Hepatitis C virus (HCV) is a leading cause of chronic liver disease. In the developed world, injection drug use (IDU) through sharing of infected needles and other paraphernalia remains the principal risk factor for HCV transmission. Effective but expensive treatment is now possible but there remains a pressing need for a vaccine. A proportion of people who inject drugs (PWIDs) remain uninfected despite HCV exposure from a long history of sharing needles and other paraphernalia. These cases are termed exposed but uninfected (EU) and test negative for both HCV antibodies and RNA and exhibit a phenotype of resistance to HCV infection. Improved understanding of the mechanisms that confer resistance in the EUs has the potential to aid development of an effective vaccine and novel therapeutic strategies. This thesis reports on the findings from 3 different strategies to identify characteristics of HCV resistance. I used urinary metabolomics, serum lipidomics and the study of adaptive and innate immune responses. Each of these methods has demonstrated clear differences between EU cases and healthy controls and/or spontaneous resolvers of HCV infection. Urinary metabolomics suggest a potential role of the gut microbiome, the serum lipidomics showed marked differences in lipid profiles in EU cases pointing towards a perturbed lipid/virus interaction, and the immune studies confirmed previous work identifying low level T cell responses in many EU cases but has also identified a marked upregulation of interferon alpha production to low dose viral RNA in EU cases utilising ELISA assay. In conclusion, this thesis reports data that identifies a number of new findings that provide insight into mechanisms of resistance to HCV infection. My findings suggest that the complex interplay between the virus and lipids together with an upregulated innate immune response may together help determine the outcome following HCV exposure. In summary, studies performed in this thesis have demonstrated that there are different pathways that define the EU phenotype. Despite being a heterogenous subgroup of PWIDs, the EUs are clearly distinct from a healthy control population.

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