Hepatitis C virus (HCV) core protein enhances the immunogenicity of a co-delivered DNA vaccine encoding HCV structural antigens in mice

2006 ◽  
Vol 44 (1) ◽  
pp. 9 ◽  
Author(s):  
Marleny González ◽  
Liz Alvarez-Lajonchere ◽  
Julio César Alvarez-Obregón ◽  
Ivis Guerra ◽  
Ariel Viña ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dna Vaccine ◽  
Core Protein ◽  
Hcv Core Protein

scholarly journals Differential Effects on the Hepatitis C Virus (HCV) Internal Ribosome Entry Site by Vitamin B12 and the HCV Core Protein

2004 ◽  
Vol 78 (21) ◽  
pp. 12075-12081 ◽  
Author(s):  
Dongsheng Li ◽  
William B. Lott ◽  
John Martyn ◽  
Gholamreza Haqshenas ◽  
Eric J. Gowans
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Internal Ribosome Entry Site ◽  
Core Protein ◽  
Vitamin B ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Hcv Core Protein ◽  
Hcv Ires

ABSTRACT To investigate the role of the hepatitis C virus internal ribosome entry site (HCV IRES) domain IV in translation initiation and regulation, two chimeric IRES elements were constructed to contain the reciprocal domain IV in the otherwise HCV and classical swine fever virus IRES elements. This permitted an examination of the role of domain IV in the control of HCV translation. A specific inhibitor of the HCV IRES, vitamin B12, was shown to inhibit translation directed by all IRES elements which contained domain IV from the HCV and the GB virus B IRES elements, whereas the HCV core protein could only suppress translation from the wild-type HCV IRES. Thus, the mechanisms of translation inhibition by vitamin B12 and the core protein differ, and they target different regions of the IRES.

Hepatitis C virus core protein inhibits hepatitis B virus replication by downregulating HBx levels via Siah-1-mediated proteasomal degradation during coinfection

2021 ◽  
Vol 102 (12) ◽  
Author(s):  
Sujeong Lee ◽  
Hyunyoung Yoon ◽  
Jiwoo Han ◽  
Kyung Lib Jang
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Protein ◽  
Experimental Studies ◽  
Proteasomal Degradation ◽  
Hbv Replication ◽  
Hcv Core Protein ◽  
B Virus

Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the mechanism remains unclear. Here, we found that HCV core protein inhibits HBV replication by downregulating HBx levels during coinfection in human hepatoma cells. For this effect, HCV core protein increased reactive oxygen species levels in the mitochondria and activated the ataxia telangiectasia mutated-checkpoint kinase two pathway in the nucleus, resulting in an upregulation of p53 levels. Accordingly, HCV core protein induced p53-dependent activation of seven in absentia homolog one expression, an E3 ligase of HBx, resulting in the ubiquitination and proteasomal degradation of HBx. The effect of the HCV core protein on HBx levels was accurately reproduced in both a 1.2-mer HBV replicon and in vitro HBV infection systems, providing evidence for the inhibition of HBV replication by HCV core protein. The present study may provide insights into the mechanism of HCV dominance in HBV- and HCV-coinfected patients.

scholarly journals Cytokine-Modulated Natural Killer Cells Differentially Regulate the Activity of the Hepatitis C Virus

2018 ◽  
Vol 19 (9) ◽  
pp. 2771 ◽  
Author(s):  
Yoo Cho ◽  
Hwan Lee ◽  
Hyojeung Kang ◽  
Hyosun Cho
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nk Cells ◽  
Natural Killer ◽  
Core Protein ◽  
Lymphoid Cells ◽  
Hcv Rna ◽  
Cell Infection ◽  
Hcv Core Protein

HCV genotype 2a strain JFH-1 replicates and produces viral particles efficiently in human hepatocellular carcinoma (huh) 7.5 cells, which provide a stable in vitro cell infection system for the hepatitis C virus (HCVcc system). Natural killer (NK) cells are large lymphoid cells that recognize and kill virus-infected cells. In this study, we investigated the interaction between NK cells and the HCVcc system. IL-10 is a typical immune regulatory cytokine that is produced mostly by NK cells and macrophages. IL-21 is one of the main cytokines that stimulate the activation of NK cells. First, we used anti-IL-10 to neutralize IL-10 in a coculture of NK cells and HCVcc. Anti-IL-10 treatment increased the maturation of NK cells by enhancing the frequency of the CD56+dim population in NK-92 cells. However, with anti-IL-10 treatment of NK cells in coculture with J6/JFH-1-huh 7.5 cells, there was a significant decrease in the expression of STAT1 and STAT5 proteins in NK-92 cells and an increase in the HCV Core and NS3 proteins. In addition, rIL-21 treatment increased the frequency of the CD56+dim population in NK-92 cells, Also, there was a dramatic increase in the expression of STAT1 and STAT5 proteins in rIL-21 pre-stimulated NK cells and a decrease in the expression of HCV Core protein in coculture with J6/JFH-1-huh 7.5 cells. In summary, we found that the functional activation of NK cells can be modulated by anti-IL-10 or rIL-21, which controls the expression of HCV proteins as well as HCV RNA replication.

