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Review |
1 Pasteur Institute, Hepacivirus and Innate Immunity, 25/28 Rue du Dr Roux, 75724 Paris Cedex 15, France
2 University of Eastern Piedmont ‘A. Avogadro’, Department of Clinical and Experimental Medicine, Via Solaroli 17, 28100 Novara, Italy
Correspondence
Agata Budkowska
agata.budkowska{at}pasteur.fr
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ABSTRACT |
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Introduction |
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). In most cases (60–85 %), HCV infection progresses to chronic liver disease, which can lead to liver cirrhosis and hepatocarcinoma (Shepard et al., 2005). The current therapy, based on the combination of pegylated interferon with ribavirin, is effective in only 50–80 % of the patients, depending on the virus genotype, and has several serious side effects (Fried et al., 2002; Manns et al., 2001; Keam & Cvetkovic, 2008; Pawlotsky, 2006). A better understanding of the mechanisms leading to the initiation of infection is essential for the development of new therapeutic approaches targeting the early stage of the HCV replication cycle.
HCV is a small, enveloped virus belonging to the family Flaviviridae (genus Hepacivirus). HCV has a single-stranded positive sense RNA genome of about 9.6 kb, encoding a polyprotein of about 3000 amino acids (aa), which is cleaved into structural (core, E1 and E2) and non-structural (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins by host and viral proteases. Structural proteins form viral particles with the help of p7 and NS2, whereas non-structural proteins NS3 to NS5B are involved in genome replication (reviewed by Bartenschlager et al., 2004; Bartenschlager & Sparacio, 2007; Brass et al., 2006; Penin et al., 2004). The putative infectious virus particle is composed of a nucleocapsid or ribonucleoprotein complex bearing the HCV genome; this inner structure is surrounded by a phospholipid bilayer, into which E1 and E2 envelope glycoproteins are anchored. However, infectious HCV particles become tightly associated with very-low-density lipoproteins (VLDL) during virus assembly and are (co-)secreted with VLDL, although the exact nature of this association remains unclear (Gastaminza et al., 2008; Ye, 2007).
Virus entry is defined as the steps from particle binding to the host cell up to the delivery of the viral genome to its replication site within the target cell, which, in the case of HCV, is the human hepatocyte. This process relies on specific interactions between virus components, mainly envelope proteins and multiple cellular factors.
Recent advances in cell culture models have significantly contributed to our understanding of the molecular virology of HCV infection, in particular the entry steps. Before discussing these observations, we will briefly summarize the main model systems used to study HCV cell entry.
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Model systems for studies of HCV cell entry |
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; Lindenbach et al., 2005).
Plasma-derived HCV
The first approaches to studying HCV infection were based on the inoculation of primary human hepatocytes, T cells and B cells with sHCV (Shimizu et al., 1992; Fournier et al., 1998; Rumin et al., 1999). The primary limits of this system were (i) the low level of HCV replication, which required the use of RT-PCR to detect viral RNA in infected cells, (ii) difficulties in discriminating between newly synthesized and input HCV RNA and (iii) the absence or very low levels of infectious virus particle production (reviewed by von Hahn & Rice, 2008). In addition, a homogeneous and well-characterized inoculum could not be obtained due to virus heterogeneity in the serum (see below) and the association of virus particles with plasma lipoproteins.
Recombinant E2 glycoprotein
In the absence of a reliable in vitro model for virus multiplication, a truncated, soluble form of recombinant E2 glycoprotein (sE2) was used to search for candidate receptors involved in HCV cell entry. These approaches allowed the identification of two major HCV receptors: tetraspanin CD81 (Pileri et al., 1998) and human scavenger receptor class B (SR-BI/Cla1) (Scarselli et al., 2002); this provided evidence for the interaction of E2 with heparan sulphate (HS) proteoglycans (Barth et al., 2003). The limitation of this system was the fact that the viral glycoproteins E1 and E2 form a heterodimer on the viral envelope and thus isolated E2 may behave differently; indeed, in addition to hepatocytes, sE2 binds to various cell lines of human origin (Flint et al., 1999; Michalak et al., 1997).
HCV-like particles (HCV-LPs)
HCV-LPs, produced in baculovirus expression systems, bind and enter into hepatoma cells and human primary hepatocytes in a receptor-mediated manner (Barth et al., 2006a). These particles were produced using recombinant baculovirus expression vectors and insect cell cultures (Baumert et al., 1998). Although E1 and E2 form a heterodimeric complex in this system, glycosylation in insect cells does not properly mimic the situation in human cells. Moreover, the particles are not secreted but rather retained in intracellular vesicles making their preparation difficult. Finally, it is not clear how well these particles reflect the earliest stages of infection by authentic HCV.
HCV pseudoparticles (HCVpp)
An important breakthrough in getting access to a system that most closely mimics entry of authentic HCV cell entry was the development of HCV pseudotypes. This system is based on the production of lentiviral particles that incorporate unmodified HCV glycoproteins into the lipid envelope (Bartosch et al., 2003a; Hsu et al., 2003). Production of HCVpp is achieved by co-transfection of 293T cells with plasmids encoding three components: full-length E1 and E2 glycoproteins, retroviral or lentiviral core and polymerase proteins and a proviral genome carrying a marker gene, such as green fluorescent protein or luciferase. These particles are infectious and show a tropism for human liver cells. Moreover, cell entry of HCVpp is neutralized by antibodies directed against the E2 protein (Bartosch et al., 2003a; Keck et al., 2008). The main disadvantage of this system is that it mimics only the very early steps, from particle binding to liberation of the capsid. Most importantly, unlike the natural virus, HCVpp are not associated with lipoproteins, since they are produced in 293T kidney cells that do not synthesize lipoproteins.
Cell culture-produced HCV (HCVcc)
The development of the first in vitro model reproducing the complete viral replication cycle and supporting the production of authentic virus particles that are infectious in vitro and in vivo was an important milestone in the HCV field. This model is based on a particular genotype 2a virus strain, JFH-1, or chimeras of this, cloned from the serum of a patient with fulminant hepatitis C. Subclones of the human hepatoma cell line Huh-7 (Huh7.5 and Huh7-Lunet) transfected with the JFH1 genome efficiently replicate the virus and secrete infectious particles (Lindenbach et al., 2005; Wakita et al., 2005). Besides their capacity to infect naive Huh-7 cells, virus produced in vitro is infectious in chimpanzees and in uPA-SCID mice with human liver grafts (Lindenbach et al., 2006; Wakita et al., 2005), a model that has been used largely for the evaluation of antiviral compounds (Meuleman et al., 2005; Meuleman & Leroux-Roels, 2008). Although this HCV in vitro replication model mimics a natural HCV infection, it has some important limitations: it is restricted to two particular cell lines (Huh-7 and LH86), which have abnormal lipoprotein metabolism, and essentially to the JFH-1 strain. Although a highly cell culture-adapted genotype 1a strain has been described that also supports production of infectious virus in Huh-7 cells, virus titres are very low and not robust enough to allow detailed studies of virus entry. Moreover, JFH-1 particles produced in hepatoma cells have a lower specific infectivity than virus produced in infected animals (Lindenbach et al., 2006). This observation most likely reflects defective lipoprotein metabolism in Huh-7 cells and, thus, differences in the structure of virus particles produced in vitro and in vivo. Animal-derived viruses have a lower density but higher infectivity than cell culture-produced viruses, arguing that there is a more extensive or different association with lipoproteins (Lindenbach et al., 2006; Bukh & Purcell, 2006).
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Virus proteins mediating cell entry |
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; Dubuisson, 2000). Their synthesis and glycosylation of E1 and E2 take place in the endoplasmic reticulum (ER), where the N-terminal domains of E1 and E2 are directed into the ER lumen (Cocquerel et al., 2002). The transmembrane domains of E1 and E2 are multifunctional: they anchor the glycoproteins to the ER membrane and they contain sequences essential for heterodimerization and their retention in the ER (Cocquerel et al., 2000).
Studies carried out using HCVpp provided evidence that the E1–E2 heterodimer is involved in virus entry, as HCVpp expressing E1 or E2 separately are non-infectious (Bartosch et al., 2003a; Drummer et al., 2003). E2 glycoprotein probably plays a major role in the interaction between the virus and its major cellular receptors CD81 and SR-BI/Cla1. The CD81 binding region of E2 requires correctly folded E2 (Flint et al., 1999), as several E2 regions are engaged in CD81 binding. The first region is located between aa 480 and 493 (Clayton et al., 2002; Flint et al., 1999; Owsianka et al., 2001), the second spans aa 528–535 (Clayton et al., 2002; Owsianka et al., 2001), whereas the third encompasses aa 544–551 (Flint et al., 1999; Owsianka et al., 2001). In addition, specific amino acid residues conserved across all HCV genotypes that are critical for CD81 binding have been identified (W420, Y527, W529, G530 and D535) (Owsianka et al., 2006).
Antibodies directed to aa 412–423 and 432–447 block interaction of the receptor with virus-like particles (Owsianka et al., 2001) and mutation of the region between aa 612 and 620 abolishes CD81 binding. Thus, it has been proposed that a complex interplay between several regions of E2 is responsible for modulating receptor binding, possibly through intramolecular interactions (Roccasecca et al., 2003).
Hypervariable region 1 (HVR1) on E2 glycoprotein is involved in virus interaction with human SR-BI (SR-BI/Cla1) (Scarselli et al., 2002). Due to its high variability, this region may contribute to virus escape from host immune responses (von Hahn et al., 2007). Indeed, antibodies targeting HVR-1 inhibit cell entry of HCVpp and cellular binding of HCV-LPs (Barth et al., 2005; Bartosch et al., 2003b). In spite of the high sequence variability, the conformation and structural properties of HVR-1 are highly conserved, suggesting that HVR1 is indeed functional (Penin et al., 2001); nevertheless, attempts to demonstrate a direct interaction of the receptor with recombinant E1–E2 were unsuccessful (Cocquerel et al., 2006). Moreover, the role of HVR1 in HCV infection in vivo remains to be confirmed, as its deletion did not induce a loss of virus infectivity in experimentally infected chimpanzees, although infectivity of the mutant was attenuated (Forns et al., 2000).
HCV envelope glycoproteins are highly glycosylated: 4 and 11 glycosylation sites are highly conserved in E1 and E2 proteins, respectively. Glycosylation may play a key role in the HCV life cycle, as deletion or mutation of some glycosylation sites reduces infectivity of HCVpp. Moreover, some glycans decrease the sensitivity of HCVpp to neutralization by envelope-specific antibodies, but simultaneously mask the CD81 binding site (Goffard et al., 2005; Helle & Dubuisson, 2008; Helle et al., 2007).
