• Molecules and Cells
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• v.45 no.10
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• pp.702-717
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• 2022

Hepatitis C virus (HCV) infection can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV employs diverse strategies to evade host antiviral innate immune responses to mediate a persistent infection. In the present study, we show that nonstructural protein 5A (NS5A) interacts with an NF-κB inhibitor immunomodulatory kinase, IKKε, and subsequently downregulates beta interferon (IFN-β) promoter activity. We further demonstrate that NS5A inhibits DDX3-mediated IKKε and interferon regulatory factor 3 (IRF3) phosphorylation. We also note that hyperphosphorylation of NS5A mediates protein interplay between NS5A and IKKε, thereby contributing to NS5A mediated modulation of IFN-β signaling. Lastly, NS5A inhibits IKKε-dependent p65 phosphorylation and NF-κB activation. Based on these findings, we propose NS5A as a novel regulator of IFN signaling events, specifically by inhibiting IKKε downstream signaling cascades through its interaction with IKKε. Taken together, these data suggest an additional mechanistic means by which HCV modulates host antiviral innate immune responses to promote persistent viral infection.

• The Microorganisms and Industry
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• v.13 no.3
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• pp.3-11
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• 1987

Hepatitis B virus (HBV) is a very serious threat to public health in most of the developing countries of the world. It is estimated that around 300 million people worldwide are chronic carriers of this virus and will transmit the disease both vertically and horizontally. Infection by this virus may cause a wide range of clinical manifestations ranging from an asymptomatic infection to liver cirrhosis.

• Journal of Microbiology and Biotechnology
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• v.28 no.11
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• pp.1908-1915
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• 2018

Upon viral infection, the host cell recognizes the invasion through a number of pattern recognition receptors. Melanoma differentiation associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) recognize RNA molecules derived from invading viruses, activating down-stream signaling cascades, culminating in the induction of the type I interferon. On the other hand, viruses have evolved to evade type I interferon-mediated inhibition. Hepatitis E virus has been shown to encode a few antagonists of type I interferon and it is not surprising that viruses encode multiple mechanisms of viral evasion. In the present study, we demonstrated that HEV PCP strongly down-regulates MDA5-mediated activation of interferon ${\beta}$ induction in a dose-dependent manner. Interestingly, MDA5 protein expression was almost completely abolished. In addition, polyinosinic polycytidylic acid (poly(I:C))- and Sendai virus-mediated activation of type I interferon responses were similarly abrogated in the presence of HEV PCP. Furthermore, HEV PCP down-regulates several molecules that play critical roles in the induction of type I IFN expression. Taken together, these data collectively suggest that HEV-encoded PCP is a strong antagonist of type I interferon.

• Journal of Microbiology and Biotechnology
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• v.8 no.4
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• pp.361-368
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• 1998

The E2 protein of HCV (hepatitis C virus) is thought to have a potential role in the development of subunit vaccines and diagnostics. To express it by the insect cell/baculovirus expression (Bacu) system, we constructed a recombinant Autographa californica nuclear polyhedrosis virus (AcIL3E2), determined the most appropriate expression conditions in terms of host cell line and culture medium, and characterized the expressed HCV E2 protein. A culture system using Trichoplusia ni BTI-TN5Bl-4 cells and SF 900IISFM medium expressed a relatively high level of HCV E2 protein. It was revealed that its glycosylation properties and subcellular localization were almost the same as the ones in the mammalian cell expression system previously reported, suggesting the recombinant HCV E2 protein derived from our Bacu system can be utilized for development of a subunit vaccine and diagnostics. Interestingly, HCV E2 protein was not degraded at all even at 43 h post-heat shock in the heat shock-induced necrotic cells, probably due to its integration into the microsomal membrane, indicating that heat shock can be employed to purify HCV E2 protein.

• Molecules and Cells
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• v.21 no.3
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• pp.330-336
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• 2006

Since its identification in 1989, hepatitis C virus has been the subject of extensive research. The biology of the virus and the development of antiviral drugs are closely related. The RNA polymerase activity of nonstructural protein 5B was first demonstrated in 1996. NS5B is believed to localize to the perinuclear region, forming a replicase complex with other viral proteins. It has a typical polymerase structure with thumb, palm, and finger domains encircling the active site. A de novo replication initiation mechanism has been suggested. To date, many small molecule inhibitors are known including nucleoside analogues, non-nucleoside analogues, and pyrophosphate mimics. NS5B interacts with other viral proteins such as core, NS3, 4A, 4B, and 5A. The helicase activity of NS3 seems necessary for RNA strand unwinding during replication, with other nonstructural proteins performing modulatory roles. Cellular proteins interacting with NS5B include VAMP-associated proteins, heIF4AII, hPLIC1, nucleolin, PRK2, ${\alpha}$-actinin, and p68 helicase. The interactions of NS5B with these proteins might play roles in cellular trafficking, signal transduction, and RNA polymerization, as well as the regulation of replication/translation processes.

