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1
Borawski, Jason, Philip Troke, Xiaoling Puyang, Veronica Gibaja, ShanChaun Zhao, Craig Mickanin, Juliet Leighton-Davies, et al. "Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication." Journal of Virology 83, no. 19 (July 15, 2009): 10058–74. http://dx.doi.org/10.1128/jvi.02418-08.
Повний текст джерелаАнотація:
ABSTRACT Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.
2
Apriyanto, Dadan Ramadhan, Sri Hartati, and Beti Ernawati Dewi. "Anti-Hepatitis C virus activity of Garcinia lattissima Miq. stem barks methanol exctract." Berkala Penelitian Hayati 29, no. 3 (December 18, 2023): 95–98. http://dx.doi.org/10.23869/bphjbr.29.3.20233.
Повний текст джерелаАнотація:
Herbal medicine treatment for Hepatitis C Virus (HCV) infection is a promising alternative to common medical HCV treatments because it has low unwanted side effects and production costs. This study aimed to evaluate the methanol extract of Garcinia lattissima stem barks as an antiviral compound against strain JFH1 (HCV) genotype 2a. Garcinia lattissima stem bark methanolic extract (GL-SB) was added to Huh7it-1 cells infected with JFHI. Anti HCV activity was determined by Focus-forming unit (FFU) assay and the cytotoxicity activity was analyzed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. The GL-SB showed its efficacy as the anti-HCV agent with a 50% cytotoxicity concentration (CC50) of 34.2 µg/mL and a 50% effective concentration (EC50) of 4.7 µg/mL. The co-addition and post-infection phases of GL-SB showed an anti-HCV activity, according to a time-of-addition investigation. These findings imply that GL-SB might be a promising candidate for add-on therapy in the treatment of HCV infections.
3
Sam, Sung Ting, Omar Sabbar Dahham, Pei Gie Gan, N. Z. Noimam, Jingi Y. Kuan, and Abdulkader M. Alakrach. "Studies on Tensile Properties of Compatibilized and Uncompatibilized Low-Density Polyethylene/Jackfruit Seed Flour (LDPE/JFSF) Blends at Different JFSF Content." Solid State Phenomena 264 (September 2017): 120–23. http://dx.doi.org/10.4028/www.scientific.net/ssp.264.120.
Повний текст джерелаАнотація:
Currently, natural fillers seem to be the suitable materials in polymer industry, which have emerged as a viable and abundant replacement for the relatively high-cost and non-renewable conventional fillers. However, the direct introduction of natural fillers into polymer matrix could effect negatively on some properties. Therefore, the aim of this work is to evaluate the influence of jackfruit seed flour (JFSF) (before and after compatibilization) on the tensile properties of (LDPE/JFSF) blends. Different JFSF content (5, 10, 15 and 20 wt.%) with (63-100 𝜇𝑚) particle size were prepared in this work. Twin-screw extruder at 150°C and 50rpm screw speed followed by hot-compress machine at 150°C and 10MPa pressure were used respectively to produce (LDPE/JFSF) blends. Adipic acid (AA) solution was added as a compatibilizer into all blends equally (25wt% AA into 75wt% JFSf). The changes of tensile and morphological properties were investigated. Results shown decreasing on tensile strength and elongation at break of LDPE/JFSF and LDPE/JFSF/AA as JFSF increased. In contrast, Young’s modulus increased up to 10 wt.% of JFSF and then decreased. However, the addition of Adipic acid, particularly for JFSF 5wt.% has improved the tensile properties of LDPE/JFSF blends. The SEM micrographs showed the agglomeration at high JFSF content (20 wt%) which in turn effected negatively on the tensile properties. However, the blends show homogeneous surfaces as AA added.
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Valente, Mauro, Rodolfo Figueroa, and Jorge E. Fernández. "Editorial SARX-JFMF 2018." Applied Radiation and Isotopes 157 (March 2020): 109006. http://dx.doi.org/10.1016/j.apradiso.2019.109006.
Повний текст джерела
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Simister, Philip, Melanie Schmitt, Matthis Geitmann, Oliver Wicht, U. Helena Danielson, Rahel Klein, Stéphane Bressanelli, and Volker Lohmann. "Structural and Functional Analysis of Hepatitis C Virus Strain JFH1 Polymerase." Journal of Virology 83, no. 22 (September 9, 2009): 11926–39. http://dx.doi.org/10.1128/jvi.01008-09.
Повний текст джерелаАнотація:
ABSTRACT The hepatitis C virus (HCV) isolate JFH1 represents the only cloned wild-type sequence capable of efficient replication in cell culture, as well as in chimpanzees. Previous reports have pointed to the viral polymerase NS5B as a major determinant for efficient replication of this isolate. To understand the underlying mechanisms, we expressed and purified NS5B of JFH1 and of the closely related isolate J6, which replicates below the limit of detection in cell culture. The JFH1 enzyme exhibited a 5- to 10-fold-higher specific activity in vitro, consistent with the polymerase activity itself contributing to efficient replication of JFH1. The higher in vitro activity of the JFH1 enzyme was not due to increased RNA binding, elongation rate, or processivity of the polymerase but to higher initiation efficiency. By using homopolymeric and heteropolymeric templates, we found that purified JFH1 NS5B was significantly more efficient in de novo initiation of RNA synthesis than the J6 counterpart, particularly at low GTP concentrations, probably representing an important prerequisite for the rapid replication kinetics of JFH1. Furthermore, we solved the crystal structure of JFH1 NS5B, which displays a very closed conformation that is expected to facilitate de novo initiation. Structural analysis shows that this closed conformation is stabilized by a sprinkle of substitutions that together promote extra hydrophobic interactions between the subdomains “thumb” and “fingers.” These analyses provide deeper insights into the initiation of HCV RNA synthesis and might help to establish more efficient cell culture models for HCV using alternative isolates.
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Bungyoku, Yasuaki, Ikuo Shoji, Tatsuhiko Makine, Tetsuya Adachi, Kazumi Hayashida, Motoko Nagano-Fujii, Yoshi-Hiro Ide, Lin Deng, and Hak Hotta. "Efficient production of infectious hepatitis C virus with adaptive mutations in cultured hepatoma cells." Journal of General Virology 90, no. 7 (July 1, 2009): 1681–91. http://dx.doi.org/10.1099/vir.0.010983-0.
Повний текст джерелаАнотація:
Robust production of infectious hepatitis C virus (HCV) in cell culture was realized by using the JFH1 strain and the homologous chimeric J6/JFH1 strain in Huh-7.5 cells, a highly HCV-permissive subclone of Huh-7 cells. In this study, we aimed to establish a more efficient HCV-production system and to gain some insight into the adaptation mechanisms of efficient HCV production. By serial passaging of J6/JFH1-infected Huh-7.5 cells, we obtained culture-adapted J6/JFH1 variants, designated P-27, P-38 and P-47. Sequence analyses revealed that the adaptive mutant viruses P-27, P-38 and P-47 possessed eight mutations [four in E2, two in NS2, one in NS5A and one in NS5B), 10 mutations [two additional mutations in the 5′-untranslated region (5′-UTR) and core] and 11 mutations (three additional mutations in 5′-UTR, core and NS5B), respectively. We introduced amino acid substitutions into the wild-type J6/JFH1 clone, generated recombinant viruses with adaptive mutations and analysed their infectivity and ability to produce infectious viruses. The viruses with the adaptive mutations exhibited higher expression of HCV proteins than did the wild type in Huh-7.5 cells. Moreover, we provide evidence suggesting that the mutation N534H in the E2 glycoprotein of the mutant viruses conferred an advantage at the entry level. We thus demonstrate that an efficient HCV-production system could be obtained by introducing adaptive mutations into the J6/JFH1 genome. The J6/JFH1-derived mutant viruses presented here would be a good tool for producing HCV particles with enhanced infectivity and for studying the molecular mechanism of HCV entry.
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Hartati, Sri, Chie Aoki, Muhammad Hanafi, Marissa Angelina, Pratiwi Soedarmono, and Hak Hotta. "Antiviral effect of Archidendron pauciflorum leaves extract to hepatitis C virus: An in vitro study in JFH-1 strain." Medical Journal of Indonesia 27, no. 1 (May 8, 2018): 12–8. http://dx.doi.org/10.13181/mji.v27i1.2189.
Повний текст джерелаАнотація:
Background: Hepatitis C virus (HCV) is a leading cause of chronic liver diseases. Drug resistance to the regimen is also increasing. Hence, there is a need for new anti-HCV agents that are less toxic and more efficacious. The aim of this study is to evaluate the possibility of A. pauciflorum extracts can be a antiviral drug.Methods: Huh-7it cells were infected with the HCV genotype 2a strain JFH-I in the presence of methanol extracts of Archidenron pauciflorum. The methanol extract further partition used n-hexane, ethyl acetate, n-butanol, and water showed in which butanol extracts exerted the strongest IC50 (6.3 g/ml). Further, the butanol fraction was fractionated and yielded into 13 fractions.Results: The methanol extract of the leaves of A. pauciflorum exhibited concentration dependent inhibition against the JFH1 strain of HCV genotype 2a with an IC50 is 72.5 μg/ml. The butanol fraction exhibited the highest anti-HCV activity with an IC50 is 6.3 μg/ml. The butanol fraction was fractionated which yielded 13 fractions. Fractions 5 and 13 exhibited high anti-HCV activities with IC50 is 5.0 μg/ml and 8.5 μg/ml and a time-of-addition study demonstrated that fraction 5 inhibited viral infection at the post-entry step, whereas fraction 13 primarily inhibited the viral entry step.Conclusion: The extract A. pauciflorum can be used as a herbal-based antiviral drug.
