University of Virginia Health System

Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence. HCV persistent infection is a major risk factor for the development of liver cancer as well as autoimmune disease, particularly mixed cryoglobulinemia. 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 chronic hepatic injury, as well as the mechanisms involved in the establishment of HCV persistence, we have developed a first murine model to study the role of HCV gene product on immune dysregulation. We have identified the HCV core protein which functions as an immunomodulatory molecule. The expression of this protein in a recombinant vaccinia virus (vHCV-C) leads to the mortality of mice by suppressing host immune response to vaccinia virus. HCV core protein is able to suppress an in vivo anti-viral CTL response to vaccinia virus and inhibit the production of the pro-inflammatory cytokines IFN-gamma and IL-2 in vHCV-C infected mice. These observations have been confirmed by studies in transgenic mice expressing HCV core protein alone. As an initial approach to understand the molecular basis for the effects of the HCV core protein on immune dysregulation, we 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. We hypothesize that the increased apoptosis of T lymphocytes through the interaction between HCV core and Fas may play a critical role on HCV core-mediated immune dysregulation. We are further defining the underlying mechanism for core-mediated immune dysregulation. The studies proposed here will provide new and useful information on the pathogenesis of HCV infection and will help to provide a basis for the rational design of vaccines and novel therapeutic agents.