Hepatitis C Virus Entry

Hahn, Thomas von; Rice, Charles M.

doi:10.1074/jbc.r700024200

Cited by 82 publications

(69 citation statements)

References 77 publications

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“…In HCV, as in pestiviruses, E1 is half the size of E2, which is the immunodominant protein and binds a cellular receptor that is not efficiently internalized (8,9). HCV and pestiviruses both appear to require one or more coreceptors for postattachment internalization and membrane fusion (10,11). HCV and pestiviruses are also both unusually resistant to acid outside the cell yet depend on low pH and an additional activation step for fusion (6,7,12).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of cell entry by endocytic inhibitors suggests that pesti-and hepaciviruses enter the cell by clathrin-mediated endocytosis (6,7). However, pestiviruses and hepaciviruses recognize host cells by binding to cell surface receptors-CD46 and CD81, respectively-that are not significantly internalized (8,9), and one or more coreceptors are required for postattachment internalization (10,11). To deliver their single-stranded positive-sense RNA genome into the cytoplasm, pestiviruses and HCV must fuse their lipid envelope with a cellular membrane.…”

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confidence: 99%

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Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Wang

Kanai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

125

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Pestiviruses, including bovine viral diarrhea virus, are important animal pathogens and are closely related to hepatitis C virus, which remains a major global health threat. They have an outer lipid envelope bearing two glycoproteins, E1 and E2, required for cell entry. They deliver their genome into the host cell cytoplasm by fusion of their envelope with a cellular membrane. The crystal structure of bovine viral diarrhea virus E2 reveals a unique protein architecture consisting of two Ig-like domains followed by an elongated β-stranded domain with a new fold. E2 forms end-to-end homodimers with a conserved C-terminal motif rich in aromatic residues at the contact. A disulfide bond across the interface explains the acid resistance of pestiviruses and their requirement for a redox activation step to initiate fusion. From the structure of E2, we propose alternative possible membrane fusion mechanisms. We expect the pestivirus fusion apparatus to be conserved in hepatitis C virus.domain swap | family Flaviviridae | genus hepacivirus | pH sensing | fusion motif

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Wang

Kanai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

125

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“…As shown with serum-derived virus, HCV uses various processes to enter target cells, and HCVpp infection of Huh7-cells is a surrogate model for most entry pathways, including the CD81 route used here, its sole lack being entry mediated by virus when associated with lipoproteins (11,12,30,(35)(36)(37)(38)(39). In this system, CD81 and E2 clearly have a major role because anti-E2 antibodies and soluble CD81 interfere with virus entry (24,39).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

Fenouillet¹,

Lavillette²,

Loureiro³

et al. 2008

Journal of Biological Chemistry

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Disulfide bonding contributes to the function and antigenicity of many viral envelope glycoproteins. We assessed here its significance for the hepatitis C virus E2 envelope protein and a counterpart deleted for hypervariable region-1 (HVR1). All 18 cysteine residues of the antigens were involved in disulfides. Chemical reduction of up to half of these disulfides was compatible with anti-E2 monoclonal antibody reaction, CD81 receptor binding, and viral entry, whereas complete reduction abrogated these properties. The addition of 5,5-dithiobis-2-nitrobenzoic acid had no effect on viral entry. Thus, E2 function is only weakly dependent on its redox status, and cell entry does not require redox catalysts, in contrast to a number of enveloped viruses. Because E2 is a major neutralizing antibody target, we examined the effect of disulfide bonding on E2 antigenicity. We show that reduction of three disulfides, as well as deletion of HVR1, improved antibody binding for half of the patient sera tested, whereas it had no effect on the remainder. Small scale immunization of mice with reduced E2 antigens greatly improved serum reactivity with reduced forms of E2 when compared with immunization using native E2, whereas deletion of HVR1 only marginally affected the ability of the serum to bind the redox intermediates. Immunization with reduced E2 also showed an improved neutralizing antibody response, suggesting that potential epitopes are masked on the disulfide-bonded antigen and that mild reduction may increase the breadth of the antibody response. Although E2 function is surprisingly independent of its redox status, its disulfide bonds mask antigenic domains. E2 redox manipulation may contribute to improved vaccine design.

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“…Several receptors, coreceptors, and other entry factors have been discovered over the years, which link HCV entry to specialized domains of the plasma membrane, such as tetraspanin-enriched microdomains and tight junctions (8,16,59). The internalization of the viral particle occurs by clathrin-mediated endocytosis (5, 40).…”

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confidence: 99%

Identification of GBF1 as a Cellular Factor Required for Hepatitis C Virus RNA Replication

Goueslain

Alsaleh

Horellou

et al. 2010

J Virol

125

157

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In infected cells, hepatitis C virus (HCV) induces the formation of membrane alterations referred to as membranous webs, which are sites of RNA replication. In addition, HCV RNA replication also occurs in smaller membrane structures that are associated with the endoplasmic reticulum. However, cellular mechanisms involved in the formation of HCV replication complexes remain largely unknown. Here, we used brefeldin A (BFA) to investigate cellular mechanisms involved in HCV infection. BFA acts on cell membranes by interfering with the activation of several members of the family of ADP-ribosylation factors (ARF), which can lead to a wide range of inhibitory actions on membrane-associated mechanisms of the secretory and endocytic pathways. Our data show that HCV RNA replication is highly sensitive to BFA. Individual knockdown of the cellular targets of BFA using RNA interference and the use of a specific pharmacological inhibitor identified GBF1, a guanine nucleotide exchange factor for small GTPases of the ARF family, as a host factor critically involved in HCV replication. Furthermore, overexpression of a BFA-resistant GBF1 mutant rescued HCV replication in BFA-treated cells, indicating that GBF1 is the BFA-sensitive factor required for HCV replication. Finally, immunofluorescence and electron microscopy analyses indicated that BFA does not block the formation of membranous web-like structures induced by expression of HCV proteins in a nonreplicative context, suggesting that GBF1 is probably involved not in the formation of HCV replication complexes but, rather, in their activity. Altogether, our results highlight a functional connection between the early secretory pathway and HCV RNA replication.Hepatitis C virus (HCV) is an important human pathogen. It mainly infects human hepatocytes, and this often leads to chronic hepatitis, cirrhosis, or hepatocarcinoma. HCV studies have been hampered for many years by the difficulty in propagating this virus in vitro. Things have recently changed with the development of a cell culture model referred to as HCVcc (34,60,65), which allows the study of the HCV life cycle in cell culture and facilitates studies of the interactions between HCV and the host cell.HCV is an enveloped positive-strand RNA virus belonging to the family Flaviviridae (35). The viral genome contains a single open reading frame, which is flanked by two noncoding regions that are required for translation and replication. All viral proteins that are produced after proteolytic processing of the initially synthesized polyprotein are membrane associated (15,43). This reflects the fact that virtually all steps of the viral life cycle occur in close association with cellular membranes.Interactions of HCV with cell membranes begin during entry. Several receptors, coreceptors, and other entry factors have been discovered over the years, which link HCV entry to specialized domains of the plasma membrane, such as tetraspanin-enriched microdomains and tight junctions (8,16,59). The internalization of the viral particle...

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Hepatitis C Virus Entry

Cited by 82 publications

References 77 publications

Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

Identification of GBF1 as a Cellular Factor Required for Hepatitis C Virus RNA Replication

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