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Upata, Maytamart, Thanyaporn Siriwoharn, Sakunkhun Makkhun, Suthasinee Yarnpakdee, Joe M. Regenstein, and Sutee Wangtueai. "Tyrosinase Inhibitory and Antioxidant Activity of Enzymatic Protein Hydrolysate from Jellyfish (Lobonema smithii)." Foods 11, no. 4 (February 21, 2022): 615. http://dx.doi.org/10.3390/foods11040615.
Повний текст джерелаАнотація:
The optimization of antioxidant and anti-tyrosinase activity during jellyfish hydrolysate preparation was studied using a response surface methodology (RSM) with a face-centered composite design. The influence of the hydrolysis duration and the enzyme concentration on the IC50 of the DPPH and ABTS radical scavenging activity, ferric-reducing antioxidant power (FRAP), the degree of hydrolysis (DH), yield, and the IC50 value of tyrosinase inhibitory activity were determined. The optimum conditions for the production of jellyfish hydrolysate using alcalase (JFAH), flavourzyme (JFFH), or papain (JFPH) were achieved at hydrolysis times of 360, 345, or 360 min, respectively, and at an enzyme concentration of 5.0%. JFFH had the highest antioxidant and tyrosinase inhibitory activity. JFAH, JFFH, and JFPH concentrations of 2.5 mg/mL resulted in HaCaT cells (IC80) having a survival rate of 80%. The amino acid profile of JFFH contained about 43% hydrophobic and 57% hydrophilic amino acids, comprising Gly, Cys, Glx, Asx, which were dominant. The isolation of a peptide fraction from JFFH was carried out using ultrafiltration membranes (10, 3, and 1 kDa) and gel filtration chromatography. Fraction-III (1–3 kDa) showed the highest antioxidative and tyrosinase inhibitory activity.
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Liu, Shuanghu, Ren Chen, and Curt H. Hagedorn. "Direct visualization of hepatitis C virus-infected Huh7.5 cells with a high titre of infectious chimeric JFH1-EGFP reporter virus in three-dimensional Matrigel cell cultures." Journal of General Virology 95, no. 2 (February 1, 2014): 423–33. http://dx.doi.org/10.1099/vir.0.055772-0.
Повний текст джерелаАнотація:
Identification of the hepatitis C virus (HCV) JFH1 isolate enabled the development of infectious HCV cell culture systems. However, the relatively low virus titres and instability of some chimeric JFH1 reporter viruses restricts some uses of this system. We describe a higher-titre JFH1-EGFP reporter virus where the NS5A V3 region was replaced with the EGFP gene and adapted by serial passage in Huh7.5 cells. Six adaptive mutants were identified: one each in E2, P7 and NS4B, plus three in the NS5A region. These adaptive mutants increased the reporter virus titres to 1×106 immunofluorescent focus-forming units ml−1, which is the highest titre of JFH1-EGFP reporter virus reported to our knowledge. This chimeric virus did not lose EGFP expression following 40 days of passage and it can be used to test the activity of HCV antivirals by measuring EGFP fluorescence in 96-well plates. Moreover, this reporter virus allows living infected Huh7.5 cells in Matrigel three-dimensional (3D) cultures to be visualized and produces infectious viral particles in these 3D cultures. The chimeric NS5A-EGFP infectious JFH1 reporter virus described should enable new studies of the HCV life cycle in 3D cell cultures and will be useful in identifying antivirals that interfere with HCV release or entry.
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Ishii, Naoto, Koichi Watashi, Takayuki Hishiki, Kaku Goto, Daisuke Inoue, Makoto Hijikata, Takaji Wakita, Nobuyuki Kato, and Kunitada Shimotohno. "Diverse Effects of Cyclosporine on Hepatitis C Virus Strain Replication." Journal of Virology 80, no. 9 (May 1, 2006): 4510–20. http://dx.doi.org/10.1128/jvi.80.9.4510-4520.2006.
Повний текст джерелаАнотація:
ABSTRACT Recently, a production system for infectious particles of hepatitis C virus (HCV) utilizing the genotype 2a JFH1 strain has been developed. This strain has a high capacity for replication in the cells. Cyclosporine (CsA) has a suppressive effect on HCV replication. In this report, we characterize the anti-HCV effect of CsA. We observe that the presence of viral structural proteins does not influence the anti-HCV activity of CsA. Among HCV strains, the replication of genotype 1b replicons was strongly suppressed by treatment with CsA. In contrast, JFH1 replication was less sensitive to CsA and its analog, NIM811. Replication of JFH1 did not require the cellular replication cofactor, cyclophilin B (CyPB). CyPB stimulated the RNA binding activity of NS5B in the genotype 1b replicon but not the genotype 2a JFH1 strain. These findings provide an insight into the mechanisms of diversity governing virus-cell interactions and in the sensitivity of these strains to antiviral agents.
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Targett-Adams, Paul, and John McLauchlan. "Development and characterization of a transient-replication assay for the genotype 2a hepatitis C virus subgenomic replicon." Journal of General Virology 86, no. 11 (November 1, 2005): 3075–80. http://dx.doi.org/10.1099/vir.0.81334-0.
Повний текст джерелаАнотація:
Dicistronic, subgenomic hepatitis C virus (HCV) replicons were constructed containing sequences from JFH1, a genotype 2a strain, that also incorporated the firefly luciferase gene under the control of the HCV internal ribosome entry site element. Luciferase activity in Huh-7 cell extracts containing in vitro-transcribed subgenomic JFH1 RNA was monitored over a 72 h period to examine early stages of HCV replication in the absence of any selective pressure. Enzyme activities produced by the replicon were almost 200-fold greater than those generated from corresponding genotype 1b replicons and correlated with an accumulation of NS5A protein and replicon RNA. Transient replication was sensitive to IFN treatment in a dose-dependent manner and, in addition to Huh-7 cells, the U2OS human osteosarcoma cell line supported efficient replication of the JFH1 replicon. Thus, this system based on JFH1 sequences offers improvements over prior genotype 1b replicons for quantitative measurement of viral RNA replication.
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Li, You, Daisuke Yamane, and Stanley M. Lemon. "Dissecting the Roles of the 5′ Exoribonucleases Xrn1 and Xrn2 in Restricting Hepatitis C Virus Replication." Journal of Virology 89, no. 9 (February 11, 2015): 4857–65. http://dx.doi.org/10.1128/jvi.03692-14.
Повний текст джерелаАнотація:
ABSTRACTThe replication of hepatitis C virus (HCV) is uniquely dependent on a host microRNA, miR-122. Previous studies using genotype 1a H77S.3 virus demonstrated that miR-122 acts in part by protecting the RNA genome from 5′ decay mediated by the cytoplasmic 5′ exoribonuclease, Xrn1. However, this finding has been challenged by a recent report suggesting that a predominantly nuclear exoribonuclease, Xrn2, mediates the degradation of genotype 2a JFH1 RNA. Here, we dissect the roles of these two 5′ exoribonucleases in restricting the replication of different HCV strains and mediating the decay of HCV RNA. Small interfering RNA (siRNA) depletion experiments indicated that Xrn1 restricts replication of all HCV strains tested: JFH1, H77S.3, H77D (a robustly replicating genotype 1a variant), and HJ3-5 (a genotype 1a/2a chimeric virus). In contrast, the antiviral effects of Xrn2 were limited to JFH1 and H77D viruses. Moreover, such effects were not apparent in cells infected with a JFH1 luciferase reporter virus. Whereas Xrn1 depletion significantly slowed decay of JFH1 and HJ3-5 RNAs, Xrn2 depletion marginally enhanced the JFH1 RNA half-life and had no effect on HJ3-5 RNA decay. The positive effects of Xrn1 depletion on JFH1 replication were largely redundant and nonadditive with those of exogenous miR-122 supplementation, whereas Xrn2 depletion acted additively and thus independently of miR-122. We conclude that Xrn1 is the dominant 5′ exoribonuclease mediating decay of HCV RNA and that miR-122 provides protection against it. The restriction of JFH1 and H77D replication by Xrn2 is likely indirect in nature and possibly linked to cytopathic effects of these robustly replicating viruses.IMPORTANCEHCV is a common cause of liver disease both within and outside the United States. Its replication is dependent upon a small, liver-specific noncoding RNA, miR-122. Although this requirement has been exploited for the development of an anti-miR-122 antagomir as a host-targeting antiviral, the molecular mechanisms underpinning the host factor activity of miR-122 remain incompletely defined. Conflicting reports suggest miR-122 protects the viral RNA against decay mediated by distinct cellular 5′ exoribonucleases, Xrn1 and Xrn2. Here, we compare the roles of these two exoribonucleases in HCV-infected cells and confirm that Xrn1, not Xrn2, is primarily responsible for decay of RNA in cells infected with multiple virus strains. Our results clarify previously published research and add to the current understanding of the host factor requirement for miR-122.
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Shukla, Priyanka, Kristina N. Faulk, and Suzanne U. Emerson. "The entire core protein of HCV JFH1 is required for efficient formation of infectious JFH1 pseudoparticles." Journal of Medical Virology 82, no. 5 (May 2010): 783–90. http://dx.doi.org/10.1002/jmv.21660.
Повний текст джерела
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Murayama, Asako, Tomoko Date, Kenichi Morikawa, Daisuke Akazawa, Michiko Miyamoto, Minako Kaga, Koji Ishii, et al. "The NS3 Helicase and NS5B-to-3′X Regions Are Important for Efficient Hepatitis C Virus Strain JFH-1 Replication in Huh7 Cells." Journal of Virology 81, no. 15 (May 23, 2007): 8030–40. http://dx.doi.org/10.1128/jvi.02088-06.
