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5. Association between vitamin D receptor gene polymorphisms and fibrosis susceptibility in Greek patients with HCV infection.

Author

Beka, Angeliki Anna, Papadopoulos, Vasileios, Mylopoulou, Theodora, Panopoulou, Maria, Karakasiliotis, Ioannis, Mavromara, Penelope, Mimidis, Konstantinos, and Veletza, Stavroula

Subjects
VITAMIN D receptors, DISEASE susceptibility, GENETIC polymorphisms, HEPATIC fibrosis, SINGLE nucleotide polymorphisms, CYTOTOXIC T lymphocyte-associated molecule-4
Abstract

Introduction Hepatitis C virus (HCV) infection is a prime cause of chronic hepatitis worldwide, that often silently progresses to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Notably, the majority of individuals infected with HCV develop symptoms at late stages, often associated with liver damage that cannot revert after virus clearance. Thus, current antiviral therapy alone is rather insufficient to eliminate the global burden of HCV in the near future. During the past few years, vitamin D deficiency as well as certain single nucleotide polymorphisms in the vitamin D receptor (VDR) gene have been associated with liver fibrosis. Therefore, the aim of the present study was to investigate the possible correlation between VDR polymorphisms ApaI (rs7975232) and TaqI (rs731236) and the fibrosis stage of patients with HCV infection from Thrace, Greece. Methods Eighty-one patients with HCV infection underwent transient elastography for the assessment of their fibrosis stage, and PCR-restriction fragment length polymorphism (RFLP) genotyping for VDR ApaI and TaqI polymorphisms. VDR genotypes were then statistically associated with the patients' fibrosis stage using ordinal regression models. Results Non-cirrhotic stages were positively correlated with TaqI TT genotype (p=0.003) and negatively correlated with TaqI TC genotype (p=0.007). In the presence of Hardy-Weinberg equilibrium and linkage disequilibrium between the two VDR polymorphisms, mild fibrosis stages (F0-2) were correlated with ApaI/TaqI GG/TT (p=0.002) and TG/TT (p=0.008) genotypes, while cirrhotic stage F4 was associated with ApaI/TaqI TG/TC genotype (p=0.038). Conclusions TaqI TT and ApaI/TaqI GG/TT, TG/TT and TG/TC genotypes could be explored as prognostic genetic markers for fibrosis susceptibility in HCV patients. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Intergenotypic 2k/1b hepatitis C virus recombinants in the East Macedonia and Thrace region of Greece

Author

Kassela, Katerina Karakasiliotis, Ioannis Kokkiou, Eleni and Souvalidou, Fani Mimidis, Panayotis Veletza, Stavroula and Panopoulou, Maria Koskinas, John Mimidis, Konstantinos and Mavromara, Penelope

Subjects
virus diseases, digestive system diseases
Abstract

Background Intergenotypic recombinant hepatitis C virus (HCV) strains emerge rarely during coinfection of the same individual with two HCV genotypes. Few recombinant HCV strains have been identified to date and only one, CRF01 2k/1b, has become a worldwide concern. This study reevaluated the genotyping of three HCV genotype 2 strains from a group of patients with an unusually low rate of sustained virological response after pegylated interferon/ribavirin treatment. In addition, genetic determinants of host interferon resistance were evaluated. Methods The HCV type 2 strains from the patients' serum were subjected to partial sequencing of the core-E1, NS2, NS5A and NS5B regions by reverse transcription polymerase chain reaction. Furthermore, the IFNL3 rs12979860 and the IFNL4 rs368234815 single nucleotide polymorphisms were defined in two of the three patients. Results All three strains were phylogenetically related to the Russia-derived CRF01 2k/1b while they encompassed the exact same 2k/1b junction site within NS2. Conclusion This is the first report of HCV 2k/1b recombinants in Greece and the greater area of the Balkans.

Published
2019

16. Comparison of Dendritic Cell Activation by Virus-Based Vaccine Delivery Vectors Emphasizes the Transcriptional Downregulation of the Oxidative Phosphorylation Pathway

Author

Tsitoura, Eliza, primary, Kazazi, Dorothea, additional, Oz-Arslan, Devrim, additional, Sever, Elif Arik, additional, Khalili, Shirin, additional, Vassilaki, Niki, additional, Aslanoglou, Elina, additional, Dérian, Nicolas, additional, Six, Adrien, additional, Sezerman, Osman Ugur, additional, Klatzmann, David, additional, and Mavromara, Penelope, additional

Published
2019
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17. The Role of Tissue Oxygen Tension in Dengue Virus Replication

Author

Frakolaki, Efseveia, primary, Kaimou, Panagiota, additional, Moraiti, Maria, additional, Kalliampakou, Katerina, additional, Karampetsou, Kalliopi, additional, Dotsika, Eleni, additional, Liakos, Panagiotis, additional, Vassilacopoulou, Dido, additional, Mavromara, Penelope, additional, Bartenschlager, Ralf, additional, and Vassilaki, Niki, additional

Published
2018
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18. High prevalence of antibodies to core+1 /ARF protein in HCV-infected patients with advanced cirrhosis