The role of E1 in HCV infection remains poorly understood, but it appears to be involved in the fusion process (Garry & Dash, 2003; Lavillette et al., 2007). Moreover, antibodies directed against the N-terminal region of E1 reduce the binding of HCV-LPs to hepatoma cell lines and to dendritic cells (DCs), suggesting a role for this region in HCV cell entry (Barth et al., 2005; Triyatni et al., 2002).
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Virus receptors on host cells |
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), SR-BI/Cla1 (Scarselli et al., 2002), Claudin-1 (CLDN-1) (Evans et al., 2007) and occludin (Liu et al., 2009), are considered to be essential receptors or co-receptors for HCV cell entry. In addition, glycosaminoglycans, such as heparan sulfate, the lectins DC-specific intracellular adhesion molecule-3-grabbing non-integrin (SIGN) and liver-specific (L)-SIGN (Cormier et al., 2004a), and low-density lipoprotein (LDL)-receptor (LDL-R) (Agnello et al., 1999) have been implicated in HCV cell attachment and entry.
Tetraspanin CD81
CD81 is an unglycosylated membrane protein; it is an integral member of the tetraspanin family that is ubiquitously expressed. It contains four transmembrane domains, two small and one large extracellular loops (SEL and LEL, respectively) and N- and C-terminal intracellular domains. CD81 is a part of the B/T cell receptor complex and is involved in the fusion of vesicles (Hemler, 2003; Levy & Shoham, 2005). It is required for normal CD19 expression and plays multiple roles in the processing, intracellular trafficking and membrane functions of CD19 (Shoham et al., 2006).
CD81 has been proposed as an HCV receptor molecule, based on CD81 LEL binding to sE2 (Pileri et al., 1998). This binding appears to be species-specific, as sE2 does not bind mouse or rat CD81 (Flint et al., 2006). Studies with sE2 have demonstrated that the two disulphide bonds, which stabilize the loop domain, are required for the interaction between sE2 and CD81 (Pileri et al., 1998; Drummer et al., 2005). The role of CD81 in HCV infection was confirmed by several experimental approaches. Indeed, non-permissive human hepatoma cell lines such as HepG2 and HH29, which do not express CD81, become susceptible to HCVcc and HCVpp infection upon ectotopic expression of CD81 after transduction (Bartosch et al., 2003b; Cormier et al., 2004b; Lavillette et al., 2005; Zhang et al., 2004).
An HCV E2 binding region maps to the LEL of CD81 (Pileri et al., 1998; Drummer et al., 2002; Zhang et al., 2004). The site is conformational and a number of specific amino acid residues were found to be critical for the interaction with E2 (Pileri et al., 1998; Bertaux & Dragic, 2006; Drummer et al., 2002; Higginbottom et al., 2000; Zhang et al., 2004).
Monoclonal antibodies (mAbs) directed against CD81 and a soluble form of CD81 LEL inhibited HCVpp and HCVcc infectivity in vitro (Bartosch et al., 2003a; Cormier et al., 2004b; Hsu et al., 2003; Molina et al., 2008a; Wakita et al., 2005) and HCV infection in vivo (Meuleman et al., 2008). CD81-specific antibodies or downregulation of CD81 expression using siRNA also inhibited infection with sHCV (Molina et al., 2008a; Zhang et al., 2004).
Several studies suggest that CD81 actually acts as a post-binding entry molecule. In fact, antibodies against CD81 and human recombinant CD81 LEL inhibit HCV infection only after virus attachment (Cormier et al., 2004b; Flint et al., 2006; Koutsoudakis et al., 2006). Moreover, susceptibility to infection is related not only to the expression level of CD81 (Akazawa et al., 2007; Koutsoudakis et al., 2007) but also to the proportions of CD81 and SR-BI at the cell surface (Kapadia et al., 2007). EWI-2wint, a cellular partner of CD81 expressed on the cell surface, could efficiently block viral entry by inhibiting viral interaction with CD81 (Rocha-Perugini et al., 2008). The absence of this natural inhibitor of CD81 in hepatic cells may thus enable virus entry and contribute to the hepatotropism of HCV.
Recent studies elucidated the cellular pathways triggered by HCV binding to CD81. Indeed, engagement of CD81 plays a fundamental role in HCV infectivity through the activation of Rho GTP-ases and the actin-dependent relocalization of the E2/CD81 complex to cell–cell contact areas where CD81 comes into contact with the tight junction proteins occludin and CLDN-1 (Brazzoli et al., 2008), molecules recently described as HCV co-receptors (see below). Finally, CD81 engagement activates the Raf/MEK/ERK signalling cascade, which affects post-entry steps of the virus life cycle (Brazzoli et al., 2008). Thus, CD81 is not a mere attachment factor but actively promotes infection by triggering signalling cascades important for virus entry and more downstream events.
Finally, CD81 may also play a role in the modulation of the adaptive immune response through virus interaction with CD81 on T and B cells; this, in turn, could contribute to virus persistence, liver pathogenesis and, via polyclonal activation of B cells, to extrahepatic manifestations frequently observed in chronic hepatitis C patients (Crotta et al., 2002; Machida et al., 2005; Wack et al., 2001).
SR-BI/Cla1
SR-BI is expressed in various mammalian cells but is mostly expressed in the liver and steroidogenic tissues. It is a 509 aa glycoprotein with two cytoplasmic domains, two transmembrane domains and a large extracellular loop with nine potential N-glycosylation sites (Acton et al., 1994; Calvo & Vega, 1993; Rhainds & Brissette, 2004). SR-BI is a ‘multi-ligand’ receptor for various classes of lipoproteins [high-, low- and very-low-density lipoproteins (HDL, LDL and VLDL, respectively)] as well as for chemically modified lipoproteins such as oxidized and acetylated LDL. Indeed, SR-BI contains distinct binding sites that can independently interact with their respective ligands (Rhainds & Brissette, 2004). In addition, SR-BI may play the role of an endocytic receptor (Rhainds & Brissette, 2004). The essential function of SR-BI is the selective cholesteryl ester (CE) uptake from HDL. During this process, the core of CEs from the HDL particle is delivered into the cell without degradation of the protein moiety. SR-BI-mediated cholesterol efflux to HDL plays an important role in reverse cholesterol transport and atherogenesis (Krieger, 1999; Swarnakar et al., 1999).
In addition to its established function in HDL metabolism, SR-BI plays an important physiological role in the catabolism of VLDL and in the selective CE uptake from VLDL, as recently shown in a mouse model and studies on primary human hepatocytes (Van Eck et al., 2008).
SR-BI/Cla1 has been proposed to act as a putative HCV entry molecule on the basis of its reactivity with sE2 (Scarselli et al., 2002). SR-BI binding to sE2 appears to be species-specific, as mouse SR-BI does not bind sE2. The HVR-1 region of E2 is responsible for binding SR-BI, since deletion of HVR-1 impairs the interaction between SR-BI and sE2, and reduces HCVpp infectivity (Bartosch et al., 2003a; Scarselli et al., 2002). Furthermore, antibodies against SR-BI also significantly reduce HCVpp infectivity (Bartosch et al., 2003b). Similar to CD81, SR-BI acts as a ‘post-binding’ receptor; indeed, antibodies against both receptors inhibited infection when added until 60 min after virus binding (Cormier et al., 2004b; Zeisel et al., 2007).
Interestingly, HDL, the main SR-BI ligand, facilitates HCVpp and HCVcc cell entry, with no evidence for a direct interaction between HDL and virus particles (Bartosch et al., 2005; Dreux et al., 2006; Voisset et al., 2005). It has been postulated that the enhancing effect of HDL on HCVpp and HCVcc cell entry could be mediated through either an interaction between HDL and lipid membranes or the activation of SR-BI by HDL. HDL decreased the efficiency of HCV neutralizing antibodies by mechanisms related to the stimulation of cell entry (Dreux et al., 2006). In contrast with the enhancing effect of HDL, other natural SR-BI ligands, such as VLDL (Maillard et al., 2006) and oxidized LDL (von Hahn et al., 2006), had significant inhibitory effects on serum HCV and HCVpp cell entry via SR-BI, respectively.
Several studies suggest that SR-BI/Cla1 co-operatively interacts with CD81 in HCV cell entry. Indeed, HDL enhanced HCVcc infectivity only when CD81 was expressed (Zeisel et al., 2007). Furthermore, the depletion of cholesterol from cholesterol-enriched plasma membrane micro-domains by treatment with methyl-β-cyclodextrin significantly reduced the expression of CD81 but not SR-BI on the plasma membrane, decreasing levels of cell infection with HCVcc and HCVpp (Kapadia et al., 2007). Analogous to its role in the infection of hepatocytes by Plasmodium falciparum (Yalaoui et al., 2008), SR-BI could mediate an arrangement of the plasma membrane, acting as a major cholesterol provider and regulating organization of CD81 at the plasma membrane, thus ‘boosting’ permissiveness of the cell to HCV infection. The role of SR-BI was confirmed by findings that high avidity mAbs directed against SR-BI efficiently block infection of hepatoma cells in vitro (even in the presence of HDL) and of chimpanzees with cell-derived HCVcc (Catanese et al., 2007), and that the expression levels of SR-BI can modulate HCVcc infectivity (Grove et al., 2007).
SR-BI binds serum amyloid A (SAA) (Cai et al., 2005), an acute-phase protein produced primarily by the hepatocytes during infection (Uhlar & Whitehead, 1999). Human SAA inhibits HCV cell entry into Huh7.5 cells (Cai et al., 2007). Interestingly, HDL reduces the antiviral effects of SAA, suggesting a relationship between SAA, HDL and HCV infectivity, probably due to the competition between HDL and SAA. However, the exact mechanisms by which SAA affects HCV infectivity require further investigation.
Recently, the antiviral action of interferon has been linked to a decrease in the expression levels of SR-BI on the cell surface, thereby restricting virus attachment and entry into hepatocytes (Murao et al., 2008). These data underline the crucial role of SR-BI in cell infection by HCV.
Tight junction proteins: CLDN1 and occludin
Tight junctions are major components of cell–cell adhesion complexes that separate apical from basolateral membrane domains and maintain cell polarity by forming an intramembrane; this permits diffusion of certain molecules and limits others (Shin et al., 2006). The tight junction multiprotein complex is composed of four types of transmembrane proteins: occludins, Claudins, junction–associated molecules (JAMs) and the coxsackie virus B adenovirus receptors (CARs) (Greber & Gastaldelli, 2007).