Повний текст джерелаАнотація:
ABSTRACT The JFH-1 strain of hepatitis C virus (HCV) is a genotype 2a strain that can replicate autonomously in Huh7 cells. The J6 strain is also a genotype 2a strain, but its full genomic RNA does not replicate in Huh7 cells. However, chimeric J6/JFH-1 RNA that has J6 structural-protein-coding regions and JFH-1 nonstructural-protein-coding regions can replicate autonomously and produce infectious HCV particles. In order to determine the mechanisms underlying JFH-1 RNA replication, we constructed various J6/JFH-1 chimeras and tested their RNA replication and virus particle production abilities in Huh7 cells. Via subgenomic-RNA-replication assays, we found that both the JFH-1 NS5B-to-3′X (N5BX) and the NS3 helicase (N3H) regions are important for the replication of the J6CF replicon. We applied these results to full-length genomic RNA replication and analyzed replication using Northern blotting. We found that a chimeric J6 clone with JFH-1 N3H and N5BX could replicate autonomously but that a chimeric J6 clone with only JFH-1 N5BX had no replication ability. Finally, we tested the virus production abilities of these clones and found that a chimeric J6 clone with JFH-1 N3H and N5BX could produce infectious HCV particles. In conclusion, the JFH-1 NS3 helicase and NS5B-to-3′X regions are important for efficient replication and virus particle formation of HCV genotype 2a strains.
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Molina, Sonia, Valerie Castet, Lydiane Pichard-Garcia, Czeslaw Wychowski, Eliane Meurs, Jean-Marc Pascussi, Camille Sureau, et al. "Serum-Derived Hepatitis C Virus Infection of Primary Human Hepatocytes Is Tetraspanin CD81 Dependent." Journal of Virology 82, no. 1 (October 17, 2007): 569–74. http://dx.doi.org/10.1128/jvi.01443-07.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus-positive serum (HCVser, genotypes 1a to 3a) or HCV cell culture (JFH1/HCVcc) infection of primary normal human hepatocytes was assessed by measuring intracellular HCV RNA strands. Anti-CD81 antibodies and siRNA-CD81 silencing markedly inhibited (>90%) HCVser infection irrespective of HCV genotype, viral load, or liver donor, while hCD81-large intracellular loop (LEL) had no effect. However, JFH1/HCVcc infection of hepatocytes was modestly inhibited (40 to 60%) by both hCD81-LEL and anti-CD81 antibodies. In conclusion, CD81 is involved in HCVser infection of human hepatocytes, and comparative studies of HCVser versus JFH1/HCVcc infection of human hepatocytes and Huh-7.5 cells revealed that the cell-virion combination is determinant of the entry process.
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Baskov, Vladimir Evgenievich. "RESULTS OF TREATMENT OF JUVENILE FEMORAL HEAD EPIPHYSIOLYSIS." Pediatric Traumatology, Orthopaedics and Reconstructive Surgery 2, no. 3 (September 15, 2014): 14–17. http://dx.doi.org/10.17816/ptors2314-17.
Повний текст джерелаАнотація:
Juvenile femoral head epiphysiolysis (JFHE) is a relatively rare and not fully understood endocrine and orthopedic disease. For decades, the approach and techniques of surgical treatment have undergone significant changes and still continue to be improved. This paper presents a 36 year old follow-up results of treatment effects of JFHE according to one of the previously used surgical techniques.
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Singh, Harmeet, Rajan Sharma, Antima Gupta, Swati Joshi, B. N. Dar, Baljit Singh, and Savita Sharma. "Characterization of jackfruit seed enriched pasta." Quality Assurance and Safety of Crops & Foods 15, no. 2 (April 1, 2023): 11–19. http://dx.doi.org/10.15586/qas.v15i2.1217.
Повний текст джерелаАнотація:
This study aims to investigate the potential of mixing jackfruit seed flour (JFSF) with pasta and its effects on techno-functional properties, cooking behavior, textural characteristics, morphology, macromolecular interactions, and secondary structure of proteins of pasta. The results showed with increase in the addition of JFSF from 6 to 24% caused significant (P < 0.05) improvement in the functional properties, decline in the minimum cooking time (7.07 to 6.20 min), and an increase in the cooking loss (5.13 to 11.26%) as well as firmness of the pasta. Organoleptic evaluations indicated the incorporation of JFSF up to 18% without affecting the flavor. Scanning electron microscopy revealed that after cooking bell-shaped starch granules were embedded in the protein matrix. Fourier transform infrared spectra analysis of the secondary structure of protein showed that the major protein fractions were β-sheets, followed by β helix. Positive correlations between cooking losses and water solubility index and several other parameters were established using principal component analysis. Therefore, incorporating JFSF into pasta could be a promising way for developing protein-rich, high-quality pasta with improved nutritional and functional properties.
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Yi, Guanghui, Yahong Wen, Chang Shu, Qingxia Han, Kouacou V. Konan, Pingwei Li, and C. Cheng Kao. "Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses." Journal of Virology 90, no. 1 (October 14, 2015): 254–65. http://dx.doi.org/10.1128/jvi.01720-15.
Повний текст джерелаАнотація:
ABSTRACT The cyclic dinucleotide 2′,3′-cGAMP can bind the adaptor protein STING (stimulator of interferon [IFN] genes) to activate the production of type I IFNs and proinflammatory cytokines. We found that cGAMP added to the culture medium could suppress the replication of the hepatitis C virus (HCV) genotype 1b strain Con1 subgenomic replicon in human hepatoma cells. Knockdown of STING expression diminished the inhibitory effect on replicon replication, while overexpression of STING enhanced the inhibitory effects of cGAMP. The addition of cGAMP into 1b/Con1 replicon cells significantly increased the expression of type I IFNs and antiviral interferon-stimulated genes. Unexpectedly, replication of the genotype 2a JFH1 replicon and infectious JFH1 virus was less sensitive to the inhibitory effect of cGAMP than was that of 1b/Con1 replicon. Using chimeric replicons, 2a NS4B was identified to confer resistance to cGAMP. Transient expression of 2a NS4B resulted in a pronounced inhibitory effect on STING-mediated beta IFN (IFN-β) reporter activation compared to that of 1b NS4B. 2a NS4B was found to suppress STING accumulation in a dose-dependent manner. The predicted transmembrane domain of 2a NS4B was required to inhibit STING accumulation. These results demonstrate a novel genotype-specific inhibition of the STING-mediated host antiviral immune response. IMPORTANCE The cyclic dinucleotide cGAMP was found to potently inhibit the replication of HCV genotype 1b Con1 replicon but was less effective for the 2a/JFH1 replicon and infectious JFH1 virus. The predicted transmembrane domain in 2a NS4B was shown to be responsible for the decreased sensitivity to cGAMP. The N terminus of NS4B has been reported to suppress STING-mediated signaling by disrupting the interaction of STING and TBK1 and/or MAVS. We show that 2a/JFH1 NS4B has an additional mechanism to evade STING signaling through suppressing STING accumulation.
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Koutsoudakis, George, Artur Kaul, Eike Steinmann, Stephanie Kallis, Volker Lohmann, Thomas Pietschmann, and Ralf Bartenschlager. "Characterization of the Early Steps of Hepatitis C Virus Infection by Using Luciferase Reporter Viruses." Journal of Virology 80, no. 11 (June 1, 2006): 5308–20. http://dx.doi.org/10.1128/jvi.02460-05.
Повний текст джерелаАнотація:
ABSTRACT The lack of an efficient system to produce hepatitis C virus (HCV) particles has impeded the analysis of the HCV life cycle. Recently, we along with others demonstrated that transfection of Huh7 hepatoma cells with a novel HCV isolate (JFH1) yields infectious viruses. To facilitate studies of HCV replication, we generated JFH1-based bicistronic luciferase reporter virus genomes. We found that RNA replication of the reporter construct was only slightly attenuated and that virus titers produced were only three- to fivefold lower compared to the parental virus, making these reporter viruses an ideal tool for quantitative analyses of HCV infections. To expand the scope of the system, we created two chimeric JFH1 luciferase reporter viruses with structural proteins from the Con1 (genotype 1b) and J6CF (genotype 2a) strains. Using these and the authentic JFH1 reporter viruses, we analyzed the early steps of the HCV life cycle. Our data show that the mode of virus entry is conserved between these isolates and involves CD81 as a key receptor for pH-dependent virus entry. Competition studies and time course experiments suggest that interactions of HCV with cell surface-resident glycosaminoglycans aid in efficient infection of Huh7 cells and that CD81 acts during a postattachment step. The reporter viruses described here should be instrumental for investigating the viral life cycle and for the development of HCV inhibitors.
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Murakami, Kyoko, Toshiro Kimura, Motonao Osaki, Koji Ishii, Tatsuo Miyamura, Tetsuro Suzuki, Takaji Wakita, and Ikuo Shoji. "Virological characterization of the hepatitis C virus JFH-1 strain in lymphocytic cell lines." Journal of General Virology 89, no. 7 (July 1, 2008): 1587–92. http://dx.doi.org/10.1099/vir.0.83618-0.
Повний текст джерелаАнотація:
While hepatocytes are the major site of hepatitis C virus (HCV) infection, a number of studies have suggested that HCV can replicate in lymphocytes. However, in vitro culture systems to investigate replication of HCV in lymphocytic cells are severely limited. Robust HCV culture systems have been established using the HCV JFH-1 strain and Huh-7 cells. To gain more insights into the tissue tropism of HCV, we investigated the infection, replication, internal ribosome entry site (IRES)-dependent translation and polyprotein processing of the HCV JFH-1 strain in nine lymphocytic cell lines. HCV JFH-1 failed to infect lymphocytes and replicate, but exhibited efficient polyprotein processing and IRES-dependent translation in lymphocytes as well as in Huh-7 cells. Our results suggest that lymphocytic cells can support HCV JFH-1 translation and polyprotein processing, but may lack some host factors essential for HCV JFH-1 infection and replication.
