HEPATITIS C AND CRYOGLOBULINEMIA

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DESCRIPTION: There are two co-sponsors (mentors): Jack T. Stapleton, M.D., is an associate professor of medicine and Principal Investigator of the University of Iowa Subunit of the AIDS Clinical Trials Group. Douglas R. LaBrecque, M.D. is Professor, Internal Medicine, Director, Liver Service (UI), and Chief, Gastroenterology-Hepatology, at the VA Hospital, Iowa City. Hepatitis C virus (HCV) is a small RNA virus that causes chronic hepatitis in a majority of patients. Essential mixed cryoglobulinemia (EMC) has emerged as a major extrahepatic complication of chronic HCV infection and causes a variety of systemic diseases such as arthritis, vasculitis, and glomerulonephritis. The hallmark of EMC is the appearance of cold insoluble globulins with Rheumatoid Factor (RF) and cryoprecipitates. Cryoprecipitates have been shown to contain RF, anti-hepatitis C antibodies and HCV RNA, however, the role of the virus in the cause of EMC is unclear. Available evidence suggests that infectious virions may associate with cryoglobulins and contribute to the systemic disease caused by EMC. Using a newly developed technique of affinity-capture PCR the candidate and his colleagues have recently shown that HCV can bind immunoglobulin Fc fragments. Binding of virus to Fc fragments or to non-neutralizing antibody may be a key step in the pathogenesis and natural history of HCV infection and cryoglobulinemia. In this application the candidate will further characterize the kinetics and stoichiometry of virus-Fc fragment biding and will determine the site (s) on the viral envelope where this occurs. Using bacterial and eukaryotic cell expression vectors the candidate will identify the envelope protein sequences that interact specifically with Fc fragment. In patients with and without cryoglobulinemia the candidate will determine HCV envelope protein sequences specific to the clinical state and will characterize these sites as to their antigenicity and participation in cryoprecipitate formation. Finally, in vitro cellular binding studies with virus-Fc complexes and purified cryoprecipitates will determine the importance of these immunocomplexes in HCV target cell infection. Based on these approaches, the candidate hopes to elucidate the cellular mechanisms of HCV infection and identify further therapeutic options for treatment of chronic hepatitis and cryoglobulinemia due to HCV.