the likely role of a single viral protein, NS5A, in regulating multiple pivotal cellular pathways and processes in order to allow successful viral infection and replication. These results not only add to our knowledge of HCV virology and cell biology, but also provide potential novel targets and approaches for the development of new-generation anti-HCV therapies.