Hepatocyte tight junctions play key roles in several liver functions, including bile formation and secretion (Van Itallie & Anderson, 2004). The major transmembrane proteins of the tight junctions are targeted by several reoviruses, coxsackie virus B3 (CVB3), human adenoviruses Ad2/5 (Greber & Gastaldelli, 2007) and HCV (Evans et al., 2007; Liu et al., 2009; Ploss et al., 2009).
CLDN1.
Evans et al. (2007) have identified CLDN1, a member of the Claudin gene family, which is a new protein involved in HCV entry. CLDN1 is expressed in all epithelial tissues but predominantly in the liver, forming networks at tight junctions (Furuse et al., 1998). The molecule is composed of 211 aa with two extracellular loops, four transmembrane segments and three intracellular domains (Van Itallie & Anderson, 2006). The highly conserved domain in the first extracellular loop (EL1) seems to be involved in HCV entry (Evans et al., 2007).
The expression of CLDN1 confers susceptibility to HCVpp infection in non-hepatic cell lines such as 293T and SW13 (Evans et al., 2007). Moreover, silencing of CLDN1 inhibits HCV infection in susceptible cells (Huh7.5) (Evans et al., 2007). Nevertheless, there is still no evidence for a direct interaction between CLDN1 and the virus. By contrast, functional studies indicate that CLDN1 plays a role in the post-binding phase of infection, subsequent to HCV binding to CD81 and probably subsequent to HCV binding to SR-BI (Evans et al., 2007). Analogous to other viruses (Coyne & Bergelson, 2006), interactions with CLDN1 are thought to take place after a lateral migration of the virus–SR-BI/CD81 complex to tight junctions. Indeed, the initial binding of the viral particle may cluster receptor molecules to activate signalling pathways that promote transfer of the bound virus from the basolateral sinusoidal surface to the tight junction facing the bile canaliculi, since a similar mechanism has been described for the human picornavirus CVB3, whose binding to the decay-accelerating factor on the apical surface of the Caco-2 cell triggers their movement to the tight junctions and their cell entry (Coyne et al., 2007).
Two other members of the Claudin family, CLDN6 and CLDN9, also mediate HCV entry (Zheng et al., 2007; Meertens et al., 2008). As with CLDN1, these molecules are expressed in the liver; however, unlike CLDN1, they are also present in peripheral blood mononuclear cells, another possible HCV replication site in addition to the human hepatocyte. CLDN6 and CLDN9 have a highly conserved EL1 region and a significant sequence homology with CLDN1 (Zheng et al., 2007).
Recent data indicate that distribution of CLDN1 in tight junctions correlates with permissiveness to HCV infection (Liu et al., 2009; Yang et al., 2008), thereby confirming that localization of CLDN1 tight junctions is critical for viral entry and cellular tropism of HCV.
Occludin.
CLDN1 has been shown to be essential for HCV infection of human hepatoma cell lines, even though there is still no evidence that CLDN1 binds HCV directly. In addition, human cell lines such as HeLa and HepH (CD81- and SR-BI-positive) remained HCV resistant when overexpressing CLDN1, suggesting that additional factors were needed for successful HCV cell entry (Evans et al., 2007). Recent studies have provided evidence that another transmembrane component of the tight junctions that is structurally related to Claudins plays an important role in HCV cell entry and initiation of a productive HCV infection (Liu et al., 2009). Occludin is a 60 kDa protein with four transmembrane regions, two extracellular loops and N- and C-terminal cytoplasmic regions (Furuse et al., 1993). Occludin participates in both cell–cell adhesion in the paracellular space and anchoring of the junctional complex to the cytoskeleton. The latter function is accomplished through binding of the C-terminal cytoplasmic region of occludin to scaffolding zonula occludens proteins (ZO-1, -2 and -3) which mediate binding to cytoskeletal actin (Peng et al., 2003). The occludin polypeptide is delivered to the plasma membrane in a microtubule- and temperature-dependent manner, whereas its steady state localization at the cell surface depends on intact microfilaments (Subramanian et al., 2007). Targeting CLDN1 and occludin by siRNA and shRNA interference demonstrated that reduction of the expression of both of these molecules inhibited HCVpp and HCVcc cell entry (Liu et al., 2009). Confocal microscopy analyses showed that occludin accumulates in the ER and co-localizes with the E2 HCV protein (Benedicto et al., 2008). The E2–occludin association was further confirmed by co-immunoprecipitation and pull-down assays (Benedicto et al., 2008; Liu et al., 2009) using a JFH1 variant. Recently, it has been shown that human occludin renders murine cells infectable with HCVpp (Ploss et al., 2009). Together, these data suggest that occludin interacts directly with E2, facilitating viral entry through hepatocyte tight junctions, and that this process may require a delicate molecular architecture of proteins occurring at tight junctions.
A striking observation, however, was that HCV infection may alter localization of tight junction proteins (Benedicto et al., 2008; Liu et al., 2009). Indeed, expression levels of CLDN1 and occludin were downregulated following infection, rendering the infected cells refractory to HCVpp superinfection (Liu et al., 2009). Thus, it appears that HCV infection leads to global reduction of tight junction proteins in HCV infected cells. As tight junction proteins are critical in maintaining the polarity of hepatocytes and their essential functions, altered expression of tight junction proteins may lead to several reported symptoms, including cholestatic disorders.
Glycosaminoglycans (GAGs)
GAGs are linear polysaccharides expressed on the cell surface that act as binding sites for many viruses. GAGs may serve as ‘primary’, low affinity, but abundant receptors, involved in the initial interaction of the virus with the cell surface prior to binding to high affinity receptors (Barth et al., 2003; Germi et al., 2002). There are different types of GAGs, but highly sulphated GAGs in particular, such as HS, appear to be involved in interaction with several viruses, triggering their subsequent uptake. Likewise, docking between HCV and cellular GAGs has been observed (Barth et al., 2006b; Cribier et al., 1998; Germi et al., 2002; Thomssen et al., 1992). In addition, heparin, an HS analogue, and heparinase, an enzyme degrading HS, inhibit HCV attachment to cells and treating cells with glycosidases reduces HCV infectivity (Barth et al., 2006b; Basu et al., 2007; Koutsoudakis et al., 2006; Morikawa et al., 2007).
Attachment of the virus to HS may play an essential role in the early steps of HCV infection. However, the exact role of GAGs in HCV cell entry remains unclear. sE2 binds to heparin with high affinity, but studies with HCVpp, which carry E1–E2 heterodimers on their surface, failed to confirm these findings (Callens et al., 2005). These observations suggest that either the HS binding site is not accessible on the functional E1–E2 heterodimer or the attachment of authentic HCV particles to cellular GAGs is mediated by lipoproteins associated with virus particles. Indeed, HCV can bind and enter the cell by the HS-dependent pathway due to the interaction of virus-associated lipoproteins with lipoprotein lipase (LPL), mediating HCV cell entry (Andréo et al., 2007).
Lectins: DC-SIGN and L-SIGN
Lectins are another class of molecules involved in binding and cell entry of several viruses. DC-SIGN and L-SIGN are homotetrameric type II membrane proteins from the C-type lectin family. They contain a carbohydrate recognition domain in their extracellular C-terminal region; this domain binds virus carbohydrates in a calcium-dependent manner.
Both lectins are involved in binding, internalization and elimination of a variety of pathogens (Cambi et al., 2005; Van Kooyk & Geijtenbeek, 2003). Some viruses bypass this mechanism and use C-lectins as cell attachment and entry factors. L-SIGN and DC-SIGN bind sE2 with high affinity through high mannose-type oligosaccharides, but also interact with HCVpp (Lozach et al., 2004; Pöhlmann et al., 2003) and natural viruses from sera of infected individuals (Gardner et al., 2003). DC-SIGN is expressed on Kuppfer cells, DCs and lymphocytes. L-SIGN is expressed in liver sinusoidal endothelial cells. DC-SIGN and L-SIGN may thus function as capture receptors capable of transmitting the virus to permissive cells and may play a role in the initiation of HCV infection and tissue tropism (Cormier et al., 2004a; Gardner et al., 2003; Lozach et al., 2004).
The asialoglycoprotein receptor (Stockert, 1995) has also been proposed as a cell surface molecule that might be involved in HCV cell entry (Saunier et al., 2003). Indeed, it is expressed on the surface of liver cells and has the capacity to bind and internalize HCV-LPs, but its relevance for HCV infection remains to be demonstrated.
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Mechanism of HCV cell entry |
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). This mechanism is pH-dependent, with an optimum at about pH 5.5; indeed, HCVpp and HCVcc entry can be blocked by substances that block acidification of early endosomes (Blanchard et al., 2006; Hsu et al., 2003; Koutsoudakis et al., 2006; Meertens et al., 2006).
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). Characterization of fusion determinants led to the conclusion that three discrete regions of both E1 and E2 proteins participate in the membrane fusion process (Lavillette et al., 2007); indeed, several hydrophobic patches have been identified in both E1 and E2 glycoproteins (Pérez-Berná et al., 2008). However, neither of the HCV receptors has yet been shown to mediate viral fusion. Recent data from our group suggest that HCV cell entry is also dependent on an intact microtubule network firstly for virus transport between its cell attachment site and the site where fusion takes place and also later after nucleocapsid release into the cytoplasm (Roohvand et al., 2009). |
Role of lipoproteins in virus cell entry |
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; Kapadia & Chisari, 2005; Ye et al., 2003; Ye, 2007). Moreover, HCV infection is known to induce large changes in cellular lipid metabolism, including abnormal levels of serum lipoproteins (reduced) in chronic HCV infection and an accumulation of lipids in liver parenchymal cells (steatosis) (André et al., 2005; Petit et al., 2003).
HCV particles in patient sera
Although detailed morphological analysis of authentic HCV particles is missing, we can assume that virus particles are most likely composed of the nucleocapsid surrounded by the lipid envelope into which E1 and E2 glycoproteins are embedded. However, HCV circulates in patient sera as a very heterogeneous population of particles with a density between 1.03 and 1.34 g ml–1 (André et al., 2005). Only a minor population of serum particles has properties corresponding to the canonical ‘flavivirus-like’ particles (Petit et al., 2005). Instead, various unconventional forms of HCV were detected in HCV-positive sera and characterized. These include lipo-viro particles (LVPs) (André et al., 2002; Nielsen et al., 2006), exosomes [membranous vesicles bearing HCV envelope proteins, viral RNA and CD81 (Masciopinto et al., 2004)] and non-enveloped (‘naked’) nucleocapsids (Maillard et al., 2001).
