Hepatitis C virus infection in humans is almost invariably associated with viral persistence. HCV persistent infection is a major risk factor for the development of hepatocellular carcinoma and also leads to the development of autoimmune disease, particularly autoimmune hepatitis. The high incidence of persistent infection with HCV suggests that this virus has evolved one or more mechanisms to evade and possibly suppress the host immune response. To begin to dissect the immunopathogenesis of liver injury as well as the mechanisms involved in the establishment of HCV persistence, the investigators have developed a murine model of CD2/core transgenic mice by directing the expression of HCV core protein in T lymphocytes. T lymphocytes support the HCV infection and replication of virus. Using this transgenic system, they hope to study the role of HCV core protein on immune dysregulation and its consequences on the development of liver injury. Preliminary studies indicate that expression of the HCV core gene product in a recombinant vaccinia virus (vHCV-C) suppressed an in vivo anti-viral cytotoxic T lymphocyte (CTL) response to vaccinia virus and a marked inhibition of the production of the proinflammatory cytokines IFN-gamma and IL-2 in vHCV-C infected mice. These observations have been confirmed in CD2/core transgenic mice in which the expression of core protein was directed to T lymphocytes. In order to understand the molecular basis for the effects of the HCV core protein on immune dysregulation, the investigators examined its biochemical interaction with host proteins. This analysis revealed that the HCV core protein physically associated with Fas, a member of tumor necrosis receptor family, and this interaction led to an increased susceptibility of T lymphocytes to Fas-mediated apoptosis. Strikingly, in parallel to autoimmune hepatitis, massive lymphocytic infiltration was noted around the portal vein of liver in CD2/core transgenic mice and these intrahepatic lymphocytes were associated with liver injury. These observations, in conjunction with the binding ability of core protein to Fas, lead to the hypothesis for the development of autoimmune hepatitis induced by HCV. The increased apoptotic T lymphocytes induced by HCV core may infiltrate into the liver through their trafficking pathway and induce liver injury. In order to test this hypothesis and further investigate the underlying mechanisms, the investigators will examine the immune dysregulation in CD2/core transgenic mice in the first aim of the proposal. They will then characterize the intrahepatic lymphocytes and analyze the core-mediated liver injury in CD2/core transgenic mice.
| Soguero, Carolina; Joo, Myungsoo; Chianese-Bullock, Kimberly A et al. (2002) Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol 76:9345-54 |
| Yao, Z Q; Nguyen, D T; Hiotellis, A I et al. (2001) Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. J Immunol 167:5264-72 |
