Academic literature on the topic 'HCV membranous web'
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Journal articles on the topic "HCV membranous web"
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Egger, Denise, Benno Wölk, Rainer Gosert, Leonardo Bianchi, Hubert E. Blum, Darius Moradpour, and Kurt Bienz. "Expression of Hepatitis C Virus Proteins Induces Distinct Membrane Alterations Including a Candidate Viral Replication Complex." Journal of Virology 76, no. 12 (June 15, 2002): 5974–84. http://dx.doi.org/10.1128/jvi.76.12.5974-5984.2002.
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ABSTRACT Plus-strand RNA viruses characteristically replicate their genome in association with altered cellular membranes. In the present study, the capacity of hepatitis C virus (HCV) proteins to elicit intracellular membrane alterations was investigated by expressing, in tetracycline-regulated cell lines, a comprehensive panel of HCV proteins individually as well as in the context of the entire HCV polyprotein. As visualized by electron microscopy (EM), expression of the combined structural proteins core-E1-E2-p7, the NS3-4A complex, and protein NS4B induced distinct membrane alterations. By immunogold EM (IEM), the membrane-altering proteins were always found to localize to the respective altered membranes. NS4B, a protein of hitherto unknown function, induced a tight structure, designated membranous web, consisting of vesicles in a membranous matrix. Expression of the entire HCV polyprotein gave rise to membrane budding into rough endoplasmic reticulum vacuoles, to the membranous web, and to tightly associated vesicles often surrounding the membranous web. By IEM, all HCV proteins were found to be associated with the NS4B-induced membranous web, forming a membrane-associated multiprotein complex. A similar web-like structure in livers of HCV-infected chimpanzees was previously described (Pfeifer et al., Virchows Arch. B., 33:233-243, 1980). In view of this finding and the observation that all HCV proteins accumulate on the membranous web, we propose that the membranous web forms the viral replication complex in HCV-infected cells.
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Gosert, Rainer, Denise Egger, Volker Lohmann, Ralf Bartenschlager, Hubert E. Blum, Kurt Bienz, and Darius Moradpour. "Identification of the Hepatitis C Virus RNA Replication Complex in Huh-7 Cells Harboring Subgenomic Replicons." Journal of Virology 77, no. 9 (May 1, 2003): 5487–92. http://dx.doi.org/10.1128/jvi.77.9.5487-5492.2003.
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ABSTRACT Formation of a membrane-associated replication complex, composed of viral proteins, replicating RNA, and altered cellular membranes, is a characteristic feature of plus-strand RNA viruses. Here, we demonstrate the presence of a specific membrane alteration, designated the membranous web, that contains hepatitis C virus (HCV) nonstructural proteins, as well as viral plus-strand RNA, in Huh-7 cells harboring autonomously replicating subgenomic HCV RNAs. Metabolic labeling with 5-bromouridine 5′-triphosphate in the presence of actinomycin D revealed that the membranous web is the site of viral RNA synthesis and therefore represents the replication complex of HCV.
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Sagan, Selena M., Yanouchka Rouleau, Cynthia Leggiadro, Lubica Supekova, Peter G. Schultz, Andrew I. Su, and John Paul Pezacki. "The influence of cholesterol and lipid metabolism on host cell structure and hepatitis C virus replication." Biochemistry and Cell Biology 84, no. 1 (February 1, 2006): 67–79. http://dx.doi.org/10.1139/o05-149.
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The hepatitis C virus (HCV) replicates on a membrane protein complex composed of viral proteins, replicating RNA, and altered cellular membranes. Small-molecule inhibitors of cellular lipid–cholesterol metabolism such as 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 all show a negative effect on HCV replication. Perturbation of host cell lipid and cholesterol metabolism can disrupt replication complexes by altering membranous structures where replication occurs. Changes in cholesterol and (or) lipid composition can have a general effect on membrane structure. Alternatively, metabolic changes can exert a more subtle influence over replication complexes by altering localization of host proteins through alterations in lipid anchoring. Here, we use Huh-7 cells harboring subgenomic HCV replicons to demonstrate that 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 do not disrupt the membranous web where replication occurs, whereas cholesterol-depleting agents such as β-cyclodextrin do. Cellular imaging suggests that the HCV RNA can remain associated with subcellular compartments connected with replication complexes in the presence of metabolic inhibitors. Therefore, at least 2 different molecular mechanisms are possible for the inhibition of HCV replication through the modulation of cellular lipid and cholesterol metabolism.Key words: hepatitis C virus, lipid metabolism, fluorescence microscopy, electron microscopy, membranous web, statins.