Most circulating HCV particles are of low density due to association with β-lipoproteins (Thomssen et al., 1992; Agnello et al., 1999; Prince et al., 1996). Only a very low-density population of sHCV was highly infectious in chimpanzees (Beach et al., 1992; Bradley et al., 1991) and tissue culture cells, and LDL-R appeared to play an important role in infection (Agnello et al., 1999; André et al., 2002; Bradley et al., 1991; Monazahian et al., 1999). In contrast, high-density populations of HCV were poorly infectious (Bradley et al., 1991; Agnello et al., 1999). These studies suggest that lipoproteins play a critical role in the infectivity of natural HCV.
Low-density, highly infectious HCV in the serum primarily corresponds to LVPs, which are lipoprotein-like structures composed of triglyceride-rich lipoproteins containing apolipoprotein (Apo)B and ApoE, viral nucleocapsids and envelope glycoproteins (André et al., 2002; Nielsen et al., 2006; Diaz et al., 2006). These particles contain ApoB100, which is of hepatic origin and an integral part of VLDL. However, the presence of ApoB48, normally produced by enterocytes, suggests that a part of circulating LVPs may originate not only from the liver but also from the intestine (Diaz et al., 2006).
Recently, Lindenbach et al. (2006) provided evidence that the specific infectivity of HCVcc produced in vitro and recovered from experimentally infected chimpanzees or uPA-SCID mice with human liver grafts was higher and buoyant density was lower than those of the same virus strain produced in cell culture. Thus, the association between virus particles and lipoproteins may confer higher viral infectivity. In accordance with this notion, HCVcc infection in vitro could be efficiently inhibited not only by antibodies directed against the HCV envelope but also by antibodies against ApoB-containing lipoproteins (Andréo et al., 2007), supporting the essential role of lipoproteins in virus cell entry and in the initiation of infection.
Role of lipoproteins in virus interaction with SR-BI/Cla1
No evidence for an interaction between SR-BI and the E1–E2 heterodimer is available (Cocquerel et al., 2006), despite the direct interaction between sE2 and SR-BI (Scarselli et al., 2002) and the unequivocal role of this receptor in HCVpp and HCVcc cell entry (Kapadia et al., 2007; Bartosch et al., 2003b). In addition, natural serum-derived HCV does not recognize SR-BI directly via viral envelope glycoproteins; instead, ApoB lipoproteins associated with virus particles play a key role in the initial interaction of the receptor by serum-derived authentic HCV (Maillard et al., 2006). In fact, polyvalent high-affinity anti-E1 and -E2 antibodies, or antibodies directed against HVR-1 and inhibiting HCVpp infection, did not block virus–SR-BI interactions. In contrast, VLDL, a natural ligand of the receptor, and antibodies directed against β-lipoproteins were found to be extremely efficient inhibitors of SR-BI-mediated virus uptake. Thus, natural serum-derived HCV recognizes SR-BI indirectly via ApoB-containing lipoproteins (mainly VLDL) associated with virus particles. VLDL promotes virus uptake and protects the virus against potentially neutralizing antibodies. These data corroborate in vitro studies showing that SR-BI facilitates the clearance of VLDL (Van Eck et al., 2008) and clinical observations that genetic variation of the SR-BI gene locus is associated with alterations in the metabolism of ApoB-containing lipoproteins in humans (Peréz-Martínez et al., 2003). These data could explain the co-existence of infectious virus particles with neutralizing antibodies in the sera of most HCV-infected individuals; the antibodies are potentially neutralizing but are not able to control chronic HCV infection (von Hahn et al., 2007; Haberstroh et al., 2008).
LDL-R
Another lipoprotein receptor potentially involved in the uptake of lipoprotein-associated HCV into hepatocytes is LDL-R. Hepatocytes acquire cholesterol via endocytosis involving LDL-R. The most important ligands for this receptor are LDLs, which are responsible for the transport of the majority of plasma cholesterol. After binding to the receptor, LDLs are internalized by clathrin-mediated endocytosis and are transported to endosomes, where the acidic pH induces the release of lipoprotein particles from LDL-R. Lipoproteins are subsequently degraded in lysosomes and cholesterol is released into the cells (Rudenko & Deisenhofer, 2003).
The role of LDL-R in HCV entry was first proposed by Agnello et al. (1999). The authors demonstrated that lipoprotein-associated HCV from patient sera and other viruses from the family Flaviviridae utilize LDL-R for cell entry. In accordance with these observations, LVPs isolated from patient sera were shown to infect hepatoma cells in an LDL-R-dependent manner (André et al., 2002). Nevertheless, the function of LDL-R in HCV infection remains controversial, as the role of this receptor in the in vitro HCVcc infection model has not yet been demonstrated. More recently, the significance of LDL-R in HCV infection of primary human hepatocytes has been confirmed (Molina et al., 2007). Moreover, the correlation of cell surface expression of LDL-R in patients with chronic HCV infection and with a high viral load implies that LDL-R is actually involved in the viral replication cycle in vivo (Petit et al., 2007). It is conceivable that, similar to SR-BI, LDL-R may participate in virus cell entry via interaction with lipoproteins that are associated with HCV at an early step of infection, preceding virus interaction with CD81 (Fig. 2). However, one cannot exclude the possibility that LDL-R mediates an alternative pathway of HCV cell entry.
|
). After digestion by LPL, VLDL particles are transformed into intermediate-density lipoproteins; these are efficiently removed from the plasma by the LDL-R family on hepatocytes or further transformed by hepatic lipase into LDL (Merkel et al., 2002).
We have recently demonstrated that LPL mediates the binding and uptake of lipoprotein-associated HCV particles to different types of cells (Andréo et al., 2007). The mechanism of action of LPL on natural HCV involves the formation of a bridge between virus-associated lipoproteins and HS at the cell surface (Andréo et al., 2007). LPL-mediated cellular uptake of the virus may involve HCV receptors or receptors from the LDL-R family or the HS endocytic pathway, independent from other receptors. LPL mediates cellular uptake of HCV to human hepatoma cells, but has a potent inhibitory effect on HCVcc infection in vitro (JFH1 strain), probably leading to a non-productive pathway of virus cell entry in this experimental system (Andréo et al., 2007). Since lipoproteins associated with virus particles are essential for LPL-mediated virus uptake, these observations suggest that LPL could be a natural modulator of HCV infectivity in vivo and that the LPL effect could depend on the composition of virus-associated lipoproteins.
Role of apolipoproteins in HCV cell entry
Human apolipoproteins are protein constituents of chylomicrons, VLDL and HDL. In particular, ApoCs have an inhibitory or stimulatory effect on a variety of receptors [such as LDL-R, VLDL-R and LDL-R-related protein (LRP)] and enzymes involved in lipoprotein metabolism (such as LPL and hepatic lipase). Indeed, ApoC2 is an important activator of LPL, whereas ApoC3 inhibits lipolysis of TG-rich lipoproteins, hampering the interaction of these lipoproteins with the HS–LPL complex (Jong et al., 1999), and acts as an inhibitor of lipoprotein receptors (LDL-R and LRP).
HCV circulating in patient sera contains ApoE and ApoB as a part of VLDL and/or LDL (André et al., 2002; Maillard et al., 2006; Nielsen et al., 2006). The association of ApoC1 with infectious particles in the serum of experimentally infected chimpanzees has also been documented (Meunier et al., 2008).
Apolipoproteins are also efficient regulators of HCV infectivity. Indeed, ApoC1, an exchangeable apolipoprotein that predominantly resides in HDL, enhances HCVpp cell entry when exogenously supplied (Meunier et al., 2005). When released from HDL, ApoC1 promotes HCV membrane fusion between viral and cellular membranes in the liposome system, suggesting interplay between the HVR1 of the HCV E2 glycoprotein, HDL and SR-BI (Dreux et al., 2007). siRNAs targeting ApoB (Huang et al., 2007) or ApoE (Chang et al., 2007) efficiently inhibit release of HCV and HCV infectivity is positively correlated with levels of secreted ApoE (Chang et al., 2007). As all these apolipoproteins (B, E and C1) are components of VLDL, these studies confirm that mechanisms of infectious HCV secretion follow the secretion pathway of VLDL, and underline the enhancing effect of lipoproteins (and their protein components) on the infectivity of the virus.
ApoC3 is a known inhibitor of lipoprotein receptors (LDL-R and LRP) and LPL activity (Jong et al., 1999). Recent studies identified ApoC3 as a potential plasma biomarker associated with the resolution of acute HCV infection (Molina et al., 2008b), suggesting an important role of this apolipoprotein in the outcome of HCV infection.
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Role of lipoproteins in the formation and secretion of HCV particles |
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). This ApoB-containing VLDL precursor (pre-VLDL) subsequently fuses with triglyceride droplets in the ER/golgi luminal compartment. This process is also mediated by MTPs (Shelness & Sellers, 2001). Incomplete VLDL is not secreted by hepatocytes, but is targeted for degradation by LDL-R (Larsson et al., 2004).
Recent studies provided evidence that HCV-associated lipoproteins are not simply adsorbed at the surface of virus particles circulating in patient sera, but that VLDLs are an integral part of HCV particles. Indeed, Nielsen et al. (2006) have shown that ApoB remains associated with infectious HCV after treatment of the virus with either deoxycholic acid or NP-40. This indicates that a firm binding exists between HCV and ApoB-containing lipoproteins. In addition, the production and release of HCV by the human hepatoma cell line Huh-7 depends on the assembly and secretion of VLDL, and drugs that block VLDL assembly (such as MTP inhibitors or siRNA targeting ApoB or ApoE) also inhibit the secretion of HCV particles (Huang et al., 2007). In accordance with these observations, the density of intracellular virus particles produced in vitro is much higher than that of secreted HCVcc (Gastaminza et al., 2006, 2008). High-density (immature) HCV particles are actively degraded in a proteasome-independent manner, whereas low-density, i.e. VLDL-associated, HCV particles are efficiently secreted from infected cells. These findings provide an explanation for the presence of very-low-density, infectious virus particles circulating in patient sera and the role of lipoprotein receptors for virus cell entry.
