The project 2 of HCV Cooperative Research Center alms to understand the regulation of adaptive Immunity via the Interaction of HCV-infected hepatocytes with CD4 T cells during acute HCV Infection. HCV Infection In humans is remarkably efficient In establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CDS T cells are Involved in controlling HCV Infection;but. In chronic HCV patients, severe CD4 and CDS T cell dysfunction has been observed. This suggests that HCV may employ some mechanism to counteract or possibly suppress the host T cell response. The primary site of viral replication is within hepatocytes in the liver. During HCV Infection, there is the increased population of CD4 T cells in the liver sinusoid, which allows close contact with HCV-infected hepatocytes. To determine whether the Interaction of HCV-infected hepatocytyes with CD4 T cells alters CD4 T cell helper function on shaping CDS T cell effector antiviral activity, we conducted co-culture studies of HCV-infected hepatocytes with CD4 T cells. Our preliminary studies, we demonstrated that hepatocytes expressing whole HCV proteins (I.e. HCV+ hepatocytes) upregulated the ligand of PD-1 negative costimulatory molecule, B7-H1, and TGF-b synthesis. In addition, HCV+ hepatocytes are capable of impairing CD4 T cell function including Inhibition of IFN-g production. Based on these findings, we hypothesize that HCV+ hepatocyte-mediated Inhibition of CD4 T cell function plays a pivotal role In Impairing antiviral CDS T cell effector function. To test this hypothesis, we propose three specific alms, we will first explore the mechanism for HCV+ hepatocytemediated Inhibition of CD4 T cell responses. Second, we will determine the impact of HCV+ hepatocyteinduced CD4 T cell dysfunction on regulating antiviral CDS T cell effector function. Lastly, we will examine the status of CD4 T cell differentiation and correlate it with the outcome of HCV infection during acute HCV patients. Results of these studies will provide valuable insight Into designing therapeutic strategies against to HCV Infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BP-M)
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University of Colorado Denver
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