• Journal of Microbiology and Biotechnology
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• v.29 no.7
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• pp.1137-1143
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• 2019

Hepatitis E virus (HEV) accounts for 20 million infections in humans worldwide. In most cases, the infections are self-limiting while HEV genotype 1 infection cases may lead to lethal infections in pregnant women (~ 20% fatality). The lack of small animal models has hampered detailed analysis of virus-host interactions and HEV-induced pathology. Here, by employing a recently developed culture-adapted HEV, we demonstrated that methyltransferase, a non-structural protein, strongly inhibits melanoma differentiation-associated gene 5 (MDA5)-mediated activation of type I interferon responses. Compared to uninfected controls, HEV-infected cells display significantly lower levels of $IFN-{\beta}$ promoter activation when assessed by luciferase assay and RT-PCR. HEV genome-wide screening showed that HEV-encoded methyltransferase (MeT) strongly inhibits MDA5-mediated transcriptional activation of $IFN-{\beta}$ and $NF-{\kappa}B$ in a dose-responsive manner whether or not it is expressed in the presence/absence of a tag fused to it. Taken together, current studies clearly demonstrated that HEV MeT is a novel antagonist of MDA5-mediated induction of $IFN-{\beta}$ signaling.

• IMMUNE NETWORK
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• v.23 no.4
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• pp.30.1-30.18
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• 2023

About 0.8 million people die because of hepatitis B virus (HBV) infection each year. In around 5% of infected adults, the immune system is ineffective in countering HBV infection, leading to chronic hepatitis B (CHB). CHB is associated with hepatocellular carcinoma, which can lead to patient death. Unfortunately, although current treatments against CHB allow control of HBV infection, they are unable to achieve complete eradication of the virus. Cytokines of the IFN family represent part of the innate immune system and are key players in virus elimination. IFN secretion induces the expression of interferon stimulated genes, producing proteins that have antiviral properties and that are essential to cell-autonomous immunity. IFN-α is commonly used as a therapeutic approach for CHB. In addition, IFN-γ has been identified as the main IFN family member responsible for HBV eradication during acute infection. In this review, we summarize the key evidence gained from cellular or animal models of HBV replication or infection concerning the potential anti-HBV roles of IFN-γ with a particular focus on some IFN-γ-inducible genes.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1297-1303
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• 2012

Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-${\beta}$ pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.

• The Journal of Korean Society of Virology
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• v.30 no.2
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• pp.151-159
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• 2000

Hepatitis C virus (HCV) is one of the important human pathogen that can cause acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Recently, the third generation radiation immuno assay (RIA) method has been developed as a very sensitive test to detect anti-HCV antibody. However, false positive is the problem with RIA test. To solve this the RIA results were compared to those of 5-antigen recombinant immunoblot assay (5-RIBA) and reverse transcription-polymerase chain reaction (RT-PCR). Among 12,767 serum samples tested from clinic visitors, total 275 (2.2%) samples were antibody positive by RIA. RIBA was performed with 148 RIA positives cases but among them was shown eighty five was antibody positive and sixty three (42.6%) was negative result. However, nested RT-PCR test was shown also carried out with 43 positive, 6 intermediates and 25 negatives of RIBA. As a result of the nested RT-PCR results, HCV antigen were detected in RIBA positive, 33.3% (2/6) RIBA intermediate and 12% (3/25). Clinical syndrome of all 148 patients as a with chronic active hepatitis (46.0%), cirrhosis (18.9%), hepatocellular carcinoma (8.1%) and others (27.0%) and they were positive in reaction by RIA test. But RIBA positive patients with 34.9% of chronic active hepatitis, 18.6% of cirrhosis, 4.6% of hepatocellular carcinoma and 41.9% of others were detected to be positive case by nested RT-PCR.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.2 no.1
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• pp.109-115
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• 1999

Hepatitis C virus (HCV) has been identified as an important cause of posttransfusion hepatitis, but vertical transmission of chronic infected HCV RNA positive mothers has been documented in some cases. The reports of the risk of perinatal infection have been widely varied in the literature. The authors experienced one case of vertical transmission of HCV in an infant of a mother who had hepatitis C during pregnancy. At admission, HCV RNA (+), Ig G anti HCV (+) and Ig M anti HCV (+) were found in the mother. Also at admission, HCV RNA (+), Ig G anti HCV (+), Ig M anti HCV (+), elevation of liver aminotransferase level and hepatosplenomegaly on ultrasonography were found in the baby on day 31. HCV RNA (-), Ig M anti HCV (-) and normal of liver aminotransferase level were noted on day 250 in the serum of the infant. We used reverse transcriptase polymerase chain reaction (RT-PCR) technique to find a very small amount of HCV RNA in the serum. All the findings suggest vertical transmission of HCV RNA from mother to infant during 3rd trimester of pregnancy.