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Kaul, Artur, Ilka Woerz, Philip Meuleman, Geert Leroux-Roels, and Ralf Bartenschlager. "Cell Culture Adaptation of Hepatitis C Virus and In Vivo Viability of an Adapted Variant." Journal of Virology 81, no. 23 (September 19, 2007): 13168–79. http://dx.doi.org/10.1128/jvi.01362-07.
Повний текст джерелаАнотація:
ABSTRACT Production of infectious hepatitis C virus in cell culture has become possible because of the unique properties of the JFH1 isolate. However, virus titers are rather low, limiting the utility of this system. Here we describe the generation of cell culture-adapted JFH1 variants yielding higher titers of infectious particles and enhanced spread of infection in cultured cells. Sequence analysis of adapted genomes revealed a complex pattern of mutations that differed in two independent experiments. Adaptive mutations were observed both in the structural and in the nonstructural regions, with the latter having the highest impact on enhancement of virus titers. The major adaptive mutation was identified in NS5A, and it enhanced titers of three intergenotypic chimeras consisting of the structural region of a genotype 1a, 1b, or 3a isolate and the remainder of the JFH1 isolate. The mutation resides at the P3 position of the NS5A-B cleavage site and slows down processing, implying that subtle differences in replication complex formation appear to determine the efficiency of virus formation. Highly adapted JFH1 viruses carrying six mutations established a robust infection in uPA-transgenic SCID mice xenografted with human hepatocytes. However, the mutation in NS5A which enhanced virus titers in cell culture the most had reverted to wild type in nearly half of the viral genomes isolated from these animals at 15 weeks postinoculation. These results argue for some level of impaired fitness of this mutant in vivo.
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Delgrange, David, André Pillez, Sandrine Castelain, Laurence Cocquerel, Yves Rouillé, Jean Dubuisson, Takaji Wakita, Gilles Duverlie, and Czeslaw Wychowski. "Robust production of infectious viral particles in Huh-7 cells by introducing mutations in hepatitis C virus structural proteins." Journal of General Virology 88, no. 9 (September 1, 2007): 2495–503. http://dx.doi.org/10.1099/vir.0.82872-0.
Повний текст джерелаАнотація:
Recently, the characterization of a cell culture system allowing the amplification of an authentic virus, named hepatitis C virus cell culture (HCVcc), has been reported by several groups. To obtain higher HCV particle productions, we investigated the potential effect of some amino acid changes on the infectivity of the JFH-1 isolate. As a first approach, successive infections of naïve Huh-7 cells were performed until high viral titres were obtained, and mutations that appeared during this selection were identified by sequencing. Only one major modification, N534K, located in the E2 glycoprotein sequence was found. Interestingly, this mutation prevented core glycosylation of E2 site 6. In addition, JFH-1 generated with this modification facilitated the infection of Huh-7 cells. In a second approach to identify mutations favouring HCVcc infectivity, we exploited the observation that a chimeric virus containing the genotype 1a core protein in the context of JFH-1 background was more infectious than wild-type JFH-1 isolate. Sequence alignment between JFH-1 and our chimera, led us to identify two major positions, 172 and 173, which were not occupied by similar amino acids in these two viruses. Importantly, higher viral titres were obtained by introducing these residues in the context of wild-type JFH-1. Altogether, our data indicate that a more robust production of HCVcc particles can be obtained by introducing a few specific mutations in JFH-1 structural proteins.
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Steinmann, Eike, Christiane Brohm, Stephanie Kallis, Ralf Bartenschlager, and Thomas Pietschmann. "Efficient trans-Encapsidation of Hepatitis C Virus RNAs into Infectious Virus-Like Particles." Journal of Virology 82, no. 14 (May 14, 2008): 7034–46. http://dx.doi.org/10.1128/jvi.00118-08.
Повний текст джерелаАнотація:
ABSTRACT Recently, complete replication of hepatitis C virus (HCV) in tissue culture was established using the JFH1 isolate. To analyze determinants of HCV genome packaging and virion assembly, we developed a system that supports particle production based on trans-packaging of subgenomic viral RNAs. Using JFH1 helper viruses, we show that subgenomic JFH1 replicons lacking the entire core to NS2 coding region are efficiently encapsidated into infectious virus-like particles. Similarly, chimeric helper viruses with heterologous structural proteins trans-package subgenomic JFH1 replicons. Like authentic cell culture-produced HCV (HCVcc) particles, these trans-complemented HCV particles (HCVTCP) penetrate target cells in a CD81 receptor-dependent fashion. Since HCVTCP production was limited by competition between the helper and subgenomic RNA and to avoid contamination of HCVTCP stocks with helper viruses, we created HCV packaging cells. These cells encapsidate various HCV replicons with high efficiency, reaching infectivity titers up to 106 tissue culture infectious doses 50 per milliliter. The produced particles display a buoyant density comparable to HCVcc particles and can be propagated in the packaging cell line but support only a single-round infection in naïve cells. Together, this work demonstrates that subgenomic HCV replicons are assembly competent, thus excluding cis-acting RNA elements in the core-to-NS2 genomic region essential for RNA packaging. The experimental system described here should be helpful to decipher the mechanisms of HCV assembly and to identify RNA elements and viral proteins involved in particle formation. Similar to other vector systems of plus-strand RNA viruses, HCVTCP may prove valuable for gene delivery or vaccination approaches.
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Shao, Run-Xuan, Leiliang Zhang, Lee F. Peng, Eileen Sun, Woo Jin Chung, Jae Yong Jang, Wei-Lun Tsai, Guibenson Hyppolite, and Raymond T. Chung. "Suppressor of Cytokine Signaling 3 Suppresses Hepatitis C Virus Replication in an mTOR-Dependent Manner." Journal of Virology 84, no. 12 (April 7, 2010): 6060–69. http://dx.doi.org/10.1128/jvi.02484-09.
Повний текст джерелаАнотація:
ABSTRACT We and others have observed that hepatic levels of suppressor of cytokine signaling 3 (SOCS3) are significantly higher in persons with chronic hepatitis C, particularly those who are nonresponders to interferon (IFN) treatment, than in healthy individuals. However, the relationship between SOCS3 and hepatitis C virus (HCV) replication remains unclear. Given its putative role, we hypothesized that SOCS3 is permissive for viral replication. We therefore used the OR6 cell line, which harbors a genotype 1b full-length HCV replicon, and the genotype 2a full-length HCV strain JFH1 infection system to analyze the effects of SOCS3 overexpression and short hairpin RNA (shRNA)-mediated knockdown on HCV replication. We further analyzed the role of mTOR in the effects of SOCS3 by treating selected cells with rapamycin. OR6 cells and JFH1-infected Huh7.5.1 cells expressed significantly less SOCS3 than control cells. Furthermore, inhibition of HCV replication with the HCV protease inhibitor BILN 2061 restored SOCS3 protein levels. SOCS3 overexpression in OR6 cells and JFH1-infected Huh7.5.1 cells resulted in significantly lower HCV replication than that in the control cells, despite SOCS3-related inhibition of STAT1 phosphorylation and type I IFN signaling. In contrast, JFH1-infected cells with stable SOCS3 knockdown expressed higher levels of HCV proteins and RNA than did control cells. SOCS3-targeting shRNA also knocked down mTOR and phospho-mTOR. The mTOR inhibitor rapamycin reversed the inhibitory effects of SOCS3. In independent investigations, SOCS3 unexpectedly suppressed HCV replication in an mTOR-dependent manner. These findings suggest that increased SOCS3 levels consistently observed in chronic IFN nonresponders may reflect a compensatory host antiviral response to persistent infection and that manipulation of SOCS3/mTOR may offer benefit against HCV infection.
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Grove, Joe, Thierry Huby, Zania Stamataki, Thomas Vanwolleghem, Philip Meuleman, Michelle Farquhar, Anne Schwarz, et al. "Scavenger Receptor BI and BII Expression Levels Modulate Hepatitis C Virus Infectivity." Journal of Virology 81, no. 7 (January 10, 2007): 3162–69. http://dx.doi.org/10.1128/jvi.02356-06.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus (HCV) enters cells via a pH- and clathrin-dependent endocytic pathway. Scavenger receptor BI (SR-BI) and CD81 are important entry factors for HCV internalization into target cells. The SR-BI gene gives rise to at least two mRNA splice variants, SR-BI and SR-BII, which differ in their C termini. SR-BI internalization remains poorly understood, but SR-BII is reported to endocytose via a clathrin-dependent pathway, making it an attractive target for HCV internalization. We demonstrate that HCV soluble E2 can interact with human SR-BI and SR-BII. Increased expression of SR-BI and SR-BII in the Huh-7.5 hepatoma cell line enhanced HCV strain J6/JFH and JFH infectivity, suggesting that endogenous levels of these receptors limit infection. Elevated expression of SR-BI, but not SR-BII, increased the rate of J6/JFH infection, which may reflect altered intracellular trafficking of the splice variants. In human plasma, HCV particles have been reported to be complexed with lipoproteins, suggesting an indirect interaction of the virus with SR-BI and other lipoprotein receptors. Plasma from J6/JFH-infected uPA-SCID mice transplanted with human hepatocytes demonstrates an increased infectivity for SR-BI/II-overexpressing Huh-7.5 cells. Plasma-derived J6/JFH infectivity was inhibited by an anti-E2 monoclonal antibody, suggesting that plasma virus interaction with SR-BI was glycoprotein dependent. Finally, anti-SR-BI antibodies inhibited the infectivity of cell culture- and plasma-derived J6/JFH, suggesting a critical role for SR-BI/II in HCV infection.
