The stimulation and maintenance of T cell responses in early HCV infection

The purpose of this study was to investigate early immunological events that might determine outcome in hepatitis C infection, examining key factors in the stimulation and maintenance of an effective immune response in a longitudinal cohort, either with or without alpha interferon therapy. This study demonstrated the importance of the HCV-specific cytokine environment early in infection in determining the effector function of HCV-specific T cells. Clearance of HCV was associated with a significantly higher magnitude and breadth of HCV-specific IFN-y (magnitude p<0.001, breadth p=0.003) and IL-2 (breadth p=0.017) T cell responses,which were maintained after viral clearance. In contrast, those with viral persistence had a significantly higher magnitude of IL-10 early in infection (p=0.048) in the relative absence of Th1 cytokines. There was also a significantly higher ratio of IFN-y to IL-10 production early in infection in those with viral clearance compared to persistence (p=0.002). Furthermore, IL-2 and IFN-y negatively correlated with viral load, whereas production of IL-10 was positively correlated with viral load (p<0.05). In addition, a significantly lower HCV-specific IFN-y response in HIV/HCV co-infection correlated with CD4 counts, demonstrating the importance of CD4 help in maintaining the effector and memory responses. Analysis of the cellular source of the key cytokines revealed that IFN-y was largely produced by CD8+ T cells and NK cells, whereas IL-10 was produced by monocytes and, in those with viral persistence, a subset of CD8+ T cells. Whether these CD8+ T cells are regulatory T cells remains to be determined, but it does suggest effector T cell responses are being down-regulated by IL-10 in those with viral persistence. The delicate balance of IFN-y and IL-10 early in HCV infection was demonstrated further through the addition of recombinant cytokines or neutralizing antibodies, where critical IFN-y effector responses could be restored by blocking IL-10. Effector functions could be restored by the addition of monocyte-derived dendritic cells to the cultures. We demonstrated that the function of DC in early and chronic HCV was comparable to healthy controls, and thus suggested a promising role for DC in immunotherapies. This study advances our understanding of the mechanisms behind an effective immune response in clearance of HCV in a unique cohort of predominantly IDU. It has illustrated the critical role of IFN-y and IL-2 early in HCV in viral clearance, and the contrasting role of IL-10 in viral persistence. This research highlights the importance of the priming environment, CD4 help and low viral loads in the induction of Th1 cytokines for viral clearance. Furthermore this study demonstrated the importance of the ratio of IFN-y to IL- 10 production early in HCV infection in determining virological outcome, and suggests that it could be used as a prognostic indicator for viral clearance and could be of great interest for the development of new therapies for HCV and in enhancing the efficacy of antiviral treatment.