T-cell and dendritic cell function and the effects of combination therapy in hepatitis C virus infection
Hepatitis C Virus infects 170 million people worldwide. Following primary infection approximately 15% of individuals resolve infection spontaneously whilst the remainder develop persistent infection. Combination therapy (interferon-alpha and ribavirin) is now the mainstay of treatment and, depending on viral genotype, results in sustained virological response- (SVR) in 45%-75% of individuals. My aim is to detennine aspects of cellular immunity that are associated with viral control. I have studied this in the setting of spontaneous viral control and also anti-viral drug therapy. The introduction outlines our current understanding of HCV cellular immunity. The first data chapter (chapter 3) is a comprehensive analysis of CD8+ T- cell responses in resolved and persistent infection. I show that individuals with resolved infection have broader and stronger T-cell responses and target diverse epitopes. I next (chapter 4) explore the effect of combination therapy on T-cell responses and show that CD4+ T-cell responses are enhanced and peak late in individuals who have a SVR. I hypothesise that the enhancement of T-cell responses during combination therapy are mediated indirectly through effects on dendritic cells and show that both EFN-a and ribavirin may modulate dendritic cell function (chapter 5). It has been reasoned that the attenuated T-cell responses found in persistent HCV infection may be accounted for by impaired antigen presentation. Against this theory, I report (chapter 6) that DCs derived from HCV infected individuals can indeed prime a naive T-cell response and that they retain normal stimulatory capacity. As T-cell responses can be restored by therapy it is clear that these have not been clonally deleted, but they must below the level of detection using current technology. I apply (chapter 7) the technique of magnetic enrichment to detect HCV-specific populations that are otherwise invisible. Finally I discuss the wider implication of my findings and outline future work that may evolve from this work.