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Takeda, Midori, Masanori Ikeda, Yasuo Ariumi, Takaji Wakita, and Nobuyuki Kato. "Development of hepatitis C virus production reporter-assay systems using two different hepatoma cell lines." Journal of General Virology 93, no. 7 (July 1, 2012): 1422–31. http://dx.doi.org/10.1099/vir.0.040725-0.
Повний текст джерелаАнотація:
A hepatitis C virus (HCV) infection system was developed previously using the HCV JFH-1 strain (genotype 2a) and HuH-7 cells, and this cell culture is so far the only robust production system for HCV. In patients with chronic hepatitis C, the virological effects of pegylated interferon and ribavirin therapy differ depending on the HCV strain and the genetic background of the host. Recently, we reported the hepatoma-derived Li23 cell line, in which the JFH-1 life cycle is reproduced at a level almost equal to that in HuH-7-derived RSc cells. To monitor the HCV life cycle more easily, we here developed JFH-1 reporter-assay systems using both HuH-7- and Li23-derived cell lines. To identify any genetic mutations by long-term cell culture, HCV RNAs in HuH-7 cells were amplified 130 days after infection and subjected to sequence analysis to find adaptive mutation(s) for robust virus replication. We identified two mutations, H2505Q and V2995L, in the NS5B region. V2995L but not H2505Q enhanced JFH-1 RNA replication. However, we found that H2505Q but not V2995L enhanced HCV RNA replication of strain O (genotype 1b). We also selected highly permissive D7 cells by serial subcloning of Li23 cells. The expression levels of claudin-1 and Niemann–Pick C1-like 1 in D7 cells are higher than those in parental Li23 cells. In this study, we developed HCV JFH-1 reporter-assay systems using two distinct hepatoma cell lines, HuH-7 and Li23. The mutations in NS5B resulted in different effects on strains O and JFH-1 HCV RNA replication.
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Iswanto, A. H., F. Febrianto, Y. S. Hadi, S. Ruhendi, and D. Hermawan. "Jatropha fruit hulls (JFH) particleboard:Effect of acetic acid treatment and ratio of JFH and non-wood particles." IOP Conference Series: Earth and Environmental Science 126 (March 2018): 012015. http://dx.doi.org/10.1088/1755-1315/126/1/012015.
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Lam, Angela M., Christine Espiritu, Shalini Bansal, Holly M. Micolochick Steuer, Congrong Niu, Veronique Zennou, Meg Keilman, et al. "Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus." Antimicrobial Agents and Chemotherapy 56, no. 6 (March 19, 2012): 3359–68. http://dx.doi.org/10.1128/aac.00054-12.
Повний текст джерелаАнотація:
ABSTRACTPSI-7977, a prodrug of 2′-F-2′-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirmed that the S282T change conferred resistance to PSI-7977. Subsequently, we evaluated the ability of PSI-7977 to select for resistance using GT 1a, 1b, and 2a (JFH-1) replicon cells. S282T was the common mutation selected among all three genotypes, but while it conferred resistance to PSI-7977 in GT 1a and 1b, JFH-1 GT 2a S282T showed only a very modest shift in 50% effective concentration (EC50) for PSI-7977. Sequence analysis of the JFH-1 NS5B region indicated that additional amino acid changes were selected both prior to and after the emergence of S282T. These include T179A, M289L, I293L, M434T, and H479P. Residues 179, 289, and 293 are located within the finger and palm domains, while 434 and 479 are located on the surface of the thumb domain. Data from the JFH-1 replicon variants showed that amino acid changes within the finger and palm domains together with S282T were required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons.
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Sarhan, Mohammed A., Annie Y. Chen, Rodney S. Russell, and Tomasz I. Michalak. "Patient-derived hepatitis C virus and JFH-1 clones differ in their ability to infect human hepatoma cells and lymphocytes." Journal of General Virology 93, no. 11 (November 1, 2012): 2399–407. http://dx.doi.org/10.1099/vir.0.045393-0.
Повний текст джерелаАнотація:
Hepatitis C virus (HCV) is a hepatotropic virus that also infects cells of the immune system. HCV clones cultivated in human hepatoma Huh-7.5 cells have significantly advanced our understanding of HCV replication and candidate hepatocyte receptors. However, naturally occurring patient-derived HCV, in contrast to the HCV JFH-1 clone, is unable to infect Huh-7.5 cells, while it can replicate in human primary T-cells and selected T-cell lines. To better understand this incongruity, we examined the susceptibility of primary T-cells, PBMCs and T-cell lines to infection with patient-derived HCV, the classical HCV JFH-1 and a cell culture-adapted JFH1T known to be highly infectious to Huh-7.5 cells. We also tested whether Huh-7.5 cells are prone to virus readily infecting T-lymphocytes. The results revealed that while primary T-cells and Molt4 and Jurkat T-cell lines were susceptible to patient-derived HCV, they were resistant to infection with either JFH1T or JFH-1. However, the JFH1T clone interacted more firmly, although non-productively, with the cells than JFH-1. Further, Huh-7.5 cells robustly supported replication of JFH1T but not patient-derived, wild-type virus, despite using highly sensitive detection assays. In conclusion, JFH-1 and JFH1T clones were unable to establish productive infection in human primary T-cells, PBMCs and T-cell lines known to be prone to infection by patient-derived HCV, while Huh-7.5 cells were resistant to infection with naturally occurring virus infecting immune cells. The data showed that the ability to infect lymphocytes is a characteristic of native virus but not laboratory HCV clones.
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Tscherne, Donna M., Matthew J. Evans, Thomas von Hahn, Christopher T. Jones, Zania Stamataki, Jane A. McKeating, Brett D. Lindenbach, and Charles M. Rice. "Superinfection Exclusion in Cells Infected with Hepatitis C Virus." Journal of Virology 81, no. 8 (February 7, 2007): 3693–703. http://dx.doi.org/10.1128/jvi.01748-06.
Повний текст джерелаАнотація:
ABSTRACT Superinfection exclusion is the ability of an established virus infection to interfere with infection by a second virus. In this study, we found that Huh-7.5 cells acutely infected with hepatitis C virus (HCV) genotype 2a (chimeric strain J6/JFH) and cells harboring HCV genotype 1a, 1b, or 2a full-length or subgenomic replicons were resistant to infection with cell culture-produced HCV (HCVcc). Replicon-containing cells became permissive for HCVcc infection after treatment with an HCV-specific protease inhibitor. With the exception of cells harboring a J6/JFH-FLneo replicon, infected or replicon-containing cells were permissive for HCV pseudoparticle (HCVpp) entry, demonstrating a postentry superinfection block downstream of primary translation. The surprising resistance of J6/JFH-FLneo replicon-containing cells to HCVpp infection suggested a defect in virus entry. This block was due to reduced expression of the HCV coreceptor CD81. Further analyses indicated that J6/JFH may be toxic for cells expressing high levels of CD81, thus selecting for a CD81low population. CD81 down regulation was not observed in acutely infected cells, suggesting that this may not be a general mechanism of HCV superinfection exclusion. Thus, HCV establishes superinfection exclusion at a postentry step, and this effect is reversible by treatment of infected cells with antiviral compounds.
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Grabski, Elena, Ilka Wappler, Stephanie Pfaender, Eike Steinmann, Sibylle Haid, Andrzej Dzionek, Thomas Pietschmann, and Ulrich Kalinke. "Efficient Virus Assembly, but Not Infectivity, Determines the Magnitude of Hepatitis C Virus-Induced Interferon Alpha Responses of Plasmacytoid Dendritic Cells." Journal of Virology 89, no. 6 (December 31, 2014): 3200–3208. http://dx.doi.org/10.1128/jvi.03229-14.
Повний текст джерелаАнотація:
ABSTRACTWorldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV.IMPORTANCEAlthough pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses.
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Mohd-Ismail, Nur Khairiah, Lin Deng, Sunil Kumar Sukumaran, Victor C. Yu, Hak Hotta, and Yee-Joo Tan. "The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1." Journal of Virology 83, no. 19 (July 15, 2009): 9993–10006. http://dx.doi.org/10.1128/jvi.00509-09.
Повний текст джерелаАнотація:
ABSTRACT The hepatitis C virus (HCV) core protein is known to modulate apoptosis and contribute to viral replication and pathogenesis. In this study, we have identified a Bcl-2 homology 3 (BH3) domain in the core protein that is essential for its proapoptotic property. Coimmunoprecipitation experiments showed that the core protein interacts specifically with the human myeloid cell factor 1 (Mcl-1), a prosurvival member of the Bcl-2 family, but not with other prosurvival members (Bcl-XL and Bcl-w). Moreover, the overexpression of Mcl-1 protects against core-induced apoptosis. By using peptide mimetics, core was found to release cytochrome c from isolated mitochondria when complemented with Bad. Thus, core is a bona fide BH3-only protein having properties similar to those of Noxa, a BH3-only member of the Bcl-2 family that binds preferentially to Mcl-1. There are three critical hydrophobic residues in the BH3 domain of the core protein, and they are essential for the proapoptotic property of the core protein. Furthermore, the genotype 1b core protein is more effective than the genotype 2a core protein in inducing apoptosis due to a single-amino-acid difference at one of these hydrophobic residues (residue 119). Replacing this residue in the J6/JFH-1 infectious clone (genotype 2a) with the corresponding amino acid in the genotype 1b core protein produced a mutant virus, J6/JFH-1(V119L), which induced significantly higher levels of apoptosis in the infected cells than the parental J6/JFH-1 virus. Furthermore, the core protein of J6/JFH-1(V119L), but not that of J6/JFH-1, interacted with Mcl-1 in virus-infected cells. Taken together, the core protein is a novel BH3-only viral homologue that contributes to the induction of apoptosis during HCV infection.