The property that makes the virus unique is that the entire virion is not exposed to serum during circulation and virus particles have to escape from VLDL-derived lipoprotein particles in endocytic vesicles. Exactly what triggers the escape of the virus from VLDL particles during cell entry so that E2 glycoprotein can react with virus receptors and induce envelope fusion still remains to be elucidated.
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Conclusions |
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Recent studies underline the importance of VLDL in the assembly and secretion of infectious HCV particles, in accordance with the association of the majority of the circulating virus with ApoB- and ApoE-containing lipoproteins and their role in virus infectivity. Several observations suggest that lipoproteins play an important role in virus cell entry and initiation of infection. It is conceivable that HCV infection is initiated by the interaction between the lipoprotein-associated virus particle and lipoprotein receptors SR-BI/Cla1 and/or LDL-R. In addition, cell surface proteoglycans facilitate infection, probably in a lipoprotein-dependent manner (Fig. 2
).
Apart from lipoproteins, other host molecules, such as LPL (Andréo et al., 2007) or EWI-2wint (Rocha-Perugini et al., 2008), may contribute to the hepatotropism of HCV. Indeed, LPL, which targets lipoproteins to the liver, may be involved in the early steps of HCV cell entry. LPL may act as a natural modulator of HCV infectivity, affecting the lipoprotein composition of virus particles, which is apparently different for viruses produced in vivo and those produced in currently available in vitro cell culture models (Huh-7 and LH86 hepatoma cell lines). Additionally, EWI-2wint, a cellular partner and natural inhibitor of CD81, could also regulate cell invasion by HCV. The various forms of HCV circulating in patient sera could allow the virus to use different pathways of cell entry and thus different modes of infection.
The development of the HCVcc system is a major accomplishment, permitting important insights into virus–host cell interaction. However this system also has some limitations, including genetic defects of the cell lines used, which do not permit normal production of lipoproteins compared with primary human hepatocytes. These defects may affect virus composition; therefore, the results obtained in this culture system do not necessarily reflect the in vivo situation properly (Bukh & Purcell, 2006).
A detailed understanding of the mechanism of HCV entry is fundamental for the development of new therapeutic strategies to fight HCV infection. Indeed, molecules that target envelope glycans (such as inhibitors of glycosylation) or lectins (such as cyanovirin-N) to inhibit virus binding to cell surface receptors or imminosugars have been proposed as antiviral drugs (Helle et al., 2006; Steinmann et al., 2007). Likewise, drugs that downregulate expression of HCV receptors at the surface of hepatocytes may be used to block HCV cell entry. Indeed, alpha interferon, in addition to other effects, downregulates cell surface expression of SR-BI and LDL-R (Murao et al., 2008). Finally, molecules targeting the microtubule network may prevent initiation of productive HCV infection and drugs downregulating hepatic VLDL production limit virus propagation by affecting morphogenesis and release of progeny virus from infected cells. In light of the currently limited therapeutic options, the need for more efficacious therapies is obvious.
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ACKNOWLEDGEMENTS |
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REFERENCES |
|---|
Agnello, V., Abel, G., Elfahal, M., Knight, G. B. & Zhang, Q. X. (1999). Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A 96, 12766–12771.
Akazawa, D., Date, T., Morikawa, K., Murayama, A., Miyamoto, M., Kaga, M., Barth, H., Baumert, T. F., Dubuisson, J. & Wakita, T. (2007). CD81 expression is important for the permissiveness of Huh7 cell clones for heterogeneous hepatitis C virus infection. J Virol 81, 5036–5045.
André, P., Komurian-Pradel, F., Deforges, S., Perret, M., Berland, J. L., Sodoyer, M., Pol, S., Bréchot, C., Paranhos-Baccalà, G. & Lotteau, V. (2002). Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol 76, 6919–6928.
André, P., Perlemuter, G., Budkowska, A., Bréchot, C. & Lotteau, V. (2005). Hepatitis C virus particles and lipoprotein metabolism. Semin Liver Dis 25, 93–104.[CrossRef][Medline]
Andréo, U., Maillard, P., Kalinina, O., Walic, M., Meurs, E., Martinot, M., Marcellin, P. & Budkowska, A. (2007). Lipoprotein lipase mediates hepatitis C virus (HCV) cell entry and inhibits HCV infection. Cell Microbiol 9, 2445–2456.[CrossRef][Medline]
Bartenschlager, R. & Sparacio, S. (2007). Hepatitis C virus molecular clones and their replication capacity in vivo and in cell culture. Virus Res 127, 195–207.[CrossRef][Medline]
Bartenschlager, R., Frese, M. & Pietschmann, T. (2004). Novel insights into hepatitis C virus replication and persistence. Adv Virus Res 63, 71–180.[Medline]
Barth, H., Schafer, C., Adah, M. I., Zhang, F., Linhardt, R. J., Toyoda, H., Kinoshita-Toyoda, A., Toida, T., Van Kuppevelt, T. H. & other authors (2003). Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J Biol Chem 278, 41003–41012.
Barth, H., Ulsenheimer, A., Pape, G. R., Diepolder, H. M., Hoffmann, M., Neumann-Haefelin, C., Thimme, R., Henneke, P., Klein, R. & other authors (2005). Uptake and presentation of hepatitis C virus-like particles by human dendritic cells. Blood 105, 3605–3614.
Barth, H., Liang, T. J. & Baumert, T. F. (2006a). Hepatitis C virus entry: molecular biology and clinical implications. Hepatology 44, 527–535.[CrossRef][Medline]
Barth, H., Schnober, E. K., Zhang, F., Linhardt, R. J., Depla, E., Boson, B., Cosset, F. L., Patel, A. H., Blum, H. E. & Baumert, T. F. (2006b). Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction. J Virol 80, 10579–10590.
Bartosch, B., Dubuisson, J. & Cosset, F. L. (2003a). Infectious hepatitis C virus pseudo-particles containing functional E1–E2 envelope protein complexes. J Exp Med 197, 633–642.
Bartosch, B., Vitelli, A., Granier, C., Goujon, C., Dubuisson, J., Pascale, S., Scarselli, E., Cortese, R., Nicosia, A. & Cosset, F. L. (2003b). Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J Biol Chem 278, 41624–41630.
Bartosch, B., Verney, G., Dreux, M., Donot, P., Morice, Y., Penin, F., Pawlotsky, J. M., Lavillette, D. & Cosset, F. L. (2005). An interplay between hypervariable region 1 of the hepatitis C virus E2 glycoprotein, the scavenger receptor BI, and high-density lipoprotein promotes both enhancement of infection and protection against neutralizing antibodies. J Virol 79, 8217–8229.
Basu, A., Kanda, T., Beyene, A., Saito, K., Meyer, K. & Ray, R. (2007). Sulfated homologues of heparin inhibit hepatitis C virus entry into mammalian cells. J Virol 81, 3933–3941.
Baumert, T. F., Ito, S., Wong, D. T. & Liang, T. J. (1998). Hepatitis C virus structural proteins assemble into virus-like particles in insect cells. J Virol 72, 3827–3836.
Beach, M. J., Meeks, E. L., Mimms, L. T., Vallari, D., DuCharme, L., Spelbring, J., Taskar, S., Schleicher, J. B., Krawczynski, K. & Bradley, D. W. (1992). Temporal relationships of hepatitis C virus RNA and antibody responses following experimental infection of chimpanzees. J Med Virol 36, 226–237.[Medline]
Benedicto, I., Molina-Jiménez, F., Barreiro, O., Maldonado-Rodríguez, A., Prieto, J., Moreno-Otero, R., Aldabe, R., López-Cabrera, M. & Majano, P. L. (2008). Hepatitis C virus envelope components alter localization of hepatocyte tight junction-associated proteins and promote occludin retention in the endoplasmic reticulum. Hepatology 48, 1044–1053.[CrossRef][Medline]
Bertaux, C. & Dragic, T. (2006). Different domains of CD81 mediate distinct stages of hepatitis C virus pseudoparticle entry. J Virol 80, 4940–4948.
Blanchard, E., Belouzard, S., Goueslain, L., Wakita, T., Dubuisson, J., Wychowski, C. & Rouille, Y. (2006). Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 80, 6964–6972.
Bradley, D., McCaustland, K., Krawczynski, K., Spelbring, J., Humphrey, C. & Cook, E. H. (1991). Hepatitis C virus: buoyant density of the factor VIII-derived isolate in sucrose. J Med Virol 34, 206–208.[Medline]
Brass, V., Moradpour, D. & Blum, H. E. (2006). Molecular virology of hepatitis C virus (HCV): 2006 update. Int J Med Sci 3, 29–34.[Medline]
Brazzoli, M., Bianchi, A., Filippini, S., Weiner, A., Zhu, Q., Pizza, M. & Crotta, S. (2008). CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. J Virol 82, 8316–8329.
Bukh, J. & Purcell, R. H. (2006). A milestone for hepatitis C virus research: a virus generated in cell culture is fully viable in vivo. Proc Natl Acad Sci U S A 103, 3500–3501.
Cai, L., de Beer, M. C., de Beer, F. C. & van der Westhuyzen, D. R. (2005). Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem 280, 2954–2961.
Cai, Z., Cai, L., Jiang, J., Chang, K. S., van der Westhuyzen, D. R. & Luo, G. (2007). Human serum amyloid A protein inhibits hepatitis C virus entry into cells. J Virol 81, 6128–6133.
Callens, N., Ciczora, Y., Bartosch, B., Vu-Dac, N., Cosset, F. L., Pawlotsky, J. M., Penin, F. & Dubuisson, J. (2005). Basic residues in hypervariable region 1 of hepatitis C virus envelope glycoprotein E2 contribute to virus entry. J Virol 79, 15331–15341.
Calvo, D. & Vega, M. A. (1993). Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family. J Biol Chem 268, 18929–18935.
Cambi, A., Koopman, M. & Figdor, C. G. (2005). How C-type lectins detect pathogens. Cell Microbiol 7, 481–488.[CrossRef][Medline]
Catanese, M. T., Graziani, R., von Hahn, T., Moreau, M., Huby, T., Paonessa, G., Santini, C., Luzzago, A., Rice, C. M. & other authors (2007). High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein. J Virol 81, 8063–8071.
Chang, K. S., Jiang, J., Cai, Z. & Luo, G. (2007). Human apolipoprotein E is required for infectivity and production of hepatitis C virus in cell culture. J Virol 81, 13783–13793.
Clayton, R. F., Owsianka, A., Aitken, J., Graham, S., Bhella, D. & Patel, A. H. (2002). Analysis of antigenicity and topology of E2 glycoprotein present on recombinant hepatitis C virus-like particles. J Virol 76, 7672–7682.
