We plan to examine the role of these and other genes in acute HCV infection in both the systemic and local host/virus interaction. Acutely-infected liver tissue is difficult to obtain because most acute HCV infections are not identified, and because it is inappropriate to perform liver biopsies in these cases. Thus we will use two different approaches. First, we will study the gene expression patterns in peripheral blood mononuclear cells (PBMCs) collected from Egyptian health care workers with acute HCV (provided by Dr. Sanaa Kamal) and compare these to PBMCs from patients with genotype-matched chronic HCV and to healthy volunteers. We will develop predictive models to test which gene subsets are most associated with clinical outcomes such as the establishment of chronic infection. Second, we will use the recurrence of HCV post transplantation as a model of acute hepatitis in vivo. We will take biopsies of the donor liver PRIOR to transplantation and then follow gene expression levels over time as the virus infects the graft. After transplantation the HCV-naïve liver rapidly and universally becomes infected with HCV, though only 70% of patients develop histological evidence of recurrence on liver biopsies taken 3 and/or 6 months post-transplant. It is these patients who we currently treat for recurrent HCV using PegIFN/Rib. As before, we will develop predictive models to associate gene subsets with clinical outcomes. We have achieved more than a 60% response rate by encouraging treatment adherence despite the even more grueling side effects after transplantation. Thus, as for the treatment of HCV prior to transplantation a significant fraction of patients do not respond to therapy and are needlessly exposed to morbid side effects: the key clinical outcome we will consider is response to therapy with PegIFN/Rib. Another outcome of interest is the rapid development of cirrhosis within 5 years in 25-30% of patients, and the development of an aggressive fibrosing cholestatic state in 7-9% within 2 years of transplant. Together these data will point to the genes important for the immunological response that results in disease persistence or elimination (acute HCV in health care workers) and progression of liver disease (post-transplantation patients). Highly up- and down-regulated genes will be further studied in the HCV replicon model.