Novel methods are disclosed for the long-term culture of human primary hepatocytes in tissue culture system. This culture system supports the replication, gene expression and dissemination of a multitude of pathogenic agents that reside in, or pass through, the liver. Among these, the invention advantageously provides for efficient hepatitis C virus (HCV) replication, and dissemination. Additionally disclosed are methods for the determining cellular receptors, hepatocyte cell subtypes, and host cell molecules required for efficient hepatic pathogen replication, expression and dissemination.