Liver transplantation as a model to better understand the cell entry of hepatitis C virus

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive anti-viral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to re-infect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants re-infecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pre-transplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glyco proteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.