Virus-host interactions in hepatitis C virus infection: implications for pathogenesis and therapy

Virus-host interactions are crucial for the pathogenesis of Hepatitis C. Disease progression and response to therapy depends from viral and host factors and from their mutual interactions. The study of host and viral factors is also of primary importance for the development of new antiviral therapies. The goal of this work was to investigate some of the most relevant viral and host factors in order to improve their knowledge and the possibility to translate this knowledge to a useful clinical application. CHAPTER 2: Metabolism of Phosphatidylinositol 4-Kinase IIIα-Dependent PI4P is Subverted by HCV and Is Targeted by a 4-Amino Quinazoline with Antiviral Activity The enzymatic activity of PI4KIIIα is required for efficient HCV RNA Replication and the direct activation of this lipid kinase by HCV is critical for the integrity of the viral replication complex. Since we demonstrated that the anti-HCV compound AL-9 is an inhibitor of PI4KIIIα, this kinase is a suitable antiviral target for the treatment of HCV. CHAPTERS 3-4: Unraveling host responses to the emergence of hepatitis C virus particles with defective RNA genomes HCV particles with defective RNA genomes have been recently identified in the serum of some patients with chronic HCV infection and represent a significant proportion of viral load. In order to investigate whether HCV defective genomes could play a role in any of the hepatic disease manifestations associated with chronic HCV infection, or affect response to antiviral therapy, we adopted a two-fold ex vivo/in vitro approach. On one hand, we performed a retrospective screening campaign aiming at assessing the presence of defective genomes in the serum of HCV-infected individuals stratified according to disease severity as well as response to PEG-IFNα/RBV combination therapy (CHAPTER 3). On another hand, we studied the direct role of defective HCV genomes in hepatocyte injury using an infectivity model system in vitro (CHAPTER 4).