Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein

Ray, Ranjit; Lagging, L. M.; Meyer, Keith; Steele, Robert

doi:10.1016/0168-1702(95)00034-n

Cited by 247 publications

(178 citation statements)

References 23 publications

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“…The core protein has also been shown to act in ways that might confer a survival advantage on HCV. It can modulate cellular and viral promoter activities, [31][32][33][34] bind to host RNA helicase to interfere with host RNA translation, and interact with host. 35 Recent data has suggested that HCV core may mediate an immunosupressive effect in vivo.…”

Section: Discussionmentioning

confidence: 99%

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

et al. 1999

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How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virushost interactions in the selection of HCV mutations.

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Section: Discussionmentioning

confidence: 99%

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

et al. 1999

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“…20 Besides its function as a component of viral nucleocapsids, core protein has been shown to target a wide spectrum of viral and cellular factors and different signaling pathways. 21,[24][25][26][27][28] Here, we provide evidence for the contribution of HCV core protein in the development of hepatic angiogenesis, during chronic HCV infection, by the regulation of multiple pathways.…”

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confidence: 99%

“…20 This polyprotein is cleaved by both host and viral proteases to generate four structural proteins (C, E1, E2, and P7) and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). [21][22][23][24] Core protein is derived from the first 191 amino acids of the N-terminal of the precursor polyprotein. 20 Besides its function as a component of viral nucleocapsids, core protein has been shown to target a wide spectrum of viral and cellular factors and different signaling pathways.…”

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confidence: 99%

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

et al. 2009

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Chronic hepatitis C virus (HCV) infection is associated with the production of serum cytokines, including transforming growth factor (TGF)-␤2. Despite the occurrence of hepatic angiogenesis in liver conditions, the role of HCV proteins in this context is currently unknown. We demonstrated that the development of hepatic neoangiogenesis in patients infected with HCV is associated with the expression of TGF-␤2 and vascular endothelial growth factor (VEGF) and with activation of endothelial cells, as evidenced by CD34 expression. The analysis of liver biopsies of HCV-positive and HCV-negative patients using immunostaining showed significant elevation of TGF-␤2, VEGF, and CD34 expression in patients who were HCV-positive. Using an HCV established culture system, we confirmed further the production of both TGF-␤2 and VEGF proteins, in the hepatoma cell lines HepG2 and Huh7 by transfection with full-length HCV RNA (JFH1) or by the regulated expression of core. In addition, regulated expression of core protein in HepG2 or Huh7 cells was found to induce expression and activation of the transcription factor E2F1 and apoptosis signal-regulating kinase 1 (ASK1), activation of c-jun-N-terminal kinase (JNK) and p38, and extracellular-regulated kinase (ERK), and transcription factors activator protein 1 (AP-1), activating transcription factor 2 (ATF-2), cyclic adenosine monophosphate response element binding (CREB), E2F1, hypoxia inducing factor 1 alpha (HIF-1␣), and specificity protein 1. Furthermore, data obtained from inhibitor experiments revealed the importance of E2F1 and ASK1 in the modulation of core-induced activation of JNK and p38 pathways and suggested an essential role for JNK, p38, and ERK pathways in the regulation of core-induced production of TGF-␤2 and VEGF proteins. Thus, our data provide insight into the molecular mechanisms whereby core protein mediates the development of hepatic angiogenesis in patients with chronic HCV infection.

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“…24,25 Moreover, the viral core protein also acts as a transcriptional regulator of various viral and cellular genes, including c-myc, c-fos, retinoblastoma susceptibility gene, p53, p21, hepatitis B virus and long terminal repeats of respiratory syncytial virus and human immunodeficiency virus. [26][27][28] In addition, the core protein may transform immortalized rat embryo fibroblasts into a tumorigenic phenotype. 29 All these versatile functions suggest that HCV core protein may directly modulate cellular signaling.…”

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confidence: 99%

Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates

et al. 1999

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Hepatitis C virus (HCV) is the major etiologic agent of post-transfusion and sporadic non-A, non-B hepatitis. 1 Persistent HCV infection, which develops in at least 70% to 80% of infected patients, often progresses to chronic hepatitis and is highly correlated with the development of cirrhosis and hepatocellular carcinoma. 2-4 Neither a vaccine, nor effective therapy are currently available for HCV, other than interferon alfa combined with ribavirin. 5,6

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Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein

Cited by 247 publications

References 23 publications

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates

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