Hepatitis C virus (HCV) has emerged as a major public health problem. World wide, as many as 200 million people are infected. In the United States, an estimated 3.9 million are infected, with 2.7 million Americans chronically infected. The immune response of the patient determines if the patient is cured of the virus, develops a lifelong infection, or develops severe liver disease. Progress in the treatment and prevention of HCV is severely hampered by the lack of a suitable animal model. Chimpanzees are the only animals other than humans that are infected with HCV. The pathogenesis differs from human hepatitis, however. Furthermore, the ethics and availability of chimpanzees limits the studies that can be done. A promising model was recently developed by engrafting human hepatocytes in immune deficient mice. This model, however, cannot assess the immune response to the virus or vaccines. We have developed technology for engrafting human liver cells in immune competent pigs. The innovations include transplanting cells into fetal pigs in utero and the development of unique transgenic pigs that enhance the growth of human liver cells. This study will inoculate HCV into hybrid swine with human liver cells and evaluate the virus proliferation, monitor the persistence of the virus and liver disease, and characterize the immune response. A large animal immune compentent model of HCV will lead to a better understanding of the pathogenesis of hepatitis C virus and to more effective vaccines and immune therapy. [unreadable] [unreadable]