Influence of liver normoxia on intra- and extra-hepatic NK cell function in HCV infection

have previously generated a murine tropic HCV (mtHCV) strain harboring three mutations within the viral envelope proteins allowing productive entry into mouse cell lines. In this study we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro. Using a highly sensitive, Cre-activatable we demonstrate that mtJc1 also can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry was more efficient when mouse CD81 and OCLN were overexpressed and was still relying on expression of mouse CD81 and SCARB1. To validate viral uptake specificity and to establish a host environment that may be more conducive to viral replication we utilized a number of mouse mutant strains with targeted disruptions in genes involved in HCV entry or antiviral innate immune defenses, respectively. In addition, we are in the process of testing directly the impact of host genetics HCV persistence utilizing different inbred mouse strains. Using human liver chimeric mice we show that the gain of function mutations of mtHCV are stably maintained over time. We observed transient replication of mtHCV in STAT1 deficient mice and highly immunocompromized mice engrafted with allogeneic STAT1-/hepatocytes. These results establish proof-of-concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. Additional viral adaptations are likely needed to increase the robustness of a murine model system for hepatitis C.