Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKε and TBK1 functions

2012 ◽  
Vol 85 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Pasi Kaukinen ◽  
Maarit Sillanpää ◽  
Laura Nousiainen ◽  
Krister Melén ◽  
Ilkka Julkunen
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Cell ◽  
Antiviral Response

scholarly journals Hepatitis C Virus E2—Host Cell Receptor, HSPA5, Binding Site Prediction

2020 ◽  
Author(s):  
Alaa Elgohary ◽  
Abdo Elfiky
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Cell ◽  
Cyclic Peptide ◽  
Causative Factor ◽  
Cell Receptor ◽  
Binding Mode ◽  
Structural Protein ◽  
The Unfolded Protein Response

Hepatitis C Virus (HCV) is the main causative factor for liver cirrhosis and the development of liver cancer, with a confirmed ~ 180 million infections worldwide. E2 is an HCV structural protein responsible for virus entry to the host cell. Heat Shock Protein A5 (HSPA5), also termed BiP and GRP78, is the master regulator of the unfolded protein response mechanism, where it mainly localizes in the lumen of the Endoplasmic Reticulum (ER) in normal conditions. Under the stress of HCV infection or carcinogenesis, HSPA5 is upregulated. Consequently, HSPA5 escapes the ER retention localization and translocates to the cytoplasm and plasma membrane. Pep42, a cyclic peptide that was reported to target explicitly cell-surface HSPA5 in vivo. Owing to the high sequence and structural conservation between the C554-C566 region of HCV E2 and the Pep42, then we propose that the HCV E2 C554-C566 region could be the recognition site. The motivation of this work is to predict the possible binding mode between HCV E2 and HSPA5 by implementing molecular docking to test such proposed binding. Docking results reveal the high potent binding of the HCV E2 C554-C566 region to HSPA5 substrate-binding domain β (SBDβ). Moreover, the full-length HCV E2 also exhibits high binding potency to HSPA5 SBDβ. Defining the binding mode between HCV E2 and HSPA5 is of significance, so one can interfere with such binding and reducing the viral infection.

scholarly journals Dissecting the Interferon-Induced Inhibition of Hepatitis C Virus Replication by Using a Novel Host Cell Line

2005 ◽  
Vol 79 (21) ◽  
pp. 13778-13793 ◽  
Author(s):  
Marc P. Windisch ◽  
Michael Frese ◽  
Artur Kaul ◽  
Martin Trippler ◽  
Volker Lohmann ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Cell ◽  
Cell Line ◽  
Nuclear Translocation ◽  
Hepatoma Cell ◽  
Hepatoma Cell Line ◽  
Adaptive Mutations ◽  
Antiviral Compounds ◽  
Ifn Γ

ABSTRACT The Hepatitis C virus (HCV), a member of the family Flaviviridae, is a major cause of chronic liver disease. Patients are currently treated with alpha interferon (IFN-α) that is given alone or in combination with ribavirin. Unfortunately, this treatment is ineffective in eliminating the virus in a large proportion of individuals. IFN-induced antiviral activities have been intensively studied in the HCV replicon system. It was found that both IFN-α and IFN-γ inhibit HCV replicons, but the underlying mechanisms have not yet been identified. Of note is that nearly all of these studies were performed with the human hepatoma cell line Huh-7. Here, we report that genotypes 1b and 2a replicons also replicate in the human hepatoblastoma cell line HuH6. Similar to what has been described for Huh-7 cells, we observed that efficient HCV replication in HuH6 cells depends on the presence of cell culture-adaptive mutations and the permissiveness of the host cell. However, three major differences exist: in HuH6 cells, viral replication is (i) independent from ongoing cell proliferation, (ii) less sensitive to certain antiviral compounds, and (iii) highly resistant to IFN-γ. The latter is not due to a general defect in IFN signaling, as IFN-γ induces the nuclear translocation of signal transducer and activator of transcription 1 (STAT1), the enhanced transcription of several IFN-regulated genes, and the inhibition of unrelated viruses such as influenza A virus and Semliki Forest virus. Taken together, the results establish HuH6 replicon cells as a valuable tool for IFN studies and for the evaluation of antiviral compounds.

scholarly journals Hepatitis C Virus Nonstructural 5A Protein Induces Interleukin-8, Leading to Partial Inhibition of the Interferon-Induced Antiviral Response

2001 ◽  
Vol 75 (13) ◽  
pp. 6095-6106 ◽  
Author(s):  
Stephen J. Polyak ◽  
Khalid S. A. Khabar ◽  
Denise M. Paschal ◽  
Heather J. Ezelle ◽  
Gilles Duverlie ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Response ◽  
Full Length ◽  
Interleukin 8 ◽  
Antiviral Resistance ◽  
Ns5a Protein ◽  
Terminal Amino

ABSTRACT Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). The HCV nonstructural 5A (NS5A) protein has been implicated in HCV antiviral resistance in many studies. NS5A antagonizes the IFN antiviral response in vitro, and one mechanism is via inhibition of a key IFN-induced enzyme, the double-stranded-RNA-activated protein kinase (PKR). In the present study we determined if NS5A uses other strategies to subvert the IFN system. Expression of full-length NS5A proteins from patients who exhibited a complete response (FL-NS5A-CR) or were nonresponsive (FL-NS5A-NR) to IFN therapy in HeLa cells had no effect on IFN induction of IFN-stimulated gene factor 3 (ISGF-3). Expression of mutant NS5A proteins lacking 110 (NS5A-ΔN110), 222 (NS5A-ΔN222), and 334 amino-terminal amino acids and mutants lacking 117 and 230 carboxy-terminal amino acids also had no effect on ISGF-3 induction by IFN. Expression of FL-NS5A-CR and FL-NS5A-NR did not affect IFN-induced STAT-1 tyrosine phosphorylation or upregulation of PKR and major histocompatibility complex class I antigens. However, NS5A expression in human cells induced interleukin 8 (IL-8) mRNA and protein, and this effect correlated with inhibition of the antiviral effects of IFN in an in vitro bioassay. NS5A induced transcription of a reporter gene driven by the IL-8 promoter, and the first 133 bp of the IL-8 promoter made up the minimal domain required for NS5A transactivation. NS5A-ΔN110 and NS5A-ΔN222 stimulated the IL-8 promoter to higher levels than did the full-length NS5A protein, and this correlated with increased nuclear localization of the proteins. Additional mutagenesis of the IL-8 promoter suggested that NF-κB and AP-1 were important in NS5A-ΔN222 transactivation in the presence of tumor necrosis factor alpha and that NF–IL-6 was inhibitory to this process. This study suggests that NS5A inhibits the antiviral actions of IFN by at least two mechanisms and provides the first evidence for a biological effect of the transcriptional activity of the NS5A protein. During HCV infection, viral proteins may induce chemokines that contribute to HCV antiviral resistance and pathogenesis.

scholarly journals Hepatitis c virus and host cell lipids: An intimate connection

RNA Biology ◽  
2011 ◽  
Vol 8 (2) ◽  
pp. 258-269 ◽  
Author(s):  
Gualtiero Alvisi ◽  
Vanesa Madan ◽  
Ralf Bartenschlager
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Cell ◽  
Intimate Connection
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