Characterization of Hepatitis C Virus E2 Glycoprotein Interaction with a Putative Cellular Receptor, CD81

Flint, Mike; Maidens, Catherine; Loomis-Price, Larry; Shotton, C; Dubuisson, Jean; Monk, Peter N.; Higginbottom, Adrian; Levy, Shoshana; McKeating, Jane A.

doi:10.1128/jvi.73.8.6235-6244.1999

Cited by 430 publications

(194 citation statements)

References 32 publications

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“…Antibodies. Monoclonal antibodies (mAbs) anti-HCV E1 glycoprotein (A4), 16 anti-HCV E2 glycoprotein (3/11; kindly provided by J. McKeating, University of Birmingham, UK)(17), 17 anti-yellow fever virus (YFV) envelope protein (2D12) (ATCC CRL-1689), anti-bovine viral diarrhea virus (BVDV) NS3 protein (Osc-23), 18 anti-NS5A antibody (Ab) (AUSTRAL Biologicals, San Ramon, CA), and anti-CD81 mAb JS-81 CD81 (BD Pharmingen, San Diego, CA) were used in this study. Cy3-, Alexa 488-and phycoerythrin (PE)conjugated secondary Abs were from Jackson Immu-noResearch (West Grove, PA), Invitrogen, and BD Pharmingen, respectively.…”

Section: Methodsmentioning

confidence: 99%

The antimalarial ferroquine is an inhibitor of hepatitis C virus

et al. 2013

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Hepatitis C virus (HCV) is a major cause of chronic liver disease. Despite recent success in improving anti-HCV therapy, additional progress is still needed to develop cheaper and interferon (IFN)-free treatments. Here, we report that ferroquine (FQ), an antimalarial ferrocenic analog of chloroquine, is a novel inhibitor of HCV. FQ potently inhibited HCV infection of hepatoma cell lines by affecting an early step of the viral life cycle. The antiviral activity of FQ on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition to its effect on HCV entry, FQ also inhibited HCV RNA replication, albeit at a higher concentration. We also showed that FQ has no effect on viral assembly and virion secretion. Using a binding assay at 48C, we showed that FQ does not prevent attachment of the virus to the cell surface. Furthermore, virus internalization was not affected by FQ, whereas the fusion process was impaired in the presence of FQ as shown in a cell-cell fusion assay. Finally, virus with resistance to FQ was selected by sequential passage in the presence of the drug, and resistance was shown to be conferred by a single mutation in E1 glycoprotein (S327A). By inhibiting cell-free virus transmission using a neutralizing antibody, we also showed that FQ inhibits HCV cell-to-cell spread between neighboring cells. Combinations of FQ with IFN, or an inhibitor of HCV NS3/4A protease, also resulted in additive to synergistic activity. Conclusion: FQ is a novel, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals. (HEPATOLOGY 2013;58:86-97) H epatitis C virus (HCV) is a major cause of chronic liver disease (CLD). Approximately 160 million individuals suffer from chronic hepatitis C, putting them at risk to develop cirrhosis and hepatocellular carcinoma. 1 Recent improvements in the standard-of-care therapy, currently a combination of pegylated interferon (IFN) alpha (Peg-IFN-a), ribavirin (RBV), and one of two drugs interfering with the virally encoded NS3/4A protease, have raised the hope that HCV infection can be managed efficiently in countries with adequate medical infrastructure. 2 However, the current mode of treatment is not equally effective for all HCV genotypes and significant side effects are still observed. Efforts are currently being

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Section: Methodsmentioning

confidence: 99%

The antimalarial ferroquine is an inhibitor of hepatitis C virus

et al. 2013

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“…HS-GAG (Chen et al, 1997b;Germi et al, 2002) Yellow fever virus HS-GAG (Germi et al, 2002) HCV LDLR protein family (Agnello et al, 1999;Monazahian et al, 1999); CD81 (Pileri et al, 1998;Flint et al, 1999); tamarin CD81 (Allander et al, 2000); human SR-BI (Scarselli et al, 2002) BVDV LDLR protein family (Agnello et al, 1999) GB virus C/hepatitis G virus LDLR protein family (Agnello et al, 1999) CSFV HS-GAG (Hulst et al, 2000(Hulst et al, , 2001 (continues) FMDV HS-GAG Sa-Carvalho et al, 1997;Fry et al, 1999;Baranowski et al, 2000); integrins v 3 (Fox et al, 1989;Berinstein et al, 1995;Jackson et al, 1997;Neff et al, 1998), v 6 (Jackson et al, 2000b), v 1 (Jackson et al, 2002), 5 1 (Jackson et al, 2000a) Picornaviridae (cardiovirus)…”