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Wölk, Benno, Benjamin Büchele, Darius Moradpour, and Charles M. Rice. "A Dynamic View of Hepatitis C Virus Replication Complexes." Journal of Virology 82, no. 21 (August 20, 2008): 10519–31. http://dx.doi.org/10.1128/jvi.00640-08.
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ABSTRACT Hepatitis C virus (HCV) replicates its genome in a membrane-associated replication complex (RC). Specific membrane alterations, designated membranous webs, represent predominant sites of HCV RNA replication. The principles governing HCV RC and membranous web formation are poorly understood. Here, we used replicons harboring a green fluorescent protein (GFP) insertion in nonstructural protein 5A (NS5A) to study HCV RCs in live cells. Two distinct patterns of NS5A-GFP were observed. (i) Large structures, representing membranous webs, showed restricted motility, were stable over many hours, were partitioned among daughter cells during cell division, and displayed a static internal architecture without detectable exchange of NS5A-GFP. (ii) In contrast, small structures, presumably representing small RCs, showed fast, saltatory movements over long distances. Both populations were associated with endoplasmic reticulum (ER) tubules, but only small RCs showed ER-independent, microtubule (MT)-dependent transport. We suggest that this MT-dependent transport sustains two distinct RC populations, which are both required during the HCV life cycle.
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Blanchard, Emmanuelle, and Philippe Roingeard. "The Hepatitis C Virus-Induced Membranous Web in Liver Tissue." Cells 7, no. 11 (November 1, 2018): 191. http://dx.doi.org/10.3390/cells7110191.
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Host cell membrane rearrangements induced by the hepatitis C virus (HCV) have been exclusively studied in vitro. These studies have shown that HCV induces double-membrane vesicles (DMVs), which probably serve to separate replication sites from the cytoplasmic sensors of the innate immune response. We report for the first time the observation of HCV-induced membrane rearrangements in liver biopsy specimens from patients chronically infected with HCV. Unlike observations performed in vitro, the membranous web detected in liver tissue seems essentially made of clusters of single-membrane vesicles derived from the endoplasmic reticulum and close to lipid droplets. This suggests that the DMVs could be a hallmark of laboratory-adapted HCV strains, possibly due to their ability to achieve a high level of replication. Alternatively, the concealment of viral RNA in DMVs may be part of innate immune response mechanisms particularly developed in hepatoma cell lines cultured in vitro. In any case, this constitutes the first report showing the differences in the membranous web established by HCV in vitro and in vivo.
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Gouttenoire, Jérôme, Philippe Roingeard, François Penin, and Darius Moradpour. "Amphipathic α-Helix AH2 Is a Major Determinant for the Oligomerization of Hepatitis C Virus Nonstructural Protein 4B." Journal of Virology 84, no. 24 (October 6, 2010): 12529–37. http://dx.doi.org/10.1128/jvi.01798-10.
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ABSTRACT Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. It induces a specific membrane rearrangement, designated membranous web, that serves as a scaffold for the HCV replication complex. However, the mechanisms underlying membranous web formation are poorly understood. Based on fluorescence resonance energy transfer (FRET) and confirmatory coimmunoprecipitation analyses, we provide evidence for an oligomerization of NS4B in the membrane environment of intact cells. Several conserved determinants were found to be involved in NS4B oligomerization, through homotypic and heterotypic interactions. N-terminal amphipathic α-helix AH2, comprising amino acids 42 to 66, was identified as a major determinant for NS4B oligomerization. Mutations that affected the oligomerization of NS4B disrupted membranous web formation and HCV RNA replication, implying that oligomerization of NS4B is required for the creation of a functional replication complex. These findings enhance our understanding of the functional architecture of the HCV replication complex and may provide new angles for therapeutic intervention. At the same time, they expand the list of positive-strand RNA virus replicase components acting as oligomers.
