Redox modulation of the hepatitis C virus replication complex is calcium dependent

Choi, Jinah; Forman, Henry Jay; Ou, Jing-Hsiung; Lai, Michael M. C.; Seronello, Scott; Nandipati, Anna

doi:10.1016/j.freeradbiomed.2006.08.008

Cited by 29 publications

(26 citation statements)

References 57 publications

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“…In this regard, the oxidative suppression of HCV replication complex we found is highly consistent, occurring in response to H 2 O 2 , tertiary butyl hydroperoxide, extracellular generation of H 2 O 2 with glucose oxidase plus glucose, tert-butylhydroquinone, decreasing intracellular GSH content with BSO, as well as HNE [204,205] (unpublished observation). The suppression starts at concentrations as low as 0.1 µM H 2 O 2 and starts within 15 -30 min of exposure, progressively worsening by 6 hrs, and resulting in significant decreases in both the rate of HCV replication and the total viral RNA content over time.…”

Section: +supporting

confidence: 64%

“…human hepatoma cells, we also found that H 2 O 2 , at concentrations that did not deplete intracellular GSH or induce cell death, rapidly suppressed HCV RNA replication in a dose-dependent manner [204,205]. The suppressive effects of peroxide was comparable to those of interferon gamma and cyclosporine A, which are potent inhibitors of HCV replication [204,[206][207][208][209] (unpublished observation).…”

Section: +mentioning

confidence: 60%

“…The suppressive effects of peroxide was comparable to those of interferon gamma and cyclosporine A, which are potent inhibitors of HCV replication [204,[206][207][208][209] (unpublished observation). The subgenomic replicon of Con1 sequence (genotype 1b) and a genomic hybrid derived from Con1/H77c sequences (genotype 1a/1b) were likewise affected, and the suppression could be partially reversed with N-acetylcysteine and completely blocked by buffering intracellular calcium, suggesting a signaling event [204]. Furthermore, the mechanism most likely involved a disruption of the HCV replication complex on cell membranes, and other agents that elevated cytosolic calcium concentration had similar suppressive effects on HCV replication, as reported by others [208].…”

Section: +mentioning

confidence: 64%

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Redox regulation of hepatitis C in nonalcoholic and alcoholic liver

Seronello

Sheikh²,

Choi

2007

Free Radical Biology and Medicine

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Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that is estimated to have infected 170 million people worldwide. HCV can cause serious liver disease in humans such as cirrhosis, steatosis, and hepatocellular carcinoma. HCV induces a state of oxidative/nitrosative stress in patients through multiple mechanisms, and this redox perturbation has been recognized as a key player in the HCV-induced pathogenesis. Studies have shown that alcohol synergizes with HCV in the pathogenesis of liver disease, and part of these effects may be mediated by reactive species that are generated during hepatic metabolism of alcohol. Furthermore, reactive species and alcohol may influence HCV replication and the outcome of interferon therapy. Alcohol consumption has also been associated with increased sequence heterogeneity of the HCV RNA sequences, suggesting multiple modes of interaction between alcohol and HCV.This review summarizes current understanding of oxidative and nitrosative stress during HCV infection and possible combined effects of HCV, alcohol, and reactive species in the pathogenesis of liver disease.

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Section: +supporting

confidence: 64%

Section: +mentioning

confidence: 60%

Section: +mentioning

confidence: 64%

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Redox regulation of hepatitis C in nonalcoholic and alcoholic liver

Seronello

Sheikh²,

Choi

2007

Free Radical Biology and Medicine

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“…27,28,30,31 Furthermore, NAC and VE canceled the anti-HCV activity of CsA. 31,32 Although we also examined whether NAC and VE canceled the anti-HCV activity of HA-719 in LucNeo#2 cells, they did not weaken the anti-HCV activity of HA-719 (data not shown).…”

Section: Discussionmentioning

confidence: 93%

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Ito

Toyama

Okamoto

et al. 2015

Antivir Chem Chemother

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Background: The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. Methods: To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. Results: The 50% effective concentration (EC 50 ) of HA-719 for hepatitis C virus replication was 0.058 AE 0.012 mM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 mM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC 50 ¼ 5.66 AE 0.92 mM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B. Conclusion: None of the amino acid mutations in the resistant clone corresponds to those reported to confer drugresistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents.

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“…Several mechanisms have been identified by which HCV infection can lead to the induction of ROS/RNS, including mitochondrial alterations (12)(13)(14)(15)(16); redistribution of calcium between the ER, cytoplasm, and mitochondria (17)(18)(19)(20)(21)(22)(23); increased expression of NADPH oxidases (24,25); enhanced expression of CYP2E1 (26 -29); as well as ER stress and the unfolded protein response (10,18,22,30,31). Oxidative stress also impacts the HCV life cycle at the level of replication and translation and can lead to viral genome heterogeneity, possibly facilitating viral escape from immune detection (32)(33)(34)(35)(36). A better understanding of the cellular events that accompany oxidative/nitrosative stress is likely to contribute to our understanding of the pathogenesis of HCV, as well as provide insight into the HCV life cycle.…”

mentioning

confidence: 99%

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Douglas

Lewis

et al. 2016

Journal of Biological Chemistry

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Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and ␤-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor ␣, which plays a dominant role in the expression of ␤-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor ␣ is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced ␤-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced ␤-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.With ϳ200 million people infected worldwide, hepatitis C virus (HCV) 2 is a global health problem and a major cause of viral hepatitis. Persistent infection occurs in ϳ70% of infected patients leading to inflammation, insulin resistance, steatosis, fibrosis, and hepatocellular carcinoma (1). Current direct-acting antivirals are predicted to be a cure for most patients, but the high cost of this treatment means that the pathological consequences of persistent HCV infection will remain a concern.Although the pathology associated with chronic HCV infection was initially thought to be due to HCV-specific immune responses (2), the current opinion is that direct cytopathic effects in virally infected cells also contribute to HCV-associated liver injury (3, 4). The cellular mechanisms by which HCV replication might mediate liver injury are unclear, but there is no doubt that oxidative/nitrosative stress in HCV-infected cells plays an important role in the initiation and progression of liver damage (3, 5, 6). Oxidative/nitrosative stress essentially arises when the production of reactive oxygen (...

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Redox modulation of the hepatitis C virus replication complex is calcium dependent

Abstract: Reactive species and perturbation of the redox balance have been implicated in the pathogenesis of many viral diseases, including hepatitis C. Previously, we made a surprising discovery that concentrations of H 2 O 2 that are non-toxic to host cells disrupted hepatitis C virus

Cited by 29 publications

References 57 publications

Redox regulation of hepatitis C in nonalcoholic and alcoholic liver

Redox regulation of hepatitis C in nonalcoholic and alcoholic liver

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

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