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Taguwa, Shuhei, Toru Okamoto, Takayuki Abe, Yoshio Mori, Tetsuro Suzuki, Kohji Moriishi, and Yoshiharu Matsuura. "Human Butyrate-Induced Transcript 1 Interacts with Hepatitis C Virus NS5A and Regulates Viral Replication." Journal of Virology 82, no. 6 (December 26, 2007): 2631–41. http://dx.doi.org/10.1128/jvi.02153-07.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is required for the replication of the viral genome and is involved in several host signaling pathways. To gain further insight into the functional role of NS5A in HCV replication, we screened human cDNA libraries by a yeast two-hybrid system using NS5A as the bait and identified human butyrate-induced transcript 1 (hB-ind1) as a novel NS5A-binding protein. Endogenously and exogenously expressed hB-ind1 was coimmunoprecipitated with NS5A of various genotypes through the coiled-coil domain of hB-ind1. The small interfering RNA (siRNA)-mediated knockdown of hB-ind1 in human hepatoma cell lines suppressed the replication of HCV RNA replicons and the production of infectious particles of HCV genotype 2a strain JFH1. Furthermore, these reductions were canceled by the expression of an siRNA-resistant hB-ind1 mutant. Among the NS5A-binding host proteins involved in HCV replication, hB-ind1 exhibited binding with FKBP8, and hB-ind1 interacted with Hsp90 through the FxxW motif in its N-terminal p23 homology domain. The impairment of the replication of HCV RNA replicons and of the production of infectious particles of JFH1 virus in the hB-ind1 knockdown cell lines was not reversed by the expression of an siRNA-resistant hB-ind1 mutant in which the FxxW motif was replaced by AxxA. These results suggest that hB-ind1 plays a crucial role in HCV RNA replication and the propagation of JFH1 virus through interaction with viral and host proteins.
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Liang, Hua, Rodney S. Russell, Nicole L. Yonkers, David McDonald, Benigno Rodriguez, Clifford V. Harding, and Donald D. Anthony. "Differential Effects of Hepatitis C Virus JFH1 on Human Myeloid and Plasmacytoid Dendritic Cells." Journal of Virology 83, no. 11 (March 18, 2009): 5693–707. http://dx.doi.org/10.1128/jvi.02671-08.
Повний текст джерелаАнотація:
ABSTRACT Dendritic cells (DCs) are reported to be functionally deficient during chronic hepatitis C virus (HCV) infection. Differing results have been reported on direct effects of intact replicative-form HCV on DC function. To better understand the effect of HCV on DC function, we treated freshly purified human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) with HCV JFH1. We found that HCV upregulated mDC maturation marker (CD83, CD86, and CD40) expression and did not inhibit Toll-like receptor 3 (TLR3) ligand [poly(I:C)]-induced mDC maturation, a finding consistent with the phenotype of DCs from HCV-infected subjects. At the same time, HCV JFH1 inhibited the ability of poly(I:C)-treated mDCs to activate naive CD4 T cells. In contrast, although there was no direct effect of virus on pDC maturation, HCV JFH1 inhibited TLR7 ligand (R848)-induced pDC CD40 expression, and this was associated with impaired ability to activate naive CD4 T cells. Parallel experiments with recombinant HCV proteins indicated HCV core protein may be responsible for a portion of the activity. Furthermore, HCV-mediated mDC maturation was dependent upon CD81-E2 interaction and, in part, TLR2. Using UV-treated HCV, we show that HCV-mediated mDC and pDC maturation is virus replication independent and, using strand specific PCR, we found no evidence for HCV replication within DCs. Because these effects of HCV on DC subset maturation and function in part recapitulate direct ex vivo analysis of DCs in chronic HCV infection, the mechanisms described here likely account for a portion of the DC subset defects observed in vivo.
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Kanda, Tatsuo, Robert Steele, Ranjit Ray, and Ratna B. Ray. "Small Interfering RNA Targeted to Hepatitis C Virus 5′ NontranslatedRegion Exerts Potent Antiviral Effect." Journal of Virology 81, no. 2 (November 1, 2006): 669–76. http://dx.doi.org/10.1128/jvi.01496-06.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. Interferon alone or together with ribavirin is the only therapy for HCV infection; however, a significant number of HCV-infected individuals do not respond to this treatment. Therefore, the development of new therapeutic options against HCV is a matter of urgency. In the present study, we have examined vectors carrying short hairpin RNA (shRNA) targeting the 5′ nontranslated conserved region of the HCV genome for inhibition of virus replication. Initially, three sequences were selected, and all three shRNAs (psh-53, psh-274, and psh-375) suppressed HCV internal ribosome entry site (IRES)-mediated translation to different degrees in Huh-7 cells. Next, we introduced siRNA into Huh-7.5 cells persistently infected with HCV genotype 2a (JFH1). The most efficient inhibition of JFH1 replication was observed with psh-274, targeted to the portion from subdomain IIId to IIIe of the IRES. Subsequently, Huh-7.5 cells stably expressing psh-274 further displayed a significant reduction in HCV JFH1 replication. The effect of psh-274 on cell-culture-grown HCV genotype 1a (H77) was also evaluated, and inhibition of virus replication and infectivity titers was observed. In the absence of a cell-culture-grown HCV genotype 1b, the effects of psh-274 on subgenomic and full-length replicons were examined, and efficient inhibition of genome replication was observed. Therefore, we have identified a conserved sequence targeted to the HCV genome that can inhibit replication of different genotypes, suggesting the potential of siRNA as an additional therapeutic modality against HCV infection.
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Binder, Marco, Doris Quinkert, Olga Bochkarova, Rahel Klein, Nikolina Kezmic, Ralf Bartenschlager, and Volker Lohmann. "Identification of Determinants Involved in Initiation of Hepatitis C Virus RNA Synthesis by Using Intergenotypic Replicase Chimeras." Journal of Virology 81, no. 10 (March 7, 2007): 5270–83. http://dx.doi.org/10.1128/jvi.00032-07.
Повний текст джерелаАнотація:
ABSTRACT The 5′ nontranslated region (NTR) and the X tail in the 3′ NTR are the least variable parts of the hepatitis C virus (HCV) genome and play an important role in the initiation of RNA synthesis. By using subgenomic replicons of the HCV isolates Con1 (genotype 1) and JFH1 (genotype 2), we characterized the genotype specificities of the replication signals contained in the NTRs. The replacement of the JFH1 5′ NTR and X tail with the corresponding Con1 sequence resulted in a significant decrease in replication efficiency. Exchange of the X tail specifically reduced negative-strand synthesis, whereas substitution of the 5′ NTR impaired the generation of progeny positive strands. In search for the proteins involved in the recognition of genotype-specific initiation signals, we analyzed recombinant nonstructural protein 5B (NS5B) RNA polymerases of both isolates and found some genotype-specific template preference for the 3′ end of positive-strand RNA in vitro. To further address genotype specificity, we constructed a series of intergenotypic replicon chimeras. When combining NS3 to NS5A of Con1 with NS5B of JFH1, we observed more-efficient replication with the genotype 2a X tail, indicating that NS5B recognizes genotype-specific signals in this region. In contrast, a combination of the NS3 helicase with NS5A and NS5B was required to confer genotype specificity to the 5′ NTR. These results present the first genetic evidence for an interaction between helicase, NS5A, and NS5B required for the initiation of RNA synthesis and provide a system for the specific analysis of HCV positive- and negative-strand syntheses.
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Chang, Serena, and Gyongyi Szabo. "Loss of TLR7 receptor expression in HCV viral infection as a potential mechanism to evade the innate immune system (45.13)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S59. http://dx.doi.org/10.4049/jimmunol.178.supp.45.13.
Повний текст джерелаАнотація:
Abstract Hepatitis C Virus (HCV), a single stranded RNA virus that causes chronic inflammation in the liver, has evolved ways to interfere with the innate and adaptive immune system for survival. Recent studies show that Toll-like Receptor (TLR) 7 agonists decrease HCV expression in patients and infected cell lines, through a Type 1 IFN-mediated pathway. As it is unknown whether HCV interferes with TLR7 or its pathway, we investigated changes in TLR7 expression during HCV infection. Compared to 75% of the positively stained TLR7 expressing controls, human hepatoma cells infected with the replicating JFH-1 HCV clone, showed only 25% TLR7 expression by flow cytometry. Cells expressing full-length or sub genomic HCV replicons followed the same pattern as JFH-1 with 11% and 18% TLR7 expression compared to the wild-type expressing 56% and 42%. Micro array analysis of HCV infected livers showed a decrease in TLR7 mRNA expression suggesting in vivo correlation. TLR7-mediated signaling involves activation of IRF7 and IRF3 for type I IFN induction. IRF7 nuclear protein levels in JFH-1 cells were equivalent to control cells, as opposed to a drastic reduction in IRF3 levels and IP-10, an IFN-inducible gene, in JFH-1 cells vs. control cells. These results demonstrate an attenuation of TLR7 expression in Hepatitis C Virus infection that may represent a novel mechanism to prevent sufficient innate immune responses in HCV elimination.
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Kato, Takanobu, Takuya Matsumura, Theo Heller, Satoru Saito, Ronda K. Sapp, Krishna Murthy, Takaji Wakita, and T. Jake Liang. "Production of Infectious Hepatitis C Virus of Various Genotypes in Cell Cultures." Journal of Virology 81, no. 9 (February 14, 2007): 4405–11. http://dx.doi.org/10.1128/jvi.02334-06.