Section: Dengue Virusmentioning

confidence: 99%

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

Baranowski

Ruiz-Jarabo

Pariente

et al. 2003

Advances in Virus Research

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Receptor classCellular structure a Extracellular matrix components, sugar derivatives and lipids GalactosylceramideGangliosides Glycosaminoglycans (heparan and chondroitin sulfates) Phospholipids Sialic acid (N-acetylneuraminic acid, N-acetyl-9-O-acetylneuraminic acid and N-glycolylneuraminic acid 3-O-sulfated heparan sulfate Cell adhesion and cell-cell contact proteins -Dystroglycan Coxsackievirus-adenovirus receptor (CAR; Ig superfamily) CD4 (Ig superfamily) CEACAMs (including Bgp1a, Bgp2, and pregnancy-specific glycoprotein) Intercellular adhesion molecule type 1 (ICAM-1; Ig superfamily) Integrins Junction adhesion molecule (JAM) Laminin receptor (high affinity) MHC class I and 2 -microglobulin Neural cell adhesion molecule (NCAM) Signaling lymphocyte activation molecule

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“…The receptor binding domain of E2 encompasses polyprotein residues 384 to 661. The recombinant forms E2 661 and E2 715 lack the transmembrane domain, are efficiently secreted by transfected cells, and maintain the capability to interact with CD81 and SR-BI (13,23). HCV E2 also binds to two C-type lectins, dendritic-cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and liver/lymph node-specific intercellular adhesion molecule 3-grabbing nonintegrin (L-SIGN) (24,37,52), a calcium-dependent lectin expressed on liver sinusoidal endothelial cells that may favor infection by trapping the virus and facilitating the interactions with hepatocytes.…”

mentioning

confidence: 99%

CD81 Is a Central Regulator of Cellular Events Required for Hepatitis C Virus Infection of Human Hepatocytes

Brazzoli

Bianchi

Filippini

et al. 2008

J Virol

170

167

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Infection with hepatitis C virus (HCV) is still a major public health problem, and the events leading to hepatocyte infection are not yet fully understood. Combining confocal microscopy with biochemical analysis and studies of infection requirements using pharmacological inhibitors and small interfering RNAs, we show here that engagement of CD81 activates the Rho GTPase family members Rac, Rho, and Cdc42 and that the block of these signaling pathways drastically reduces HCV infectivity. Activation of Rho GTPases mediates actin-dependent relocalization of the HCV E2/CD81 complex to cell-cell contact areas where CD81 comes into contact with the tight-junction proteins occludin, ZO-1, and claudin-1, which was recently described as an HCV coreceptor. Finally, we show that CD81 engagement activates the Raf/MEK/ERK signaling cascade and that this pathway affects postentry events of the virus life cycle. In conclusion, we describe a range of cellular events that are manipulated by HCV to coordinate interactions with its multiple coreceptors and to establish productive infections and find that CD81 is a central regulator of these events.Hepatitis C virus (HCV), the causal agent of hepatitis C, is a positive-strand RNA virus that belongs to the Flaviviridae family (11). The genome encodes a single polyprotein that is processed by a combination of host and viral peptidases into at least 10 different structural and nonstructural proteins. The HCV envelope is formed by the two heavily N-glycosylated type I transmembrane proteins E1 and E2, which are present on the virus as heterodimers (44,48) anchored to a host cellderived double-layer lipid membrane.HCV infects mainly hepatocytes, but the precise mechanisms of early infection are largely unknown. As for other flaviviruses, it is generally accepted that HCV glycoproteins E1 and E2 play a major role in virus binding and entry into target cells (58).Several putative HCV receptors have been identified so far. Some of these, like the low-density lipoprotein (LDL) receptor (LDLR) (1) and other cell surface proteins involved in serum lipoprotein binding and metabolism, seem to act as relatively nonspecific attachment factors to allow virus concentration on the cell surface, as in the infected host, HCV can be associated with LDL and very low-density lipoprotein (VLDL). The tetraspanin molecule CD81 (49) and the scavenger receptor class B type I (SR-BI) (54) were both identified as putative receptors based on their interaction with recombinant soluble E2 (rE2) protein, and their role has been confirmed by means of HCV pseudotyped retroviral particles (2,14,29) and by the recently established in vitro infectious HCV system (HCVcc) (21,(30)(31)(32)59). In addition, CD81 has been shown to play a role in the infection of primary human hepatocytes by serumderived HCV (45). CD81 is an integral membrane protein that shows the structure common to all tetraspanins, with four transmembrane domains delimiting a large extracellular loop and a small extracellular loop and three short intracel...

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Characterization of Hepatitis C Virus E2 Glycoprotein Interaction with a Putative Cellular Receptor, CD81

Cited by 430 publications

References 32 publications

The antimalarial ferroquine is an inhibitor of hepatitis C virus

The antimalarial ferroquine is an inhibitor of hepatitis C virus

Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

CD81 Is a Central Regulator of Cellular Events Required for Hepatitis C Virus Infection of Human Hepatocytes

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