DETERMINANTS OF NEUTRALIZATION IN ENVELOPE PROTEINS OF HEPATITIS C VIRUS
Wasilewski, Lisa Naomi
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Hepatitis C Virus (HCV) is a chronic viral infection of humans which poses a significant global health threat. Millions of affected individuals are at risk for cirrhosis and hepatocellular carcinoma and as yet, no vaccine exists. Despite recent significant advances in HCV treatment, development of an HCV vaccine is a vital component in the effort to eradicate the virus. It has been demonstrated that broadly neutralizing antibodies (bNAbs) can prevent HCV infection despite a broad range of genetic variability and, as such, may serve as a useful tool for vaccine development. However, current understanding of bNAbs is still limited, particularly in regard to specific determinants of neutralization. In this thesis, we seek to gain a better understanding of viral polymorphisms which confer resistance to neutralization by both polyclonal plasma and broadly neutralizing monoclonal antibodies. Here, we identify a polymorphism which renders Bole1a, a computationally derived, ancestral genotype 1a HCV strain resistant to neutralization by both polyclonal plasma and multiple broadly neutralizing monoclonal antibodies. A considerable amount of work has gone towards developing research models which effectively mimic aspects of the viral life cycle in infected individuals. It is critical to define the relative benefits and limitations of different model systems in order to understand the effects of each. Two commonly used models are the HCV pseudoparticle system (HCVpp) and HCV cell culture (HCVcc). This thesis undertakes to describe the development of an efficient means by which to expand the repertoire of HCVcc constructs and to systematically compare the relative fitness and neutralization resistance of HCV envelope proteins in both the HCVpp and HCVcc model systems. In doing so, we show differences in HCV envelope fitness measured using the two systems but demonstrate strong agreement between antibody neutralization measured using HCVpp or HCVcc.