Final Report Summary - VIRAFRONT (Viral frontiers – species barriers of hepatitis C virus replication)
The major objective of VIRAFRONT was to define the determinants that preclude propagation of hepatitis C virus (HCV), a virus with narrow species tropism that only infects humans and chimpanzees, in mouse liver cells. We have created novel mouse liver-derived cell lines to show that efficient HCV propagation can be established in tissue culture provided two important criteria are met: First, the mouse liver cells need to be engineered to produce at least two human cell entry factors to allow HCV to access the cells. Alternatively, a virus variant that has adapted to utilize the mouse homolog of one of these human entry factors can be utilized. Second, mouse endogenous cellular innate immune defenses have to be inactivated to allow HCV to propagate. Using these cells we were able to identify constitutively expressed murine restriction factors that partially restrict HCV. Moreover, we were able to create a mouse adapted HCV population with increased replication fitness in mouse liver derived cells. Collectively, these findings guide future work to establish fully immune competent mouse models for HCV which will be used to understand HCV immune control, pathogenesis and for vaccine development.