Cocquerel, L., Wychowski, C., Minner, F., Penin, F. & Dubuisson, J. (2000). Charged residues in the transmembrane domains of hepatitis C virus glycoproteins play a major role in the processing, subcellular localization, and assembly of these envelope proteins. J Virol 74, 3623–3633.
Cocquerel, L., Op de Beeck, A., Lambot, M., Roussel, J., Delgrange, D., Pillez, A., Wychowski, C., Penin, F. & Dubuisson, J. (2002). Topological changes in the transmembrane domains of hepatitis C virus envelope glycoproteins. EMBO J 21, 2893–2902.[CrossRef][Medline]
Cocquerel, L., Voisset, C. & Dubuisson, J. (2006). Hepatitis C virus entry: potential receptors and their biological functions. J Gen Virol 87, 1075–1084.
Cormier, E. G., Durso, R. J., Tsamis, F., Boussemart, L., Manix, C., Olson, W. C., Gardner, J. P. & Dragic, T. (2004a). L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci U S A 101, 14067–14072.
Cormier, E. G., Tsamis, F., Kajumo, F., Durso, R. J., Gardner, J. P. & Dragic, T. (2004b). CD81 is an entry coreceptor for hepatitis C virus. Proc Natl Acad Sci U S A 101, 7270–7274.
Coyne, C. B. & Bergelson, J. M. (2006). Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119–131.[CrossRef][Medline]
Coyne, C. B., Shen, L., Turner, J. R. & Bergelson, J. M. (2007). Coxsackievirus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5. Cell Host Microbe 2, 181–192.[CrossRef][Medline]
Cribier, B., Schmitt, C., Kirn, A. & Stoll-Keller, F. (1998). Inhibition of hepatitis C virus adsorption to peripheral blood mononuclear cells by dextran sulfate. Arch Virol 143, 375–379.[CrossRef][Medline]
Crotta, S., Stilla, A., Wack, A., D'Andrea, A., Nuti, S., D'Oro, U., Mosca, M., Filliponi, F., Brunetto, R. M. & other authors (2002). Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 195, 35–41.[CrossRef][Medline]
Deleersnyder, V., Pillez, A., Wychowski, C., Blight, K., Xu, J., Hahn, Y. S., Rice, C. M. & Dubuisson, J. (1997). Formation of native hepatitis C virus glycoprotein complexes. J Virol 71, 697–704.[Abstract]
Diaz, O., Delers, F., Maynard, M., Demignot, S., Zoulim, F., Chambaz, J., Trépo, C., Lotteau, V. & André, P. (2006). Preferential association of hepatitis C virus with apolipoprotein B48-containing lipoproteins. J Gen Virol 87, 2983–2991.
Dreux, M., Pietschmann, T., Granier, C., Voisset, C., Ricard-Blum, S., Mangeot, P. E., Keck, Z., Foung, S., Vu-Dac, N. & other authors (2006). High density lipoprotein inhibits hepatitis C virus-neutralizing antibodies by stimulating cell entry via activation of the scavenger receptor BI. J Biol Chem 281, 18285–18295.
Dreux, M., Boson, B., Ricard-Blum, S., Molle, J., Lavillette, D., Bartosch, B., Pécheur, E. I. & Cosset, F. L. (2007). The exchangeable apolipoprotein ApoC-I promotes membrane fusion of hepatitis C virus. J Biol Chem 282, 32357–32369.
Drummer, H. E., Wilson, K. A. & Poumbourios, P. (2002). Identification of the hepatitis C virus E2 glycoprotein binding site on the large extracellular loop of CD81. J Virol 76, 11143–11147.
Drummer, H. E., Maerz, A. & Poumbourios, P. (2003). Cell surface expression of functional hepatitis C virus E1 and E2 glycoproteins. FEBS Lett 546, 385–390.[CrossRef][Medline]
Drummer, H. E., Wilson, K. A. & Poumbourios, P. (2005). Determinants of CD81 dimerization and interaction with hepatitis C virus glycoprotein E2. Biochem Biophys Res Commun 328, 251–257.[CrossRef][Medline]
Dubuisson, J. (2000). Folding, assembly and subcellular localization of hepatitis C virus glycoproteins. Curr Top Microbiol Immunol 242, 135–148.[Medline]
Evans, M. J., von Hahn, T., Tscherne, D. M., Syder, A. J., Panis, M., Wölk, B., Hatziioannou, T., McKeating, J. A., Bieniasz, P. D. & Rice, C. M. (2007). Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801–805.[CrossRef][Medline]
Flint, M., Maidens, C., Loomis-Price, L. D., Shotton, C., Dubuisson, J., Monk, P., Higginbottom, A., Levy, S. & McKeating, J. A. (1999). Characterization of hepatitis C virus E2 glycoprotein interaction with a putative cellular receptor, CD81. J Virol 73, 6235–6244.
Flint, M., von Hahn, T., Zhang, J., Farquhar, M., Jones, C. T., Balfe, P., Rice, C. M. & McKeating, J. A. (2006). Diverse CD81 proteins support hepatitis C virus infection. J Virol 80, 11331–11342.
Forns, X., Thimme, R., Govindarajan, S., Emerson, S. U., Purcell, R. H., Chisari, F. V. & Bukh, J. (2000). Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees. Proc Natl Acad Sci U S A 97, 13318–13323.
Fournier, C., Sureau, C., Coste, J., Ducos, J., Pageaux, G., Larrey, D., Domergue, J. & Maurel, P. (1998). In vitro infection of adult normal human hepatocytes in primary culture by hepatitis C virus. J Gen Virol 79, 2367–2374.[Abstract]
Fried, M. W., Shiffman, M. L., Reddy, K. R., Smith, C., Marinos, G., Gonçales, F. L., Jr, Häussinger, D., Diago, M., Carosi, G. & other authors (2002). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347, 975–982.
Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., Tsukita, S. & Tsukita, S. (1993). Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123, 1777–1788.
Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K. & Tsukita, S. (1998). Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141, 1539–1550.
Gardner, J. P., Durso, R. J., Arrigale, R. R., Donovan, G. P., Maddon, P. J., Dragic, T. & Olson, W. C. (2003). L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci U S A 100, 4498–4503.
Garry, R. F. & Dash, S. (2003). Proteomics computational analyses suggest that hepatitis C virus E1 and pestivirus E2 envelope glycoproteins are truncated class II fusion proteins. Virology 307, 255–265.[CrossRef][Medline]
Gastaminza, P., Kapadia, S. B. & Chisari, F. V. (2006). Differential biophysical properties of infectious intracellular and secreted hepatitis C virus particles. J Virol 80, 11074–11081.
Gastaminza, P., Cheng, G., Wieland, S., Zhong, J., Liao, W. & Chisari, F. V. (2008). Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol 82, 2120–2129.
Germi, R., Crance, J. M., Garin, D., Guimet, J., Lortat-Jacob, H., Ruigrok, R. W., Zarski, J. P. & Drouet, E. (2002). Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption. J Med Virol 68, 206–215.[CrossRef][Medline]
Goffard, A., Callens, N., Bartosch, B., Wychowski, C., Cosset, F. L., Montpellier, C. & Dubuisson, J. (2005). Role of N-linked glycans in the functions of hepatitis C virus envelope glycoproteins. J Virol 79, 8400–8409.
Greber, U. F. & Gastaldelli, M. (2007). Junctional gating: the Achilles' heel of epithelial cells in pathogen infection. Cell Host Microbe 2, 143–146.[CrossRef][Medline]
Grove, J., Huby, T., Stamataki, Z., Vanwolleghem, T., Meuleman, P., Farquhar, M., Schwarz, A., Moreau, M., Owen, J. S. & other authors (2007). Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity. J Virol 81, 3162–3169.
Haberstroh, A., Schnober, E. K., Zeisel, M. B., Carolla, P., Barth, H., Blum, H. E., Cosset, F. L., Koutsoudakis, G., Bartenschlager, R. & other authors (2008). Neutralizing host responses in hepatitis C virus infection target viral entry at postbinding steps and membrane fusion. Gastroenterology 135, 1719–1728.[CrossRef][Medline]
Helle, F. & Dubuisson, J. (2008). Hepatitis C virus entry into host cells. Cell Mol Life Sci 65, 100–112.[CrossRef][Medline]
Helle, F., Wychowski, C., Vu-Dac, N., Gustafson, K. R., Voisset, C. & Dubuisson, J. (2006). Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 281, 25177–25183.
Helle, F., Goffard, A., Morel, V., Duverlie, G., McKeating, J., Keck, Z. Y., Foung, S., Penin, F., Dubuisson, J. & Voisset, C. (2007). The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein. J Virol 81, 8101–8111.
Hemler, M. E. (2003). Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19, 397–422.[CrossRef][Medline]
Higginbottom, A., Quinn, E. R., Kuo, C. C., Flint, M., Wilson, L. H., Bianchi, E., Nicosia, A., Monk, P. N., McKeating, J. A. & Levy, S. (2000). Identification of amino acid residues in CD81 critical for interaction with hepatitis C virus envelope glycoprotein E2. J Virol 74, 3642–3649.
Hsu, M., Zhang, J., Flint, M., Logvinoff, C., Cheng-Mayer, C., Rice, C. M. & McKeating, J. A. (2003). Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A 100, 7271–7276.
Huang, H., Sun, F., Owen, D. M., Li, W., Chen, Y., Gale, M., Jr & Ye, J. (2007). Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins. Proc Natl Acad Sci U S A 104, 5848–5853.
Jong, M. C., Hofker, M. H. & Havekes, L. M. (1999). Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 19, 472–484.
Kapadia, S. B. & Chisari, F. V. (2005). Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A 102, 2561–2566.
Kapadia, S. B., Barth, H., Baumert, T., McKeating, J. A. & Chisari, F. V. (2007). Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virol 81, 374–383.
Keam, S. J. & Cvetkovi
, R. S. (2008). Peginterferon-
-2a (40 kD) plus ribavirin: a review of its use in the management of chronic hepatitis C mono-infection. Drugs 68, 1273–1317.[Medline]
Keck, Z. Y., Li, T. K., Xia, J., Gal-Tanamy, M., Olson, O., Li, S. H., Patel, A. H., Ball, J. K., Lemon, S. M. & Foung, S. K. (2008). Definition of a conserved immunodominant domain on hepatitis C virus E2 glycoprotein by neutralizing human monoclonal antibodies. J Virol 82, 6061–6066.
