High Density Lipoproteins Facilitate Hepatitis C Virus Entry through the Scavenger Receptor Class B Type I

Abstract

The scavenger receptor class B type I (SR-BI) has recently been shown to interact with hepatitis C virus (HCV) envelope glycoprotein E2, suggesting that it might be involved at some step of HCV entry into host cells. However, due to the absence of a cell culture system to efficiently amplify HCV, it is not clear how SR-BI contributes to HCV entry. Here, we sought to determine how high density lipoproteins (HDLs), the natural ligand of SR-BI, affect HCV entry. By using the recently described infectious HCV pseudotyped particles (HCVpps) that display functional E1E2 glycoprotein complexes, we showed that HDLs are able to markedly enhance HCVpp entry. We did not find any evidence of HDL association with HCVpps, suggesting that HCVpps do not enter into target cells using HDL as a carrier to bind to its receptor. Interestingly, lipid-free apoA-I and apoA-II, the major HDL apolipoproteins, were unable to enhance HCVpp infectivity. In addition, drugs inhibit- Approximately 170 million individuals are infected worldwide by hepatitis C virus (HCV).1 HCV infection causes acute hepatitis, which has a high probability of becoming chronic and in the long term can lead to cirrhosis and hepatocellular carcinoma (1). Because of the serious consequences of its infection in humans, much effort is being made to understand the basic mechanisms of HCV lifecycle. Because of the absence of an efficient cell culture system to replicate HCV, several laboratories have tried to develop surrogate models to study HCV entry (2). These models are based on the expression of HCV envelope glycoproteins E1 and E2, which form a noncovalent heterodimer. Several difficulties have been encountered in these approaches because HCV envelope glycoproteins are located in the endoplasmic reticulum (3), and their folding and assembly is very sensitive to mutations or deletions affecting the endoplasmic reticulum retention domains (4). Recently, infectious pseudotyped particles (HCVpps) that are assembled by displaying unmodified HCV envelope glycoproteins onto retroviral core particles have successfully been generated and now enable studies of HCV entry (5, 6).The cellular tropism of enveloped viruses is largely determined by selective interactions of viral envelope glycoproteins with specific cell-surface receptors. Several candidate receptors for HCV have recently been proposed. Molecules like the CD81 tetraspanin (7), the scavenger receptor class B type I (SR-BI) (8), the LDL receptor (9, 10), and the asialoglycoprotein receptor (11) are potential candidate receptors for HCV, whereas the mannose binding lectins DC-SIGN and L-SIGN have been shown to function as HCV capture receptors but do not mediate viral entry into target cells (12-16). Among these molecules there is mounting evidence that CD81 and SR-BI are necessary for HCV entry (5,6,17). Whereas the role of CD81 in HCV entry is now well documented (5,6,(17)(18)(19), the contribution of SR-BI in HCV entry needs to be further characterized. SR-BI is a 509-amino acid glycoprotein with two cytoplasmic ...

Metabolic profiles in patients with chronic hepatitis C: a case–control study

“…Recent studies indicated that lipoprotein-associated Table 4 Multiple logistic regression analysis stratified by upper limit of normal ALT levels to examine the odds of HCV patients versus non-HCV controls The models adjusted for age, sex, body mass index, adiponectin, fasting blood glucose, triglyceride, and total cholesterol a Upper limit of normal (ULN) of serum ALT level is 30 U/l for men and 20 U/l for women * P \ 0.05 ** P \ 0.1 Note: Multiple linear regression models using the presence of HCV infection as the dependent variable and age, sex, body mass index, and stratified adiponectin levels as independent variables a Categorizing serum adiponectin level to 3 groups and using serum adiponectin \4 lg/ml as reference group HCV particles may infect cells via LDL receptors [37]. HDL and scavenger receptor class B type I (SR-BI) play an active role in facilitating HCV entry but oxidized LDL (oxLDL) is a potent cell entry inhibitor [38,39]. We also found that higher TC level had a positive correlation with HCV infection while lower TC level displayed inverse correlation (data not shown).…”

A population-based study investigating the association between metabolic syndrome and Hepatitis B/C infection (Keelung Community-based Integrated Screening Study No. 10)

“…Secondly, it may be that, as suggested by recent research, HDL and its physiologically relevant receptor, Scavenger Receptor Class B Type 1 (SR-BI), play an active role in facilitating HCV entry. 5 However, no studies to date have reported similar findings for HBV infection. High serum TG levels have also been reported in subjects without hepatitis B/C infection.…”

“…4 A recent molecular study also found that HDL plays an active role in facilitating hepatitis C virus entry through the Scavenger receptor (class B type 1). 5 In addition, the results from previous studies investigating the relationship between hepatitis B infection and type 2 diabetes are inconsistent. Three studies reported a positive association between the two, [6][7][8] two found no association, 9,10 and one found an inverse association.…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] …”