This proposal is for the renewal of a highly successful Cooperative Hepatitis C Research Center that supports a multi-disciplinary program of investigation comprising three coordinated projects but interactive and complementary research aims. Each of the projects and the major research themes of the Center seek a better understanding of the host-virus interface. The research themes that bind the Center together include investigation of (1) the molecular virology of HCV and HCV-host cell interactions, and the establishment of highly permissive cell culture systems permitting the rescue of virus from synthetic RNA in vitro, (2) the cellular and whole organ response to HCV infection, including the application of high density oligonucleotide microarray expression analysis to a range of available HCV systems: cultured cells transfected with synthetic infectious RNA, HCV transgenic mice, and HCV-infected chimpanzees, and (3) viral and host factors controlling the establishment of persistent infection in experimentally infected chimpanzees, and (3) viral and host factors controlling the establishment of persistent infection in experimentally infected chimpanzees and acutely infected humans. The proposed studies thus extend from the cellular to the whole animal level, and include systems supporting efficient replication of HICV, and utilize modified infectious clones of HC to characterize viral and host cell determinants of replication. Microarray studies will investigated the impact of HCV proteins on gene expression in cells transfected with RNA, and assess gene expression in livers from HCV transgenic mice and experimentally infected chimpanzees. There are interconnected aims, wince well designed expression analyses will provide useful information concerning the nature of the restriction of HCV replication in cultured cells. Chimpanzee and human studies in Projects 2 and 3 focus on viral and host determinants of viral clearance and the critical early immune response to acute infection. An Administrative Core directs a robust Research Development Program supporting pilot research awards to investigators who are new to the field. The major projects are tightly interwoven so that advances in understanding HCV infection at the cellular level can be rapidly exploited to further understanding of disease at the level of the patient. This enhances the likelihood that knowledge arising from these studies will ultimately lead to improved control of this disease.
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