Koutsoudakis, G., Kaul, A., Steinmann, E., Kallis, S., Lohmann, V., Pietschmann, T. & Bartenschlager, R. (2006). Characterization of the early steps of hepatitis C virus infection by using luciferase reporter viruses. J Virol 80, 5308–5320.
Koutsoudakis, G., Herrmann, E., Kallis, S., Bartenschlager, R. & Pietschmann, T. (2007). The level of CD81 cell surface expression is a key determinant for productive entry of hepatitis C virus into host cells. J Virol 81, 588–598.
Krieger, M. (1999). Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI. Annu Rev Biochem 68, 523–558.[CrossRef][Medline]
Larsson, S. L., Skogsberg, J. & Bjorkegren, J. (2004). The low density lipoprotein receptor prevents secretion of dense apoB100-containing lipoproteins from the liver. J Biol Chem 279, 831–836.
Lavillette, D., Tarr, A. W., Voisset, C., Donot, P., Bartosch, B., Bain, C., Patel, A. H., Dubuisson, J., Ball, J. K. & Cosset, F. L. (2005). Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus. Hepatology 41, 265–274.[CrossRef][Medline]
Lavillette, D., Bartosch, B., Nourrisson, D., Verney, G., Cosset, F. L., Penin, F. & Pecheur, E. I. (2006). Hepatitis C virus glycoproteins mediate low pH-dependent membrane fusion with liposomes. J Biol Chem 281, 3909–3917.
Lavillette, D., Pecheur, E. I., Donot, P., Fresquet, J., Molle, J., Corbau, R., Dreux, M., Penin, F. & Cosset, F. L. (2007). Characterization of fusion determinants points to the involvement of three discrete regions of both E1 and E2 glycoproteins in the membrane fusion process of hepatitis C virus. J Virol 81, 8752–8765.
Levy, S. & Shoham, T. (2005). The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5, 136–148.[CrossRef][Medline]
Lindenbach, B. D., Evans, M. J., Syder, A. J., Wölk, B., Tellinghuisen, T. L., Liu, C. C., Maruyama, T., Hynes, R. O., Burton, D. R. & other authors (2005). Complete replication of hepatitis C virus in cell culture. Science 309, 623–626.
Lindenbach, B. D., Meuleman, P., Ploss, A., Vanwolleghem, T., Syder, A. J., McKeating, J. A., Lanford, R. E., Feinstone, S. M., Major, M. E. & other authors (2006). Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 103, 3805–3809.
Liu, S., Yang, W., Shen, L., Turner, J. R., Coyne, C. B. & Wang, T. (2009). Tight junction proteins Claudin-1 and occludin control hepatitis C virus entry and are downregulated during infection to prevent superinfection. J Virol 83, 2011–2014.
Lozach, P. Y., Amara, A., Bartosch, B., Virelizier, J. L., Arenzana-Seisdedos, F., Cosset, F. L. & Altmeyer, R. (2004). C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles. J Biol Chem 279, 32035–32045.
Machida, K., Cheng, K. T., Pavio, N., Sung, V. M. & Lai, M. M. (2005). Hepatitis C virus E2–CD81 interaction induces hypermutation of the immunoglobulin gene in B cells. J Virol 79, 8079–8089.
Maillard, P., Krawczynski, K., Nitkiewicz, J., Bronnert, C., Sidorkiewicz, M., Gounon, P., Dubuisson, J., Faure, G., Crainic, R. & Budkowska, A. (2001). Nonenveloped nucleocapsids of hepatitis C virus in the serum of infected patients. J Virol 75, 8240–8250.
Maillard, P., Huby, T., Andréo, U., Moreau, M., Chapman, J. & Budkowska, A. (2006). The interaction of natural hepatitis C virus with human scavenger receptor SR-BI/Cla1 is mediated by ApoB-containing lipoproteins. FASEB J 20, 735–737.
Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., Reindollar, R., Goodman, Z. D., Koury, K., Ling, M. & Albrecht, J. K. (2001). Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965.[CrossRef][Medline]
Masciopinto, F., Giovani, C., Campagnoli, S., Galli-Stampino, L., Colombatto, P., Brunetto, M., Yen, T. S., Houghton, M., Pileri, P. & Abrignani, S. (2004). Association of hepatitis C virus envelope proteins with exosomes. Eur J Immunol 34, 2834–2842.[CrossRef][Medline]
Mead, J. R., Irvine, S. A. & Ramji, D. P. (2002). Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 80, 753–769.[CrossRef][Medline]
Meertens, L., Bertaux, C. & Dragic, T. (2006). Hepatitis C virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles. J Virol 80, 11571–11578.
Meertens, L., Bertaux, C., Cukierman, L., Cormier, E., Lavillette, D., Cosset, F. L. & Dragic, T. (2008). The tight junction proteins claudin-1, -6, and -9 are entry cofactors for hepatitis C virus. J Virol 82, 3555–3560.
Merkel, M., Eckel, R. H. & Goldberg, I. J. (2002). Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res 43, 1997–2006.
Meuleman, P. & Leroux-Roels, G. (2008). The human liver-uPA-SCID mouse: a model for the evaluation of antiviral compounds against HBV and HCV. Antiviral Res 80, 231–238.[CrossRef][Medline]
Meuleman, P., Libbrecht, L., De Vos, R., de Hemptinne, B., Gevaert, K., Vandekerckhove, J., Roskams, T. & Leroux-Roels, G. (2005). Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology 41, 847–856.[CrossRef][Medline]
Meuleman, P., Hesselgesser, J., Paulson, M., Vanwolleghem, T., Desombere, I., Reiser, H. & Leroux-Roels, G. (2008). Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo. Hepatology 48, 1761–1768.[CrossRef][Medline]
Meunier, J. C., Engle, R. E., Faulk, K., Zhao, M., Bartosch, B., Alter, H., Emerson, S. U., Cosset, F. L., Purcell, R. H. & Bukh, J. (2005). Evidence for cross-genotype neutralization of hepatitis C virus pseudo-particles and enhancement of infectivity by apolipoprotein C1. Proc Natl Acad Sci U S A 102, 4560–4565.
Meunier, J. C., Russell, R. S., Engle, R. E., Faulk, K. N., Purcell, R. H. & Emerson, S. U. (2008). Apolipoprotein C1 association with hepatitis C virus. J Virol 82, 9647–9656.
Michalak, J. P., Wychowski, C., Choukhi, A., Meunier, J. C., Ung, S., Rice, C. M. & Dubuisson, J. (1997). Characterization of truncated forms of hepatitis C virus glycoproteins. J Gen Virol 78, 2299–2306.[Abstract]
Molina, S., Castet, V., Fournier-Wirth, C., Pichard-Garcia, L., Avner, R., Harats, D., Roitelman, J., Barbaras, R., Graber, P. & other authors (2007). The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus. J Hepatol 46, 411–419.[CrossRef][Medline]
Molina, S., Castet, V., Pichard-Garcia, L., Wychowski, C., Meurs, E., Pascussi, J. M., Sureau, C., Fabre, J. M., Sacunha, A. & other authors (2008a). Serum-derived hepatitis C virus infection of primary human hepatocytes is tetraspanin CD81 dependent. J Virol 82, 569–574.
Molina, S., Missé, D., Roche, S., Badiou, S., Cristol, J.-P., Bonfils, C., Dierick, J.-F., Veas, F., Levayer, T. & other authors (2008b). Identification of apolipoprotein C-III as a potential plasmatic biomarker associated with the resolution of hepatitis C virus infection. Proteomics Clin Appl 2, 751–761.[CrossRef]
Monazahian, M., Böhme, I., Bonk, S., Koch, A., Scholz, C., Grethe, S. & Thomssen, R. (1999). Low density lipoprotein receptor as a candidate receptor for hepatitis C virus. J Med Virol 57, 223–229.[CrossRef][Medline]
Morikawa, K., Zhao, Z., Date, T., Miyamoto, M., Murayama, A., Akazawa, D., Tanabe, J., Sone, S. & Wakita, T. (2007). The roles of CD81 and glycosaminoglycans in the adsorption and uptake of infectious HCV particles. J Med Virol 79, 714–723.[CrossRef][Medline]
Murao, K., Imachi, H., Yu, X., Cao, W. M., Nishiuchi, T., Chen, K., Li, J., Ahmed, R. A., Wong, N. C. & Ishida, T. (2008). Interferon decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes. Gut 57, 664–671.
Nielsen, S. U., Bassendine, M. F., Burt, A. D., Martin, C., Pumeechockchai, W. & Toms, G. L. (2006). Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol 80, 2418–2428.
Owsianka, A., Clayton, R. F., Loomis-Price, L. D., McKeating, J. A. & Patel, A. H. (2001). Functional analysis of hepatitis C virus E2 glycoproteins and virus-like particles reveals structural dissimilarities between different forms of E2. J Gen Virol 82, 1877–1883.
Owsianka, A. M., Timms, J. M., Tarr, A. W., Brown, R. J., Hickling, T. P., Szwejk, A., Bienkowska-Szewczyk, K., Thomson, B. J., Patel, A. H. & Ball, J. K. (2006). Identification of conserved residues in the E2 envelope glycoprotein of the hepatitis C virus that are critical for CD81 binding. J Virol 80, 8695–8704.
Pawlotsky, J. M. (2006). Therapy of hepatitis C: from empiricism to eradication. Hepatology 43, S207–S220.[CrossRef][Medline]
Peng, B. H., Lee, J. C. & Campbell, G. A. (2003). In vitro protein complex formation with cytoskeleton-anchoring domain of occludin identified by limited proteolysis. J Biol Chem 278, 49644–49651.
Penin, F., Combet, C., Germanidis, G., Frainais, P. O., Deléage, G. & Pawlotsky, J. M. (2001). Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment. J Virol 75, 5703–5710.
Penin, F., Dubuisson, J., Rey, F. A., Moradpour, D. & Pawlotsky, J. M. (2004). Structural biology of hepatitis C virus. Hepatology 39, 5–19.[CrossRef][Medline]
Pérez-Berná, A. J., Bernabeu, A., Moreno, M. R., Guillen, J. & Villalaín, J. (2008). The pre-transmembrane region of the HCV E1 envelope glycoprotein: interaction with model membranes. Biochim Biophys Acta 1778, 2069–2080.[Medline]
Peréz-Martínez, P., Ordovàs, J. M., López-Miranda, J., Gómez, P., Marín, C., Moreno, J., Fuentes, F., Fernàndez de la Puebla, R. A. & Pérez-Jiménez, F. (2003). Polymorphism exon 1 variant at the locus of the scavenger receptor class B type I gene: influence on plasma LDL cholesterol in healthy subjects during the consumption of diets with different fat contents. Am J Clin Nutr 77, 809–813.