Повний текст джерелаАнотація:
ABSTRACT A unique hepatitis C virus (HCV) strain JFH-1 has been shown to replicate efficiently in cell culture with production of infectious HCV. We previously developed a DNA expression system containing HCV cDNA flanked by two self-cleaving ribozymes to generate HCV particles in cell culture. In this study, we produced HCV particles of various genotypes, including 1a (H77), 1b (CG1b), and 2a (J6 and JFH-1), in the HCV-ribozyme system. The constructs also contain the secreted alkaline phosphatase gene to control for transfection efficiency and the effects of culture conditions. After transfection into the Huh7-derived cell line Huh7.5.1, continuous HCV replication and secretion were confirmed by the detection of HCV RNA and core antigen in the culture medium. HCV replication levels of strains H77, CG1b, and J6 were comparable, whereas the JFH-1 strain replicates at a substantially higher level than the other strains. To evaluate the infectivity in vitro, the culture medium of JFH-1-transfected cells was inoculated into naive Huh7.5.1 cells. HCV proteins were detected by immunofluorescence 3 days after inoculation. To evaluate the infectivity in vivo, the culture medium from HCV genotype 1b-transfected cells was inoculated into a chimpanzee and caused a typical course of HCV infection. The HCV 1b propagated in vitro and in vivo had sequences identical to those of the HCV genomic cDNA used for cell culture transfection. The development of culture systems for production of various HCV genotypes provides a valuable tool not only to study the replication and pathogenesis of HCV but also to screen for antivirals.
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Bentham, Matthew J., Najat Marraiki, Christopher J. McCormick, David J. Rowlands, and Stephen Griffin. "NS2 is dispensable for efficient assembly of hepatitis C virus-like particles in a bipartite trans-encapsidation system." Journal of General Virology 95, no. 11 (November 1, 2014): 2427–41. http://dx.doi.org/10.1099/vir.0.068932-0.
Повний текст джерелаАнотація:
Infectious hepatitis C virus (HCV) particle production in the genotype 2a JFH-1-based cell culture system involves non-structural proteins in addition to canonical virion components. NS2 has been proposed to act as a protein adaptor, co-ordinating the early stages of virion assembly. However, other studies have identified late-acting roles for this protein, making its precise involvement in infectious particle production unclear. Using a robust, bipartite trans-encapsidation system based upon baculovirus expression of HCV structural proteins, we have generated HCV-like particles (HCV-LP) in the absence of NS2 with overt similarity to wild-type virions. HCV-LP could transduce naive cells with trans-encapsidated subgenomic replicon RNAs and shared similar biochemical and biophysical properties with JFH-1 HCV. Both genotype 1b and JFH-1 intracellular HCV-LP were produced in the absence of NS2, whereas restoring NS2 to the JFH-1 system dramatically enhanced secreted infectivity, consistent with a late-acting role. Our system recapitulated authentic HCV particle assembly via trans-complementation of bicistronic, NS2-deleted, chimeric HCV, which is otherwise deficient in particle production. This closely resembled replicon-mediated NS2 trans-complementation, confirming that baculovirus expression of HCV proteins did not unduly affect particle production. Furthermore, this suggests that separation of structural protein expression from replicating HCV RNAs that are destined to be packaged alleviates an early stage requirement for NS2 during particle formation. This highlights our current lack of understanding of how NS2 mediates assembly, yet comparison of full-length and bipartite systems may provide further insight into this process.
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Gottwein, Judith M., Sanne B. Jensen, Yi-Ping Li, Lubna Ghanem, Troels K. H. Scheel, Stéphanie B. N. Serre, Lotte Mikkelsen, and Jens Bukh. "Combination Treatment with Hepatitis C Virus Protease and NS5A Inhibitors Is Effective against Recombinant Genotype 1a, 2a, and 3a Viruses." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 28, 2012): 1291–303. http://dx.doi.org/10.1128/aac.02164-12.
Повний текст джерелаАнотація:
ABSTRACTWith the development of directly acting antivirals, hepatitis C virus (HCV) therapy entered a new era. However, rapid selection of resistance mutations necessitates combination therapy. To study combination therapy in infectious culture systems, we aimed at developing HCV semi-full-length (semi-FL) recombinants relying only on the JFH1 NS3 helicase, NS5B, and the 3′ untranslated region. With identified adaptive mutations, semi-FL recombinants of genotypes(isolates) 1a(TN) and 3a(S52) produced supernatant infectivity titers of ∼4 log10focus-forming units/ml in Huh7.5 cells. Genotype 1a(TN) adaptive mutations allowed generation of 1a(H77) semi-FL virus. Concentration-response profiles revealed the higher efficacy of the NS3 protease inhibitor asunaprevir (BMS-650032) and the NS5A inhibitor daclatasvir (BMS-790052) against 1a(TN and H77) than 3a(S52) viruses. Asunaprevir had intermediate efficacy against previously developed 2a recombinants J6/JFH1 and J6cc. Daclatasvir had intermediate efficacy against J6/JFH1, while low sensitivity was confirmed against J6cc. Using a cross-titration scheme, infected cultures were treated until viral escape or on-treatment virologic suppression occurred. Compared to single-drug treatment, combination treatment with relatively low concentrations of asunaprevir and daclatasvir suppressed infection with all five recombinants. Escaped viruses primarily had substitutions at amino acids in the NS3 protease and NS5A domain I reported to be genotype 1 resistance mutations. Inhibitors showed synergism at drug concentrations reportedin vivo. In summary, semi-FL HCV recombinants, including the most advanced reported genotype 3a infectious culture system, permitted genotype-specific analysis of combination treatment in the context of the complete viral life cycle. Despite differential sensitivity to lead compound NS3 protease and NS5A inhibitors, genotype 1a, 2a, and 3a viruses were suppressed by combination treatment with relatively low concentrations.
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Widyawaruyanti, Aty, Adita Ayu Permanasari, Laila Nur Hidayatus, Lidya Tumewu, Tutik Sri Wahyuni, and Achmad Fuad Hafid. "ANTI HEPATITIS C ACTIVITY AND TOXICITY OF Scoparia dulcis LINN. HERB." Indonesian Journal of Tropical and Infectious Disease 8, no. 2 (July 31, 2020): 124. http://dx.doi.org/10.20473/ijtid.v8i2.12657.
Повний текст джерелаАнотація:
Hepatitis C Virus (HCV) infection is a serious public health problem since HCV is the ribonucleic acid (RNA) virus that easy to mutate. The HCV standard treatment has rapidly developed but the possibility of resistance and effectiveness of treatment needs to be considered. The medicinal plants are a source of various compounds that may potentially cure diseases including infectious diseases. Since a long years ago, medicinal plants were famous as an inherited treatment that believed to cure the disease. One of the medicinal plants is Scoparia dulcis (S. dulcis) that belongs to Scrophulariaceae family and traditionally used as remedies for digestive problems, hypertension, diabetes mellitus, bronchitis, and as an analgesic & antipyretic agent. The previous report showed that S. dulcis was known active as an antiviral against Herpes Simplex Virus (HSV) type 1 in vitro and in vivo. The aim of the study is to determine the biactivity potential of S. dulcis against HCV. Scoparia dulcis was extracted using 80% ethanol (EE) then further separated by liquid-liquid fractionation using dichloromethane (DCMF), ethyl acetate (EAF), butanol solvent (BF) and water (WF). The in vitro anti-HCV analysis was performed with Huh7it cells and HCV JFH1 (genotype 2a) by determining inhibition concentration 50 (IC50). The toxicity (Cytotoxicity Concentration 50, CC50) test was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and mechanism of action were analyzed using time addition experiment. Phytochemical groups as the suspected active compounds of S. dulcis were identified by Thin Layer Chromatography (TLC) and observed under UV 254 nm, UV 365 nm, before and after sprayed using H2SO4 10% and heated at 105oC for 5 minutes. The IC50 test result of 80% EE and DCMF showed anti-HCV activity with a value of 12.7±4.8 µg/ml and 5.8±0.69 µg/ml, while EAF, BF, and AF respectively resulted in IC50 value of >100 µg/ml that suggested there was no inhibition effect on HCV JFH1. The DCMF was the most active fraction but toxic to the cell with CC50 value >23 µg/ml and selectivity index (SI) >3.9. According to the time addition experiment data, DCMF of S. dulcis inhibited post entry step HCV JFH1 infection that it means the possibility was to inhibit virus replication and or virion release. Scoparia dulcis contain chlorophyll, flavonoids and terpenoids as the suspected active compounds for inhibition of HCV JFH1 infecton. Futher study of post-entry inhibitions of HCV infection was needed.
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Eng, Francis J., Jose L. Walewski, Arielle L. Klepper, Sarah L. Fishman, Suresh M. Desai, Laura K. McMullan, Matthew J. Evans, Charles M. Rice, and Andrea D. Branch. "Internal Initiation Stimulates Production of p8 Minicore, a Member of a Newly Discovered Family of Hepatitis C Virus Core Protein Isoforms." Journal of Virology 83, no. 7 (January 7, 2009): 3104–14. http://dx.doi.org/10.1128/jvi.01679-08.
Повний текст джерелаАнотація:
ABSTRACT The hepatitis C virus (HCV) core gene is more conserved at the nucleic acid level than is necessary to preserve the sequence of the core protein, suggesting that it contains information for additional functions. We used a battery of anticore antibodies to test the hypothesis that the core gene directs the synthesis of core protein isoforms. Infectious viruses, replicons, and RNA transcripts expressed a p8 minicore containing the C-terminal portion of the p21 core protein and lacking the N-terminal portion. An interferon resistance mutation, U271A, which creates an AUG at codon 91, upregulated p8 expression in Con1 replicons, suggesting that p8 is produced by an internal initiation event and that 91-AUG is the preferred, but not the required, initiation codon. Synthesis of p8 was independent of p21, as shown by the abundant production of p8 from transcripts containing an UAG stop codon that blocked p21 production. Three infectious viruses, JFH-1 (2a core), J6/JFH (2a core), and H77/JFH (1a core), and a bicistronic construct, Bi-H77/JFH, all expressed both p8 and larger isoforms. The family of minicores ranges in size from 8 to 14 kDa. All lack the N-terminal portion of the p21 core. In conclusion, the core gene contains an internal signal that stimulates the initiation of protein synthesis at or near codon 91, leading to the production of p8. Infectious viruses of both genotype 1 and 2 HCV express a family of larger isoforms, in addition to p8. Minicores lack significant portions of the RNA binding domain of p21 core. Studies are under way to determine their functions.
