The human scavenger class B type 1 receptor (SR-B1/Cla1) was defined as a putative receptor for hepatitis C virus (HCV) because it binds to soluble recombinant HCV envelope glycoprotein E2 (sE2). the neutralization potency of MAb C167, despite its ability to inhibit both HDL binding to cells and SR-B1-mediated lipid transfer. Of note, MAb C167 also potently blocked Huh-7.5 infection by an HCV strain recovered from HCVcc-infected chimpanzees. These results demonstrate that SR-B1 is essential for infection with HCV produced in vitro and in vivo and suggest the possible use of anti-SR-B1 antibodies as therapeutic agents. Hepatitis C virus (HCV) is the major etiological agent of both community-acquired and posttransfusion non-A, non-B viral hepatitis. Approximately NSC 74859 80% of infected patients develop chronic hepatitis, among which 20% to 30% progress to liver cirrhosis and end-stage liver disease. Chronic infection correlates with an increased risk of hepatocellular carcinoma. Currently available therapies are limited to administration of pegylated alpha interferon in combination with ribavirin (27). Such treatment is expensive, is often unsuccessful, and carries the risk of significant side effects. NSC 74859 Consequently, the development of novel therapeutic approaches against HCV remains a high-priority goal. HCV is an enveloped virus of the family whose viral genome is a single-stranded, positive-sense RNA of approximately 9.6 kb that encodes a single polyprotein of 3,010 to 3,033 amino acids that is cleaved into nine mature proteins by a combination of sponsor and viral peptidases (24). The NSC 74859 expected structural parts comprise the primary (C) (21 kDa) and two seriously N-glycosylated envelope glycoproteins, E1 (31 kDa) and E2 (70 kDa). Both E2 and E1 are thought to be type I transmembrane proteins, with N-terminal ectodomains and C-terminal hydrophobic anchors. HCV admittance into focus on cells happens after connection to specific mobile receptors via its surface area glycoproteins, and far effort happens to be specialized in uncovering the system of viral connection to focus on cells and elaborating effective approaches for avoidance and therapy. Several mobile proteins have already been suggested as putative HCV receptors (2, 4, 12, Rabbit Polyclonal to RIPK2. 15, 33, 40), but only CD81 has been shown to play an essential role in HCV cell entry through extensive studies using gene expression knockdown by small interfering RNAs (siRNAs), antibody-mediated blocking, competition with soluble receptor homologs, and gain of entry function after transducing CD81 into CD81? cell lines (5, 12, 20, NSC 74859 23, 25, 47, 48, 49). SR-B1 is a lipoprotein receptor which interacts with high-density lipoprotein (HDL), very-low-density lipoprotein, native low-density lipoprotein (LDL), chemically modified LDL (oxidized LDL [oxLDL] and acetylated LDL), and anionic phospholipids (1, 8, 11, 38). It is a 509-amino-acid cell surface glycoprotein with cytoplasmic C- and N-terminal domains separated by a large extracellular domain. SR-B1 is expressed in the liver and steroidogenic tissues, where it mediates selective cholesteryl ester uptake from HDL and acts as an endocytic receptor (7, 18, 30, 37, 41). SR-B1 was originally identified as a putative receptor for HCV because it binds soluble E2 (sE2), possibly through interaction with E2 hypervariable region 1 (HVR1; 40). Indeed, recombinant E2 lacking HVR1 did not bind SR-B1 and antibodies specific for HVR1 inhibited sE2 binding to SR-B1 (5, 40). Likewise, in vitro experiments in which human hepatoma cells were infected with retroviral pseudoparticles bearing HCV envelope glycoproteins (HCVpp) showed that deletion of HVR1 or competition with anti-HVR1 antibodies strongly reduced virus infectivity (5). Although the interaction between sE2 and SR-B1 was shown to.