scholarly journals Proteasome Activator PA28γ-Dependent Nuclear Retention and Degradation of Hepatitis C Virus Core Protein

2003 ◽  
Vol 77 (19) ◽  
pp. 10237-10249 ◽  
Author(s):  
Kohji Moriishi ◽  
Tamaki Okabayashi ◽  
Kousuke Nakai ◽  
Kyoji Moriya ◽  
Kazuhiko Koike ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Regulatory Protein ◽  
Hcv Infection ◽  
Nuclear Retention ◽  
Proteasome Activator ◽  
Hcv Core Protein ◽  
Core Proteins ◽  
Chronic Hcv

ABSTRACT Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28γ (11S regulator γ) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28γ with other Flavivirus core proteins was detected. Deletion of the PA28γ-binding region from the HCV core protein or knockout of the PA28γ gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28γ enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28γ-dependent pathway through which HCV pathogenesis may be exerted.

scholarly journals Hepatitis C Virus-Induced Rab32 Aggregation and Its Implications for Virion Assembly

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Tu M. Pham ◽  
Si C. Tran ◽  
Yun-Sook Lim ◽  
Soon B. Hwang
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Membrane Trafficking ◽  
Core Protein ◽  
Cell Types ◽  
Viral Assembly ◽  
Intracellular Membrane ◽  
Virion Assembly ◽  
Hcv Core Protein ◽  
Infected Cells

ABSTRACT Hepatitis C virus (HCV) is highly dependent on cellular factors for viral propagation. Using high-throughput next-generation sequencing, we analyzed the host transcriptomic changes and identified 30 candidate genes which were upregulated in cell culture-grown HCV (HCVcc)-infected cells. Of these candidates, we selected Rab32 for further investigation. Rab32 is a small GTPase that regulates a variety of intracellular membrane-trafficking events in various cell types. In this study, we demonstrated that both mRNA and protein levels of Rab32 were increased in HCV-infected cells. Furthermore, we showed that HCV infection converted the predominantly expressed GTP-bound Rab32 to GDP-bound Rab32, contributing to the aggregation of Rab32 and thus making it less sensitive to cellular degradation machinery. In addition, GDP-bound Rab32 selectively interacted with HCV core protein and deposited core protein into the endoplasmic reticulum (ER)-associated Rab32-derived aggregated structures in the perinuclear region, which were likely to be viral assembly sites. Using RNA interference technology, we demonstrated that Rab32 was required for the assembly step but not for other stages of the HCV life cycle. Taken together, these data suggest that HCV may modulate Rab32 activity to facilitate virion assembly. IMPORTANCE Rab32, a member of the Ras superfamily of small GTPases, regulates various intracellular membrane-trafficking events in many cell types. In this study, we showed that HCV infection concomitantly increased Rab32 expression at the transcriptional level and altered the balance between GDP- and GTP-bound Rab32 toward production of Rab32-GDP. GDP-bound Rab32 selectively interacted with HCV core protein and enriched core in the ER-associated Rab32-derived aggregated structures that were probably necessary for viral assembly. Indeed, we showed that Rab32 was specifically required for the assembly of HCV. Collectively, our study identifies that Rab32 is a novel host factor essential for HCV particle assembly.

Hepatitis C Virus (HCV) Infection, Monoclonal Immunoglobulin Specific for HCV Core Protein, and Plasma-Cell Malignancy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2712-2712
Author(s):  
Edith Bigot-Corbel ◽  
Michelle Gassin ◽  
Isabelle Corre ◽  
Didier Le Carrer ◽  
Odile Delaroche ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Plasma Cell ◽  
Core Protein ◽  
Hcv Infection ◽  
Monoclonal Immunoglobulin ◽  
Hcv Core Protein ◽  
Increased Risk ◽  
Genotype 2 ◽  
Cell Malignancy