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Kotta-Loizou, Ioly, Ioannis Karakasiliotis, Niki Vassilaki, Panagiotis Sakellariou, Ralf Bartenschlager, and Penelope Mavromara. "Expression of the Novel Hepatitis C Virus Core+1/ARF Protein in the Context of JFH1-Based Replicons." Journal of Virology 89, no. 9 (February 18, 2015): 5164–70. http://dx.doi.org/10.1128/jvi.02351-14.
Повний текст джерелаАнотація:
Hepatitis C virus contains a second open reading frame within the core gene, designated core+1/ARF. Here we demonstrate for the first time expression of core+1/ARF protein in the context of a bicistronic JFH1-based replicon and report the production of two isoforms, core+1/L (long) and core+1/S (short), with different kinetics.
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Dean, Muhajirin, Retno Handajani, and Junaidi Khotib. "Faloak (Sterculia Quadrifida R.Br) Stem Bark Extract Inhibits Hepatitis C Virus JFH1." Oriental Journal of Chemistry 35, no. 1 (February 25, 2019): 430–35. http://dx.doi.org/10.13005/ojc/350155.
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Shirakura, Masayuki, Kyoko Murakami, Tohru Ichimura, Ryosuke Suzuki, Tetsu Shimoji, Kouichirou Fukuda, Katsutoshi Abe, et al. "E6AP Ubiquitin Ligase Mediates Ubiquitylation and Degradation of Hepatitis C Virus Core Protein." Journal of Virology 81, no. 3 (November 15, 2006): 1174–85. http://dx.doi.org/10.1128/jvi.01684-06.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus (HCV) core protein is a major component of viral nucleocapsid and a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis. We previously showed that the HCV core protein is degraded through the ubiquitin-proteasome pathway. However, the molecular machinery for core ubiquitylation is unknown. Using tandem affinity purification, we identified the ubiquitin ligase E6AP as an HCV core-binding protein. E6AP was found to bind to the core protein in vitro and in vivo and promote its degradation in hepatic and nonhepatic cells. Knockdown of endogenous E6AP by RNA interference increased the HCV core protein level. In vitro and in vivo ubiquitylation assays showed that E6AP promotes ubiquitylation of the core protein. Exogenous expression of E6AP decreased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected Huh-7 cells. Furthermore, knockdown of endogenous E6AP by RNA interference increased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected cells. Taken together, our results provide evidence that E6AP mediates ubiquitylation and degradation of HCV core protein. We propose that the E6AP-mediated ubiquitin-proteasome pathway may affect the production of HCV particles through controlling the amounts of viral nucleocapsid protein.
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Li, Yujia, Max Xuezhong Ma, Bo Qin, Liang-Tzung Lin, Christopher D. Richardson, Jordan Feld, Ian D. McGilvray, and Limin Chen. "The Ubiquitin-Specific Protease 18 Promotes Hepatitis C Virus Production by Increasing Viral Infectivity." Mediators of Inflammation 2019 (November 18, 2019): 1–12. http://dx.doi.org/10.1155/2019/3124745.
Повний текст джерелаАнотація:
Background and Aims. Ubiquitin-specific protease 18 (USP18) is involved in immunoregulation and response to interferon- (IFN-) based treatment in patients chronically infected with hepatitis C virus (HCV). We investigated whether and how its upregulation alters HCV infection. Methods. Overexpression of wild-type (USP18 WT) or catalytically inactive mutant (USP18 C64S) USP18 was examined for effects on HCV replication in the absence and presence of IFNα or IFNλ using both the HCV-infective model and replicon cells. The IFN signaling pathway was assessed via STAT1 phosphorylation (western blot) and downstream ISG expression (real-time PCR). Mechanistic roles were sought by quantifying microRNA-122 levels and J6/JFH1 infectivity of Huh7.5 cells. Results. We found that overexpression of either USP18 WT or USP18 C64S stimulated HCV production and blunted the anti-HCV effect of IFNα and IFNλ in the infective model but not in the replicon system. Overexpressed USP18 showed no effect on Jak/STAT signaling nor on microRNA-122 expression. However, USP18 upregulation markedly increased J6/JFH1 infectivity and promoted the expression of the key HCV entry factor CD81 on Huh7.5 cells. Conclusions. USP18 stimulates HCV production and blunts the effect of both type I and III IFNs by fostering a cellular environment characterized by upregulation of CD81, promoting virus entry and infectivity.
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Aligeti, Mounavya, Allison Roder, and Stacy M. Horner. "Cooperation between the Hepatitis C Virus p7 and NS5B Proteins Enhances Virion Infectivity." Journal of Virology 89, no. 22 (September 9, 2015): 11523–33. http://dx.doi.org/10.1128/jvi.01185-15.
Повний текст джерелаАнотація:
ABSTRACTThe molecular mechanisms that govern hepatitis C virus (HCV) assembly, release, and infectivity are still not yet fully understood. In the present study, we sequenced a genotype 2A strain of HCV (JFH-1) that had been cell culture adapted in Huh-7.5 cells to produce nearly 100-fold-higher viral titers than the parental strain. Sequence analysis identified nine mutations in the genome, present within both the structural and nonstructural genes. The infectious clone of this virus containing all nine culture-adapted mutations had 10-fold-higher levels of RNA replication and RNA release into the supernatant but had nearly 1,000-fold-higher viral titers, resulting in an increased specific infectivity compared to wild-type JFH-1. Two mutations, identified in the p7 polypeptide and NS5B RNA-dependent RNA polymerase, were sufficient to increase the specific infectivity of JFH-1. We found that the culture-adapted mutation in p7 promoted an increase in the size of cellular lipid droplets following transfection of viral RNA. In addition, we found that the culture-adaptive mutations in p7 and NS5B acted synergistically to enhance the specific viral infectivity of JFH-1 by decreasing the level of sphingomyelin in the virion. Overall, these results reveal a genetic interaction between p7 and NS5B that contributes to virion specific infectivity. Furthermore, our results demonstrate a novel role for the RNA-dependent RNA polymerase NS5B in HCV assembly.IMPORTANCEHepatitis C virus assembly and release depend on viral interactions with host lipid metabolic pathways. Here, we demonstrate that the viral p7 and NS5B proteins cooperate to promote virion infectivity by decreasing sphingomyelin content in the virion. Our data uncover a new role for the viral RNA-dependent RNA polymerase NS5B and p7 proteins in contributing to virion morphogenesis. Overall, these findings are significant because they reveal a genetic interaction between p7 and NS5B, as well as an interaction with sphingomyelin that regulates virion infectivity. Our data provide new strategies for targeting host lipid-virus interactions as potential targets for therapies against HCV infection.
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Grove, Joe, Søren Nielsen, Jin Zhong, Margaret F. Bassendine, Heidi E. Drummer, Peter Balfe, and Jane A. McKeating. "Identification of a Residue in Hepatitis C Virus E2 Glycoprotein That Determines Scavenger Receptor BI and CD81 Receptor Dependency and Sensitivity to Neutralizing Antibodies." Journal of Virology 82, no. 24 (October 1, 2008): 12020–29. http://dx.doi.org/10.1128/jvi.01569-08.
Повний текст джерелаАнотація:
ABSTRACT Hepatitis C virus (HCV) infection is dependent on at least three coreceptors: CD81, scavenger receptor BI (SR-BI), and claudin-1. The mechanism of how these molecules coordinate HCV entry is unknown. In this study we demonstrate that a cell culture-adapted JFH-1 mutant, with an amino acid change in E2 at position 451 (G451R), has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralization by soluble CD81 and enhanced binding of recombinant E2 to cell surface-expressed and soluble CD81. Fractionation of HCV by density gradient centrifugation allows the analysis of particle-lipoprotein associations. The cell culture-adapted mutation alters the relationship between particle density and infectivity, with the peak infectivity occurring at higher density than the parental virus. No association was observed between particle density and SR-BI or CD81 coreceptor dependence. JFH-1 G451R is highly sensitive to neutralization by gp-specific antibodies, suggesting increased epitope exposure at the virion surface. Finally, an association was observed between JFH-1 particle density and sensitivity to neutralizing antibodies (NAbs), suggesting that lipoprotein association reduces the sensitivity of particles to NAbs. In summary, mutation of E2 at position 451 alters the relationship between particle density and infectivity, disrupts coreceptor dependence, and increases virion sensitivity to receptor mimics and NAbs. Our data suggest that a balanced interplay between HCV particles, lipoprotein components, and viral receptors allows the evasion of host immune responses.
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Dong, Lechao, Siwei Li, Jia Xing, Hao Lin, Shansi Wang, Xiaoyue Zeng, and Yaming Qin. "Joint features random forest (JFRF) model for mapping hourly surface PM2.5 over China." Atmospheric Environment 273 (March 2022): 118969. http://dx.doi.org/10.1016/j.atmosenv.2022.118969.
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Shirasago, Yoshitaka, Hidesuke Fukazawa, Hideki Aizaki, Tetsuro Suzuki, Takeru Suzuki, Kazuo Sugiyama, Takaji Wakita, Kentaro Hanada, Ryo Abe, and Masayoshi Fukasawa. "Thermostable hepatitis C virus JFH1-derived variant isolated by adaptation to Huh7.5.1 cells." Journal of General Virology 99, no. 10 (October 1, 2018): 1407–17. http://dx.doi.org/10.1099/jgv.0.001117.
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