Determinants of hepatitis C virus clinical outcomes
Hepatitis C virus (HCV) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCV are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCV who are treated with interferon-based therapies, only a portion are able to experience sustained virological suppression. Similarly, a number of chronically infected individuals have autoimmune extrahepatic manifestations such as the presence of autoantibodies. The pathological mechanisms behind these phenomena are not known, but it is believed that host genetic factors may play a role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCV clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCV, and the effect of ANA positivity on the natural history of HCV. Correlations were observed between female gender and geographic location and ANA positivity. No relationships were observed for an effect of ANA positivity on response rates to interferon therapy. We observed a trend of ANA positivity with faster progression of HCV-related fibrosis, although this failed to achieve statistical significance. ANA-positive individuals tended to have more plasma cells in their liver than ANA-negative individuals. This study also observed a number of correlations between genotypes of the interferon induced genes encoding the myxovirus resistance 1 protein (MxA), 2'-5'oligo-adenylate synthase 1 (OAS-1), and protein kinase (PKR), as well as genes encoding cytotoxic T-lymphocyte antigen-4 (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCV infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCV. These factors may serve as future points for investigation by basic scientists understanding the mechanisms of HCV-mediated autoimmunity. Importantly, this study suggests that low titre ANA positivity should not be a contraindication to therapy. This study also highlighted the importance of several genetic pathways in HCV infection. These may serve as targets for future pharmacologic interventions or genetic tests designed to screen for those who will not benefit from interferon therapies.