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Perez-Berna, Ana J., Nuria Benseny-Cases, María José Rodríguez, Ricardo Valcarcel, José L. Carrascosa, Pablo Gastaminza, and Eva Pereiro. "Monitoring reversion of hepatitis C virus-induced cellular alterations by direct-acting antivirals using cryo soft X-ray tomography and infrared microscopy." Acta Crystallographica Section D Structural Biology 77, no. 11 (October 27, 2021): 1365–77. http://dx.doi.org/10.1107/s2059798321009955.
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Hepatitis C virus (HCV) is an enveloped RNA virus. One of the hallmarks of HCV infection is a rearrangement of the host cell membranes, known as the `membranous web'. Full-field cryo soft X-ray tomography (cryo-SXT) in the water-window energy range (284–543 eV) was performed on the MISTRAL beamline to investigate, in whole unstained cells, the morphology of the membranous rearrangements induced in HCV replicon-harbouring cells in conditions close to the living physiological state. All morphological alterations could be reverted by a combination of sofosbuvir/daclatasvir, which are clinically approved antivirals (direct-acting antivirals; DAAs) for HCV infection. Correlatively combining cryo-SXT and 2D synchrotron-based infrared microscopy provides critical information on the chemical nature of specific infection-related structures, which allows specific patterns of the infection process or the DAA-mediated healing process to be distinguished.
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Kong, Lingbao, Akira Fujimoto, Mariko Nakamura, Haruyo Aoyagi, Mami Matsuda, Koichi Watashi, Ryosuke Suzuki, et al. "Prolactin Regulatory Element Binding Protein Is Involved in Hepatitis C Virus Replication by Interaction with NS4B." Journal of Virology 90, no. 6 (January 6, 2016): 3093–111. http://dx.doi.org/10.1128/jvi.01540-15.
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ABSTRACTIt has been proposed that the hepatitis C virus (HCV) NS4B protein triggers the membranous HCV replication compartment, but the underlying molecular mechanism is not fully understood. Here, we screened for NS4B-associated membrane proteins by tandem affinity purification and proteome analysis and identified 202 host proteins. Subsequent screening of replicon cells with small interfering RNA identified prolactin regulatory element binding (PREB) to be a novel HCV host cofactor. The interaction between PREB and NS4B was confirmed by immunoprecipitation, immunofluorescence, and proximity ligation assays. PREB colocalized with double-stranded RNA and the newly synthesized HCV RNA labeled with bromouridine triphosphate in HCV replicon cells. Furthermore, PREB shifted to detergent-resistant membranes (DRMs), where HCV replication complexes reside, in the presence of NS4B expression in Huh7 cells. However, a PREB mutant lacking the NS4B-binding region (PREBd3) could not colocalize with double-stranded RNA and did not shift to the DRM in the presence of NS4B. These results indicate that PREB locates at the HCV replication complex by interacting with NS4B. PREB silencing inhibited the formation of the membranous HCV replication compartment and increased the protease and nuclease sensitivity of HCV replicase proteins and RNA in DRMs, respectively. Collectively, these data indicate that PREB promotes HCV RNA replication by participating in the formation of the membranous replication compartment and by maintaining its proper structure by interacting with NS4B. Furthermore, PREB was induced by HCV infectionin vitroandin vivo. Our findings provide new insights into HCV host cofactors.IMPORTANCEThe hepatitis C virus (HCV) protein NS4B can induce alteration of the endoplasmic reticulum and the formation of a membranous web structure, which provides a platform for the HCV replication complex. The molecular mechanism by which NS4B induces the membranous HCV replication compartment is not understood. We screened for NS4B-associated membrane proteins by tandem affinity purification and proteome analysis, followed by screening with small interfering RNA. We identified prolactin regulatory element binding (PREB) to be a novel HCV host cofactor. PREB is induced by HCV infection and recruited into the replication complex by interaction with NS4B. Recruited PREB promotes HCV RNA replication by participating in the formation of the membranous HCV replication compartment. To our knowledge, the effect of NS4B-binding protein on the formation of the membranous HCV replication compartment is newly described in this report. Our findings are expected to provide new insights into HCV host cofactors.
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Goueslain, Lucie, Khaled Alsaleh, Pauline Horellou, Philippe Roingeard, Véronique Descamps, Gilles Duverlie, Yann Ciczora, Czeslaw Wychowski, Jean Dubuisson, and Yves Rouillé. "Identification of GBF1 as a Cellular Factor Required for Hepatitis C Virus RNA Replication." Journal of Virology 84, no. 2 (November 11, 2009): 773–87. http://dx.doi.org/10.1128/jvi.01190-09.
