Modulation of CD4+ T cells by HCV+ hepatocytes (44.15)

Abstract

Abstract Hepatitis C virus (HCV) infection results in progression to chronic disease in approximately 80% of the infected population. Individuals who clear acute infection have a strong and sustained CD4 Th1 effector response, which is lacking in those who develop persistent infection. Within the liver, an additional immunosuppression is evidenced by a decrease in the percent of IFN-gamma producing CD4+ T cells relative to the peripheral blood. Viral replication occurs primarily within hepatocytes and there is consequently a high concentration of viral products in the liver. Our goal is to determine if HCV-infected hepatocytes have an immunosuppressive effect on CD4+ T cells. We have used a modified HCV cell culture system composed of a human hepatoma cell line, Huh 7.5, containing the full-length HCV genome or the non-structural portion of the genome only. The liver environment is modeled by a co-culture system that allows for direct contact between the hepatocytes and primary CD4+ T cells. We determined that expression of the full HCV genome within hepatocytes has a suppressive effect on CD4+ T cell IFN-gamma production. The CD4+ T cells can further be characterized by a decrease in the Th1 phenotype. These results suggest that local hepatocyte driven immunosuppression may contribute to the inefficient immune responses mounted by HCV infected patients. NIH DK066754 and U19 AI066328 funded this research.