Petit, J. M., Benichou, M., Duvillard, L., Jooste, V., Bour, J. B., Minello, A., Verges, B., Brun, J. M., Gambert, P. & Hillon, P. (2003). Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis. Am J Gastroenterol 98, 1150–1154.[Medline]
Petit, M. A., Lièvre, M., Peyrol, S., De Sequeira, S., Berthillon, P., Ruigrok, R. W. & Trépo, C. (2005). Enveloped particles in the serum of chronic hepatitis C patients. Virology 336, 144–153.[CrossRef][Medline]
Petit, J. M., Minello, A., Duvillard, L., Jooste, V., Monier, S., Texier, V., Bour, J. B., Poussier, A., Gambert, P. & other authors (2007). Cell surface expression of LDL receptor in chronic hepatitis C: correlation with viral load. Am J Physiol Endocrinol Metab 293, E416–E420.
Pileri, P., Uematsu, Y., Campagnoli, S., Galli, G., Falugi, F., Petracca, R., Weiner, A. J., Houghton, M., Rosa, D. & other authors (1998). Binding of hepatitis C virus to CD81. Science 282, 938–941.
Ploss, A., Evans, M. J., Gaysinskaya, V. A., Panis, M., You, H., de Jong, Y. P. & Rice, C. M. (2009). Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457, 882–886.[CrossRef][Medline]
Pöhlmann, S., Zhang, J., Baribaud, F., Chen, Z., Leslie, G. J., Lin, G., Granelli-Piperno, A., Doms, R. W., Rice, C. M. & McKeating, J. A. (2003). Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol 77, 4070–4080.
Prince, A. M., Huima-Byron, T., Parker, T. S. & Levine, D. M. (1996). Visualization of hepatitis C virions and putative defective interfering particles isolated from low-density lipoproteins. J Viral Hepat 3, 11–17.[Medline]
Rhainds, D. & Brissette, L. (2004). The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. defining the rules for lipid traders. Int J Biochem Cell Biol 36, 39–77.[CrossRef][Medline]
Roccasecca, R., Ansuini, H., Vitelli, A., Meola, A., Scarselli, E., Acali, S., Pezzanera, M., Ercole, B. B., McKeating, J. & other authors (2003). Binding of the hepatitis C virus E2 glycoprotein to CD81 is strain specific and is modulated by a complex interplay between hypervariable regions 1 and 2. J Virol 77, 1856–1867.
Rocha-Perugini, V., Montpellier, C., Delgrange, D., Wychowski, C., Helle, F., Pillez, A., Drobecq, H., Le Naour, F., Charrin, S. & other authors (2008). The CD81 partner EWI-2wint inhibits hepatitis C virus entry. PLoS ONE 3, e1866[CrossRef][Medline]
Roohvand, F., Maillard, P., Lavergne, J. P., Boulant, S., Walic, M., Andréo, U., Goueslain, L., Helle, F., McLauchlan, J. & Budkowska, A. (2009). Initiation of hepatitis C virus infection requires the dynamic microtubule network: Role of the viral nucleocapsid protein. J Biol Chem (in press). doi:10.1074/jbc.M807873200
Rudenko, G. & Deisenhofer, J. (2003). The low-density lipoprotein receptor: ligands, debates and lore. Curr Opin Struct Biol 13, 683–689.[CrossRef][Medline]
Rumin, S., Berthillon, P., Tanaka, E., Kiyosawa, K., Trabaud, M. A., Bizollon, T., Gouillat, C., Gripon, P., Guguen-Guillouzo, C. & other authors (1999). Dynamic analysis of hepatitis C virus replication and quasispecies selection in long-term cultures of adult human hepatocytes infected in vitro. J Gen Virol 80, 3007–3018.
Saunier, B., Triyatni, M., Ulianich, L., Maruvada, P., Yen, P. & Kohn, L. D. (2003). Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus structural proteins in cultured human hepatocytes. J Virol 77, 546–559.[CrossRef][Medline]
Scarselli, E., Ansuini, H., Cerino, R., Roccasecca, R. M., Acali, S., Filocamo, G., Traboni, C., Nicosia, A., Cortese, R. & Vitelli, A. (2002). The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21, 5017–5025.[CrossRef][Medline]
Shelness, G. S. & Sellers, J. A. (2001). Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol 12, 151–157.[CrossRef][Medline]
Shepard, C. W., Finelli, L. & Alter, M. J. (2005). Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5, 558–567.[CrossRef][Medline]
Shimizu, Y. K., Iwamoto, A., Hijikata, M., Purcell, R. H. & Yoshikura, H. (1992). Evidence for in vitro replication of hepatitis C virus genome in a human T-cell line. Proc Natl Acad Sci U S A 89, 5477–5481.
Shin, K., Fogg, V. C. & Margolis, B. (2006). Tight junctions and cell polarity. Annu Rev Cell Dev Biol 22, 207–235.[CrossRef][Medline]
Shoham, T., Rajapaksa, R., Kuo, C. C., Haimovich, J. & Levy, S. (2006). Building of the tetraspanin web: distinct structural domains of CD81 function in different cellular compartments. Mol Cell Biol 26, 1373–1385.
Steinmann, E., Whitfield, T., Kallis, S., Dwek, R. A., Zitzmann, N., Pietschmann, T. & Bartenschlager, R. (2007). Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology 46, 330–338.[CrossRef][Medline]
Stockert, R. J. (1995). The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 75, 591–609.
Subramanian, V. S., Marchant, J. S., Ye, D., Ma, T. Y. & Said, H. M. (2007). Tight junction targeting and intracellular trafficking of occludin in polarized epithelial cells. Am J Physiol Cell Physiol 293, C1717–C1726.
Swarnakar, S., Temel, R. E., Connelly, M. A., Azhar, S. & Williams, D. L. (1999). Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester. J Biol Chem 274, 29733–29739.
Thomssen, R., Bonk, S., Propfe, C., Heermann, K. H., Köchel, H. G. & Uy, A. (1992). Association of hepatitis C virus in human sera with β-lipoprotein. Med Microbiol Immunol 181, 293–300.[CrossRef][Medline]
Triyatni, M., Saunier, B., Maruvada, P., Davis, A. R., Ulianich, L., Heller, T., Patel, A., Kohn, L. D. & Liang, T. J. (2002). Interaction of hepatitis C virus-like particles and cells: a model system for studying viral binding and entry. J Virol 76, 9335–9344.
Uhlar, C. M. & Whitehead, A. S. (1999). Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265, 501–523.[Medline]
Van Eck, M., Hoekstra, M., Out, R., Bos, I. S., Kruijt, J. K., Hildebrand, R. B. & Van Berkel, T. J. (2008). Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo. J Lipid Res 49, 136–146.
Van Itallie, C. M. & Anderson, J. M. (2004). The molecular physiology of tight junction pores. Physiology (Bethesda) 19, 331–338.[CrossRef][Medline]
Van Itallie, C. M. & Anderson, J. M. (2006). Claudins and epithelial paracellular transport. Annu Rev Physiol 68, 403–429.[CrossRef][Medline]
Van Kooyk, Y. & Geijtenbeek, T. B. (2003). DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 3, 697–709.[CrossRef][Medline]
Voisset, C., Callens, N., Blanchard, E., Op De Beeck, A., Dubuisson, J. & Vu-Dac, N. (2005). High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I. J Biol Chem 280, 7793–7799.
von Hahn, T. & Rice, C. M. (2008). Hepatitis C virus entry. J Biol Chem 283, 3689–3693.
von Hahn, T., Lindenbach, B. D., Boullier, A., Quehenberger, O., Paulson, M., Rice, C. M. & McKeating, J. A. (2006). Oxidized low-density lipoprotein inhibits hepatitis C virus cell entry in human hepatoma cells. Hepatology 43, 932–942.[CrossRef][Medline]
von Hahn, T., Yoon, J. C., Alter, H., Rice, C. M., Rehermann, B., Balfe, P. & McKeating, J. A. (2007). Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 132, 667–678.[CrossRef][Medline]
Wack, A., Soldaini, E., Tseng, C., Nuti, S., Klimpel, G. & Abrignani, S. (2001). Binding of the hepatitis C virus envelope protein E2 to CD81 provides a co-stimulatory signal for human T cells. Eur J Immunol 31, 166–175.[CrossRef][Medline]
Wakita, T., Pietschmann, T., Kato, T., Date, T., Miyamoto, M., Zhao, Z., Murthy, K., Habermann, A., Kräusslich, H. G. & other authors (2005). Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11, 791–796.[CrossRef][Medline]
Yalaoui, S., Huby, T., Franetich, J. F., Gego, A., Rametti, A., Moreau, M., Collet, X., Siau, A., van Gemert, G. J. & other authors (2008). Scavenger receptor BI boosts hepatocyte permissiveness to Plasmodium infection. Cell Host Microbe 4, 283–292.[CrossRef][Medline]
Yang, W., Qiu, C., Biswas, N., Jin, J., Watkins, S. C., Montelaro, R. C., Coyne, C. B. & Wang, T. (2008). Correlation of the tight junction-like distribution of Claudin-1 to the cellular tropism of hepatitis C virus. J Biol Chem 283, 8643–8653.
Ye, J. (2007). Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus. PLoS Pathog 3, e108[CrossRef][Medline]
Ye, J., Wang, C., Sumpter, R., Jr, Brown, M. S., Goldstein, J. L. & Gale, M., Jr (2003). Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci U S A 100, 15865–15870.
Zeisel, M. B., Koutsoudakis, G., Schnober, E. K., Haberstroh, A., Blum, H. E., Cosset, F. L., Wakita, T., Jaeck, D., Doffoel, M. & other authors (2007). Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology 46, 1722–1731.[CrossRef][Medline]
Zhang, J., Randall, G., Higginbottom, A., Monk, P., Rice, C. M. & McKeating, J. A. (2004). CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J Virol 78, 1448–1455.
Zheng, A., Yuan, F., Li, Y., Zhu, F., Hou, P., Li, J., Song, X., Ding, M. & Deng, H. (2007). Claudin-6 and Claudin-9 function as additional coreceptors for hepatitis C virus. J Virol 81, 12465–12471.
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ABSTRACT
Introduction