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ABSTRACT 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.
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Kim, Kiyoon, Young-seok Lee, Suyun Jeong, Daehong Kim, Suk Chon, Youngmi Kim Pak, Sungsoo Kim, Joohun Ha, Insug Kang, and Wonchae Choe. "A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin." International Journal of Molecular Sciences 21, no. 15 (August 1, 2020): 5516. http://dx.doi.org/10.3390/ijms21155516.
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Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.
Dissertations / Theses on the topic "HCV membranous web"
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Ferraris, Pauline. "Analyses ultrastructurales et biochimiques des membranes cellulaires associées aux complexes de réplication du virus de l'hépatite C." Thesis, Tours, 2011. http://www.theses.fr/2011TOUR3311/document.
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Comme pour la plupart des virus à ARN+, le VHC induit des remaniements membranaires appelés membranous web. Les protéines non structurales virales formant le complexe de réplication du virus sont associées à ces membranes néosynthétisées. La compréhension de la mise en place de ces membranes cellulaire est encore actuellement mal connue. Afin d’étudier ce phénomène, nous avons dans un premier temps sélectionné des clones cellulaires Huh7.5 hébergeants un réplicon sous-génomiquedu virus. Nous avons ainsi pu mettre en évidence la présence d’un réseau multivésiculaire semblant provenir de l’induction de mécanismes d’autophagie. Plus récemment l’utilisation du modèle de propagation du virus complet nous a permis de mieux caractériser ce réseau multivésiculaire en déterminant trois sous réseaux vésiculaires structuralement différents. L’analyse de cette étude est effectuée principalement par microscopie électronique avec des techniques innovantes tels que la reconstruction tridimensionnelle et des immunogoldsAs other RNA viruses, HCV induces membrane alterations termed membranous web and its nonstructural proteins forming the viral replication complex are associated to these neo-synthesized membranes. The mechanism underlying these host cell membranes alterations is still currently unknown. To investigate this mechanism, we initially selected Huh7.5 cells clones harbouring a HCV subgenomic replicon. We were able to demonstrate the presence of a multivesicular network apparently linked to the autophagy induction mechanisms. More recently, using the cell culture-adapted HCVsystem, we better characterized this network by determining three multivesiculars vesicles structurally different subnets. This study was carried out mainly by performing electron microscopy observations,with using innovative techniques such as three-dimensional reconstruction and immunogold
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REGHELLIN, VERONICA. "Studies on the mechanism of action of antiviral agents targeting the replication complex of hepatitis c virus." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/52708.
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At the moment, several companies are studying the clinical potential
of different all-oral combinations of direct-acting antivirals in ongoing
studies. The most promising interferon-free combination therapies
that are on the horizon include linear or cyclic NS3/4A protease
inhibitors, nucleoside as well as non-nucleoside NS5B polymerase
inhibitors , and NS5A inhibitors. DAAs that target NS3/4A (protease)
and NS5B (RNA-dependent RNA polymerase) inhibit the enzymatic
activity of these proteins. NS5A replication complex inhibitors will
likely form a component of future interferon-free drug regimens but
despite their remarkable potential to treat chronic hepatitis C, the
detailed mechanism of action for this class of drug remains unclear.
The goal of my work was to investigate the mechanism of action of
different classes of antiviral agents believed to target the NS5A
protein in the replication complex in order to improve the possibility
to translate basic knowledge to a more meaningful clinical
application. More specifically I focused my research on two classes of
compounds, characterized by distinct resistance patterns in NS5A: a
first class – with examples at the final stages of clinical development,
represented by Daclatasvir (Lemm et al., 2011), and a second class - at
earlier stages of development - represented by anilino-quinazolines
such as A-831/AZD-2836 (Quinkert et al., 2008).
I contributed to demonstrate that both of these inhibitor classes, by
binding respectively to either HCV NS5A or to an NS5A-associated
protein, PI4KIIIα, eventually interfere with the accumulation of PI4P
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and cholesterol in the HCV replication membranous compartment,
thus abrogating the ability of the virus form to replicate its RNA
genome.