Abstract Hepatitis C virus (HCV) infection can lead to B-cell malignancy via direct infection and transformation of B-lymphocytes, or via indirect transformation by chronic antigen-driven stimulation. Both mechanisms may occur simultaneously, as we previously reported in a case of HCV infection followed by plasma-cell leukemia (PCL), where blasts were infected with HCV and the monoclonal immunoglobulin (Ig) they produced was directed against the core protein of the virus (New Engl J Med, 2003; 348:178). Approximately 10% of HCV-positive patients develop a monoclonal Ig, the specificity of which is usually unknown. To evaluate the link between chronic HCV-antigen driven stimulation and plasma–cell transformation, we studied the specificity of monoclonal Ig developed in the context of HCV infection. Over a period of 13 months, sera from patients consulting or hospitalised at the Centre Hospitalier Universitaire of Nantes found positive for monoclonal Ig, were systematically tested for the presence of HCV RNA and anti-HCV Ig. Among the 700 patients thus studied, 10 (1.4%) were found positive for HCV. Purification of the monoclonal Ig was achieved for 7/10 patients. Using immunoblotting, the purified monoclonal Ig (2 IgG, 1 IgA, 1 IgM) of 4 patients, all with HCV genotype 2, recognized the C22–3 fragment of HCV-core protein; 2 (IgG) recognized NS-4 and 1 did not recognize HCV. Among the 4 patients with anti-HCV-core monoclonal Ig, two presented with mixed (type II) cryoglobulinemia and one was diagnosed with multiple myeloma. Hence, 2/5 patients with anti-HCV core monoclonal Ig developed plasma-cell malignancy. Anti-HCV treatment resulted in the disappearance of the monoclonal Ig for 3/3 treated patients. In summary, in the context of HCV infection monoclonal Ig were typically directed against the virus, and could distinguish patients with increased risk of plasma-cell malignancy. Efforts should be made to identify such patients, as anti-viral therapy should help eradicate the HCV-driven plasma-cell clone.

scholarly journals Hepatitis C Virus Core Protein Associates with Detergent-Resistant Membranes Distinct from Classical Plasma Membrane Rafts

2004 ◽  
Vol 78 (21) ◽  
pp. 12047-12053 ◽  
Author(s):  
Meirav Matto ◽  
Charles M. Rice ◽  
Benjamin Aroeti ◽  
Jeffrey S. Glenn
Keyword(s):  
Plasma Membrane ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Biology ◽  
Core Protein ◽  
Nonstructural Protein ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Classical Plasma ◽  
Detergent Resistant Membranes

ABSTRACT A subpopulation of hepatitis C virus (HCV) core protein in cells harboring full-length HCV replicons is biochemically associated with detergent-resistant membranes (DRMs) in a manner similar to that of markers of classical lipid rafts. Core protein does not, however, colocalize in immunofluorescence studies with classical plasma membrane raft markers, such as caveolin-1 and the B subunit of cholera toxin, suggesting that core protein is bound to cytoplasmic raft microdomains distinct from caveolin-based rafts. Furthermore, while both the structural core protein and the nonstructural protein NS5A associate with membranes, they do not colocalize in the DRMs. Finally, the ability of core protein to localize to the DRMs did not require other elements of the HCV polyprotein. These results may have broad implications for the HCV life cycle and suggest that the HCV core may be a valuable probe for host cell biology.

Structure and dynamics changes induced by 2,2,2-trifluoro-ethanol (TFE) on the N-terminal half of hepatitis C virus core proteinThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 315-323 ◽  
Author(s):  
Jean-Baptiste Duvignaud ◽  
Denis Leclerc ◽  
Stéphane M. Gagné
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Peer Review Process ◽  
Helical Structure ◽  
Functional Roles ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Intrinsically Unstructured Protein ◽  
Unstructured Protein

The Core protein of hepatitis C virus is involved in several interactions other than the encapsidation of viral RNA. We recently proposed that this is related to the fact that the N-terminal half of this protein (C82) is an intrinsically unstructured protein (IUP) domain. IUP domains can adopt a secondary structure when they are interacting with another molecule, such as a nucleic acid or a protein. It is also possible to mimic these conditions by modifying the environment of the protein. We investigated the propensity of this protein to fold as a function of salt concentration, detergent, pH, and 2,2,2-trifluoro-ethanol (TFE); only the addition of TFE resulted in a structural change. The effect of TFE addition was studied by circular dichroism, structural, and dynamic data obtained by NMR. The data indicate that C82 can adopt an α-helical structure; this conformation is likely relevant to one of the functional roles of the HCV Core protein.

