The objective of this proposal is to develop a murine model for human hepatitis C virus (HCV) research. Immunosuppressed murine lines which tolerate engraftment of human tissues have been used successfully for the study of other human viral pathogens. The investigator proposes to establish the potential of two newly developed murine strains for the study of HCV. The first, the NOD/scid mouse, resulted from crossing C.B-17 scid mice with the non-obese diabetic strain. The resultant NOD/scid mouse has been demonstrated to be a superior model for the engraftment of human lymphoid tissue and studies of human lymphotrophic viruses. In preliminary experiments, the applicant has demonstrated that the NOD/scid mouse may be used as a model for HCV research. Inoculation of NOD/scid mice with human fetal liver cell suspensions resulted in persistent human lymphoid engraftment. Pre-transplantation incubation of cell suspensions with human serum containing high titer HCV resulted in persistent HCV infection of the mouse (6 months), demonstrated by the detection of both HCV RNA and antigens. Despite this observation, human hepatocyte engraftment in these mice was limited. In a different murine model, mice transgenic for the expression of urokinase type tissue plasminogen activator linked to the albumin promoter (Alb-uPA mice) have been demonstrated to accept xenogenic hepatocyte transplantation. The applicant will utilize crossed NOD/scid/Alb-uPA mice as recipients for human fetal liver cell transplantation, and investigate the ability of these mice to support persistent and productive HCV infection. The candidate, David Oldach, is a board certified internist and infectious disease specialist with three years of molecular virology research experience. He has published in peer-reviewed journals and has presented his hepatitis C virus research at national and international meetings. Funding of this application will support his transition to a fully independent investigator, and in particular, support him while he acquires training in the field of immunology. The research described in this proposal will be conducted under the joint sponsorship of Dr. Garnett Kelsoe, a recognized authority on murine immunogenetics and immunology, and Dr. Robert Rohwer, an expert in the field of molecular virology with extensive experience in the development of animal models for disease.
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