Analysis of protective cellular immune responses against hepatitis C virus.

Abstract

Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. There is now considerable evidence that CD4+ T cell responses to HCV play an important role in the outcome of infection. However, the functional status of HCV-specific CD4+ve T cells in persistent infection is poorly understood and it may be necessary to use a variety of techniques in their detection and analysis. The aim of my thesis is to determine aspects of cellular immunity that are associated with viral control, here mainly focusing on CD4+ T cell responses. The first data chapter (chapter 3) gives an analysis of RlBA-indeterminate blood donors negative for HCV-PCR in whom HCV-specific T cell responses were identified, typically focused on core-derived peptides, suggesting previous exposure to HCV. I next analyse the cytokine secretion patterns in chronically HCV-infected patients and compare them with those with resolved infection (chapter 4). Using overlapping peptides, I have been able to identify HCV-specific CD4+ T cells in persistent infection that recognise the mainly conserved core region. These cells characteristically produce IFN-y but not IL-2 (IFN-y+/IL-2'). In the next chapter (chapter 5) I show that these cells have lost their ability to proliferate (IFN-y+/IL-2" /proliferation10). . In the final data chapter (chapter 6), I studied the T cell responses in a cohort of seven individuals with antibody-deficiency (CVID), who received early interferon therapy after HCV infection through contaminated y-globulin. Even in the absence of antibody responses, substantial HCV-specific T cell responses could be recovered. The implications of my findings are discussed at the end of each data chapter. A general discussion of the overall findings and future work that may evolve from this work is outlined in chapter 7. Here, I also give some preliminary data on a cohort of acutely HCV-infected individuals with and without HIV infection, showing that HCV-specific CD4+ T cell responses in acute HCV are significantly reduced in co-infection when compared with HCV mono-infection. Overall the data in this thesis provide novel insights into the immune status in specific patient groups, and the functional status of HCV-specific CD4+ T cells in persistent infection