The role of immunosenescence in chronic hepatitis C infection. (360G-Wellcome-080383_Z_06_Z)

Introduction: Hepatitis C virus (HCV) affects 0.2 - 1% of the UK population causing cirrhosis, and hepatoma in a variable proportion. Factors that increase risk of progressive liver injury include male sex, immune suppression, alcohol abuse and critically, increased age. Many studies indicate an association between broad defects of T-cell responses (specific and non-specific) and persistent infection, which may be reversed by antiviraltherapy. Reduced immune function with ageing (immunosenescence) may be accelerated by chronic viral infection. Aim: To determine whether accelerated immunosenescence is present in patients with chronic HCV infectionand correlates with impaired immune responses to HCV or clinical outcome.Methods: Analysis of circulating/intrahepatic lymphocyte phenotype and function using healthy controls matched for age, sex and CMV (i) cross-sectional study of HCV exposed subjects of varied age and severity of liver disease with and without viraemia (ii) longitudinal study of HCV infected patients undergoing antiviral therapy or transplantation for cirrhosis or hepatoma. Finally to investigate circulating/intrahepatic lymphocyte phenotype in relation to HCV-specific T-cell function. Cell-surface phenotype for senescence associated markers, telomere length, cytokine production and proliferation will be analysed by flow-cytometry and correlated with markers of HCV outcome, including hepatic fibrosis, viral loadand response to antiviral therapy.