The course of liver disease related to chronic hepatitis C virus (HCV) infection is highly variable. Disease is progressive in some individuals with chronic HCV-related hepatitis, leading to cirrhosis and liver failure, whereas other individuals never progress and die of unrelated causes. While there have been a number of studies studying the correlates of protective immunity, and there is a growing consensus among investigators that a polyclonal CD4+ and CD8+ T cell response is associated with spontaneous recovery from acute HCV, the immunologic correlates of disease progression have not been defined. Although CD4+ and CD8+ T cell responses found in peripheral blood are less intense in chronic HCV infection than those observed during acute spontaneous resolution of HCV infection, few studies have addressed whether or not the responses in chronic infection are associated with the severity of either inflammation or fibrosis. Published studies have been limited to cross sectional analysis, with the exception of our recently published work examining peripheral and intrahepatic CD4+ responses in persons with rapid progression to cirrhosis due to Schistosoma mansoni co-infection. In these studies, we showed that persons with rapid progression fail to mount and maintain an HCV-specific Th1 CD4+ response, especially in the liver. Using clinical material from persons with rapid disease progression, we will test the hypothesis that liver disease progression is related primarily to dysfunction of CD4+ T cells, with inadequate help to CD8+ and dysregulation of the NKT response. Specifically, we will 1) test the hypothesis that failure to maintain an HCV-specific, Th-1 biased CD4+ T cell response is associated with more rapid progression of liver disease; 2) determine the breadth and function of the CD8+ response, which we predict will be associated with markers of liver injury rather than prevention of progression; and 3) test the hypothesis that rapid disease progression is associated with production of proinflammatory and pro-fibrotic cytokines by CD1d-reactive natural killer T cells (NKT). Understanding immunologic correlates of disease progression is critical due to the growing proportion of persons with HCV infection of more than twenty years duration, who are at greatest risk for the complications of chronic HCV. Results of these studies will address one of the most fundamental questions in HCV liver disease pathogenesis and might suggest new therapeutic approached to prevent fibrosis progression.