Hepatitis C virus (HCV) infects 3% of the global population and HCV-related liver inflammation is a major cause of liver failure and hepatocellular carcinoma. Current treatments are based upon long courses of interferon-α (IFNα) injections, which have significant side effects and are only effective in 40-80% of individuals depending on viral genotype. Natural killer (NK) cells are innate lymphocytes, which can kill virally infected cells and are stimulated by IFNα. To establish a chronic infection HCV must evade immune responses. I hypothesised that NK cells are important for the successful eradication of HCV and that chronic HCV infection impinges upon NK cell function to prevent viral clearance. I found that NK cell function was reduced in chronic HCV and correlated with the proportion of NKp46+ NK cells in vitro. In keeping with these findings NKp46-rich intrahepatic NK cell populations were more activated and the proportion of these cells correlated with liver inflammation. During interferon-α treatment individuals who had the greatest increase in NK cell function in response to increasing stimulation had the fastest rate of viral clearance and were most likely to successfully clear the virus. Using a novel adenovirus vector expressing HCV proteins I have discovered that NS5B protein reduces NK cell cytotoxicity and cytokine production. Therefore, in this thesis I have described novel insights into the mechanisms of HCV immunoevasion, HCV-related disease pathogenesis with implications for viral eradication therapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600607 |
| Date | January 2014 |
| Creators | Pembroke, Thomas |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/58428/ |
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