Determinants of Hepatitis C Virus Clinical Outcomes

Hepatitis C VIruS (HCY) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCY are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCY who are treated with interferon-based therapies, only a portion are able 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 playa role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCY clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCY, and the effect of ANA positivity on the natural history of HCY. 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 HCY-related fibrosis, although t his 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'-5'0Iigo-adenylate synthase 1 (OASI), and protein kinase (PKR), as well as genes encoding cytotoxic T-lymphocyte antigen-s (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCY infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCY. These factors may serve as future points for investigation by basic scientists understanding the mechanisms ofHCY-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 HCY 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.