Nat. Med., published online 8 January 2012, doi:10.1038/nm.2581

The hepatitis C virus (HCV) hijacks human hepatocytes, causing serious liver disease. The HCV membrane consists of viral glycoproteins, cellular lipoproteins and cholesterol, with the latter being necessary for the infection process. Now, Sainz Jr. et al. provide evidence that HCV enters the host cells through the cell-surface Niemann-Pick C1-like 1 (NPC1L1) cholesterol absorption receptor. The infection capacity of the HCV particles declined in host cells with lower amounts of NPC1L1 compared to wild-type cells. Likewise, the authors observed a decrease in viral infection after treating the cells either with antibodies targeting the extracellular surface of NPC1L1 receptor—and specifically the large extracellular loop LEL1—or with the cholesterol-lowering drug ezetimibe, which inhibits the internalization of NPC1L1. Using a fluorescence-based method to monitor the viral entry process, they observed that NPC1L1 receptor activity is necessary for infection before viral cell membrane fusion. Also, viruses engineered to contain less or more cholesterol presented lower or higher dependence on the NPC1L1 receptor, respectively. Ezetimibe treatment of a mouse model of HCV infection significantly delayed the viral infection, providing in vivo validation of the role of the cholesterol receptor in HCV infection. Further elucidation of the recognition mechanism of HCV by the NPC1L1 receptor can provide the basis for the development of effective antivirals.