scholarly journals Hepatitis C Virus Core Protein and Cellular Protein HAX-1 Promote 5-Fluorouracil-Mediated Hepatocyte Growth Inhibition

2009 ◽  
Vol 83 (19) ◽  
pp. 9663-9671 ◽  
Author(s):  
Arup Banerjee ◽  
Kousuke Saito ◽  
Keith Meyer ◽  
Sutapa Banerjee ◽  
Malika Ait-Goughoulte ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Inhibition ◽  
Hepg2 Cells ◽  
Core Protein ◽  
Cellular Protein ◽  
P53 Expression ◽  
Hcv Core Protein ◽  
Caspase 7 ◽  
Hepatocyte Growth

ABSTRACT Hepatitis C virus (HCV) often causes chronic infection and may lead to hepatocellular carcinoma (HCC). We have shown previously that HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism for gene regulation remains unclear. In this study, a mammalian two-hybrid screen identified a novel binding partner, HS1-associated protein X-1 (HAX-1), for HCV core protein from a human liver cDNA library. An association between HAX-1 and HCV core protein was further verified by confocal microscopy and coimmunoprecipitation in HepG2 cells expressing HCV core or full-length (FL) gene. Both HCV core protein and a chemotherapeutic agent for HCC, 5-flouorouracil (5-FU), are known to modulate p53. We examined here whether an association between core and HAX-1 has any functional relevance to p53 modulation in 5-FU-treated cells. For this, the role of HAX-1 on 5-FU treatment was examined in HepG2 cells expressing HCV core or FL gene using cell proliferation, p53 expression, and caspase activation analysis. Cells expressing HCV-core or FL gene were more susceptible to 5-FU-induced growth inhibition than control cells, whereas cell survival was enhanced after suppression of HAX-1 by small interfering RNA. Further, 5-FU-mediated p53 expression was reduced with concurrent HAX-1 suppression in core- or polyprotein-expressing cells compared to control HepG2 cells, and caspase-2 and -7 activities were diminished. On the other hand, HCV core protein did not play a detectable role in 5-FU-mediated caspase-7 activation in the absence of functional p53 in Hep3B or Huh-7 cells. These observations underscore an association between HCV core and HAX-1, which promotes 5-FU mediated p53-dependent caspase-7 activation and hepatocyte growth inhibition.

scholarly journals Interaction of Hepatitis C Virus Core Protein with Viral Sense RNA and Suppression of Its Translation

1999 ◽  
Vol 73 (12) ◽  
pp. 9718-9725 ◽  
Author(s):  
Takashi Shimoike ◽  
Shigetaka Mimori ◽  
Hideki Tani ◽  
Yoshiharu Matsuura ◽  
Tatsuo Miyamura
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Firefly Luciferase ◽  
Encephalomyocarditis Virus ◽  
Hcv Rna ◽  
Dependent Manner ◽  
Genomic Rna ◽  
The Core ◽  
Hcv Core Protein

ABSTRACT To clarify the binding properties of hepatitis C virus (HCV) core protein and its viral RNA for the encapsidation, morphogenesis, and replication of HCV, the specific interaction of HCV core protein with its genomic RNA synthesized in vitro was examined in an in vivo system. The positive-sense RNA from the 5′ end to nucleotide (nt) 2327, which covers the 5′ untranslated region (5′UTR) and a part of the coding region of HCV structural proteins, interacted with HCV core protein, while no interaction was observed in the same region of negative-sense RNA and in other regions of viral and antiviral sense RNAs. The internal ribosome entry site (IRES) exists around the 5′UTR of HCV; therefore, the interaction of the core protein with this region of HCV RNA suggests that there is some effect on its cap-independent translation. Cells expressing HCV core protein were transfected with reporter RNAs consisting of nt 1 to 709 of HCV RNA (the 5′UTR of HCV and about two-thirds of the core protein coding regions) followed by a firefly luciferase gene (HCV07Luc RNA). The translation of HCV07Luc RNA was suppressed in cells expressing the core protein, whereas no significant suppression was observed in the case of a reporter RNA possessing the IRES of encephalomyocarditis virus followed by a firefly luciferase. This suppression by the core protein occurred in a dose-dependent manner. The expression of the E1 envelope protein of HCV or β-galactosidase did not suppress the translation of both HCV and EMCV reporter RNAs. We then examined the regions that are important for suppression of translation by the core protein and found that the region from nt 1 to 344 was enough to exert this suppression. These results suggest that the HCV core protein interacts with viral genomic RNA at a specific region to form nucleocapsids and regulates the expression of HCV by interacting with the 5′UTR.

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