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  • 1
    Online Resource
    Online Resource
    Hepatitis C Virus Infection Upregulates CD55 Expression on the Hepatocyte Surface and Promotes Association with Virus Particles
    American Society for Microbiology ; 2013
    In:  Journal of Virology Vol. 87, No. 14 ( 2013-07-15), p. 7902-7910
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 87, No. 14 ( 2013-07-15), p. 7902-7910
    Abstract: CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that the HCV core protein or full-length (FL) genome enhanced CD55 promoter activity in a luciferase-based assay, which was further augmented in the presence of interleukin-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core protein-mediated upregulation of CD55. HCV-infected or core protein-transfected Huh7.5 cells displayed greater viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture-grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture-grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the complement pathway, a likely mechanism for immune evasion.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00917-13
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2013
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  • 2
    Online Resource
    Online Resource
    Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes
    American Society for Microbiology ; 2015
    In:  Journal of Virology Vol. 89, No. 22 ( 2015-11-15), p. 11549-11556
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 89, No. 22 ( 2015-11-15), p. 11549-11556
    Abstract: We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621–13628, 2012, http://dx.doi.org/10.1128/JVI.02016-12 ). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected in vitro with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth. IMPORTANCE HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01946-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
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  • 3
    Online Resource
    Online Resource
    Hepatitis C Virus Activates the mTOR/S6K1 Signaling Pathway in Inhibiting IRS-1 Function for Insulin Resistance
    American Society for Microbiology ; 2012
    In:  Journal of Virology Vol. 86, No. 11 ( 2012-06), p. 6315-6322
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 86, No. 11 ( 2012-06), p. 6315-6322
    Abstract: Hepatitis C virus (HCV) infection significantly increases the prevalence of type 2 diabetes mellitus (T2DM). Insulin receptor substrate 1 (IRS-1) plays a key role in insulin signaling, thus enabling metabolic regulation in mammalian cells. We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. Inhibition of IRS-1 expression was observed in HCV-infected hepatocytes compared to that in a mock-infected control. The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. Interestingly, the phosphoS6K1 level was higher in HCV-infected hepatocytes, suggesting a novel mechanism for IRS-1 inhibition. Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00050-12
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
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  • 4
    Online Resource
    Online Resource
    Hepatitis C Virus Proteins Inhibit C3 Complement Production
    American Society for Microbiology ; 2012
    In:  Journal of Virology Vol. 86, No. 4 ( 2012-02-15), p. 2221-2228
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 86, No. 4 ( 2012-02-15), p. 2221-2228
    Abstract: The third component of human complement (C3) plays a central role in innate immune function as its activation is required to trigger classical as well as alternative complement pathways. In this study, we have observed that sera from patients chronically infected with hepatitis C virus (HCV) displayed significantly lower C3 levels than sera from healthy individuals. Liver biopsy specimens from the same patients also exhibited lower C3 mRNA expression than liver tissues from healthy donors. C3 mRNA level was reduced in hepatocytes upon infection with cell culture-grown HCV genotype 1a or 2a in vitro . Further analysis suggested that HCV core protein displayed a weak repression of C3 promoter activity by downregulating the transcription factor farnesoid X receptor (FXR). On the other hand, HCV NS5A protein strongly downregulated C3 promoter activity at the basal level or in the presence of interleukin-1β (IL-1β) as an inducer. In addition, the expression of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-1/IL-6 response element in the C3 promoter, was inhibited in liver biopsy specimens. Furthermore, expression of C/EBP-β was reduced in hepatocytes infected with cell culture-grown HCV, as well as in hepatocytes transfected with the NS5A genomic region of HCV. Together, these results underscore the role of HCV NS5A protein in impairing innate immune function.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.06577-11
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
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  • 5
    Online Resource
    Online Resource
    Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes
    American Society for Microbiology ; 2012
    In:  Journal of Virology Vol. 86, No. 24 ( 2012-12-15), p. 13621-13628
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 86, No. 24 ( 2012-12-15), p. 13621-13628
    Abstract: Hepatitis C virus (HCV)-mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes, when infected in vitro with cell culture-grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed a fibroblast-like shape and an extended life span. To understand the changes at the molecular level, we examined epithelial-mesenchymal transition (EMT) markers. Increased mRNA and protein expression levels of vimentin, snail, slug, and twist and a loss of the epithelial cell marker E-cadherin were observed. Snail and twist, when examined separately, were upregulated in chronically HCV-infected liver biopsy specimens, indicating an onset of an active EMT state in the infected liver. An increased expression level of fibroblast-specific protein 1 (FSP-1) in the infected hepatocytes was also evident, indicating a type 2 EMT state. Infected hepatocytes had significantly increased levels of phosphorylated β-catenin (Ser 552 ) as an EMT mediator, which translocated into the nucleus and activated Akt. The phosphorylation level of β-catenin at Thr 41 /Ser 45 moieties was specifically higher in control than in HCV-infected hepatocytes, implicating an inactivation of β-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture-grown HCV display EMT via the activation of the Akt/β-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategies using inhibitory molecules.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02016-12
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
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