Hepatitis C virus (HCV) isHepatitis C virus (HCV) is a major cause of posttransfusion and community-acquired hepatitis in the world (8,24,25). The majority of HCV-infected individuals develop chronic hepatitis that may progress to liver cirrhosis and hepatocellular carcinoma (15). Treatment options for chronic HCV infection are limited, and a vaccine to prevent HCV infection is not available (11,15,17).HCV has been classified in a separate genus (Hepacivirus) of the Flaviviridae family. The virion contains a positive-stranded RNA genome of approximately 9.6 kb in length (25). The genome consists of a highly conserved 5Ј noncoding region followed by a long open reading frame of 9,030 to 9,099 nucleotides that is translated into a single polyprotein of 3,010 to 3,030 amino acids. Processing of the polyprotein occurs by a combination of host and viral proteases. The HCV structural proteins comprise the putative nucleocapsid or core protein and the two envelope glycoproteins E1 and E2 (25). The E2 glycoprotein is thought to be responsible for initiating virus attachment due to its ability to bind to human cells (32).HCV purified from plasma has been reported to exist in association with plasma lipoproteins, suggesting that the virus may use the low-density lipoprotein receptor for uptake (2). In the absence of highly purified native infectious HCV particles as a tool for the study of virus-cell interaction, recombinant HCV glycoprotein E2, E1E2 liposomes (22), infectious HCV pseudotype particles expressing E1 and E2 (HCVpp) (4, 16), and HCV-like particles (HCV-LPs) (3,39,41) have been used to analyze virus-cell membrane interaction. Based on these experimental in vitro studies, CD81 (5, 32), dendritic cellspecific intercellular adhesion molecule 3 grabbing nonintegrin (33) and highly sulfated heparan sulfate (3) have been proposed to play a role in mediating E2 binding and/or HCV internalization.Recently, the scavenger receptor class B type I (SR-BI) has been proposed as a putative HCV receptor candidate (36). SR-BI, a high-density lipoprotein-binding molecule, plays a functional role in lipid metabolism and is highly expressed in hepatocytes and steroidgenic tissues (34). SR-BI is a 509-residue glycoprotein with a large extracellular loop (LEL) anchored to the plasma membrane at both the N and C termini by transmembrane domains with short extensions into the cytoplasm (21). SR-BI has been shown to play a role in mediating the binding of recombinant E2 to HepG2 hepatoma cells and the entry of recombinant HCVpp into Huh-7 hepatoma cells (5, 36). Due to the lack of convenient in vitro or in vivo models for the study of HCV infection, the