Author

Kassela, Katerina Karakasiliotis, Ioannis Charpantidis, Stefanos and Koskinas, John Mylopoulou, Theodora Mimidis, Konstantinos and Sarrazin, Christoph Grammatikos, Georgios Mavromara, Penelope

Subjects
digestive system diseases
Abstract

Hepatitis C virus (HCV) possesses a second open reading frame (ORF) within the core gene encoding an additional protein, known as the alternative reading frame protein (ARFP), F or core+1. The biological significance of the core+1/ARF protein remains elusive. However, several independent studies have shown the presence of core+1/ARFP antibodies in chronically HCV-infected patients. Furthermore, a higher prevalence of core+1/ARFP antibodies was detected in patients with HCV-associated hepatocellular carcinoma (HCC). Here, we investigated the incidence of core+1/ARFPantibodies in chronically HCV-infected patients at different stages of cirrhosis in comparison to chronically HCV-infected patients at earlier stages of disease. Using ELISA, we assessed the prevalence of anti-core+1 antibodies in 30 patients with advanced cirrhosis [model for end-stage liver disease (MELD) >= 15] in comparison with 50 patients with mild cirrhosis (MELD

Published
2017

21. Intergenotypic 2k/1b hepatitis C virus recombinants in the East Macedonia and Thrace region of Greece.

Author

Kassela, Katerina, Karakasiliotis, Ioannis, Kokkiou, Eleni, Souvalidou, Fani, Mimidis, Panayotis, Veletza, Stavroula, Panopoulou, Maria, Koskinas, John, Mimidis, Konstantinos, and Mavromara, Penelope

Subjects
HEPATITIS C virus, HEPATITIS C, ELECTRON-transfer catalysis, POLYMERASE chain reaction
Abstract

Background Intergenotypic recombinant hepatitis C virus (HCV) strains emerge rarely during coinfection of the same individual with two HCV genotypes. Few recombinant HCV strains have been identified to date and only one, CRF01 2k/1b, has become a worldwide concern. This study reevaluated the genotyping of three HCV genotype 2 strains from a group of patients with an unusually low rate of sustained virological response after pegylated interferon/ribavirin treatment. In addition, genetic determinants of host interferon resistance were evaluated. Methods The HCV type 2 strains from the patients' serum were subjected to partial sequencing of the core-E1, NS2, NS5A and NS5B regions by reverse transcription polymerase chain reaction. Furthermore, the IFNL3 rs12979860 and the IFNL4 rs368234815 single nucleotide polymorphisms were defined in two of the three patients. Results All three strains were phylogenetically related to the Russia-derived CRF01 2k/1b while they encompassed the exact same 2k/1b junction site within NS2. Conclusion This is the first report of HCV 2k/1b recombinants in Greece and the greater area of the Balkans. [ABSTRACT FROM AUTHOR]

Published
2019
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22. Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3 gene expression by repressing HNF-1 alpha activity

Author

Foka, Pelagia Karamichali, Eirini Dalagiorgou, Georgia and Serti, Elisavet Doumba, Polyxeni P. Pissas, George Kakkanas, Athanassios Kazazi, Dorothea Kochlios, Emmanouil Gaitanou, Maria Koskinas, John Georgopoulou, Urania Mavromara, Penelope

Subjects
digestive system
Abstract

Background & Aims: HCV relies on host lipid metabolism to complete its life cycle and HCV core is crucial to this interaction. Liver secreted ANGPTL-3 is an LXR-and HNF-1 alpha-regulated protein, which plays a key role in lipid metabolism by increasing plasma lipids via inhibition of lipase enzymes. Here we aimed to investigate the modulation of ANGPTL-3 by HCV core and identify the molecular mechanisms involved. Methods: qRT-PCR and ELISA were used to assess ANGPTL-3 mRNA and protein levels in HCV patients, the JFH-1 infectious system and liver cell lines. Transfections, chromatin immunoprecipitation and immunofluorescence delineated parts of the molecular mechanisms implicated in the core-mediated regulation of ANGPTL-3 gene expression. Results: ANGPTL-3 gene expression was decreased in HCV-infected patients and the JFH-1 infectious system. mRNA and promoter activity levels were down-regulated by core. The response was lost when an HNF-1 alpha element in ANGPTL-3 promoter was mutated, while loss of HNF-1 alpha DNA binding to this site was recorded in the presence of HCV core. HNF-1 alpha mRNA and protein levels were not altered by core. However, trafficking between nucleus and cytoplasm was observed and then blocked by an inhibitor of the HNF-1 alpha-specific kinase Mirk/Dyrk1B. Transactivation of LXR/RXR signalling could not restore coremediated down-regulation of ANGPTL-3 promoter activity. Conclusions: ANGPTL-3 is negatively regulated by HCV in vivo and in vitro. HCV core represses ANGPTL-3 expression through loss of HNF-1 alpha binding activity and blockage of LXR/RXR transactivation. The putative ensuing increase in serum lipid clearance and uptake by the liver may sustain HCV virus replication and persistence. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Published
2014

24. Persistence of HCV in Acutely-Infected Patients Depletes C24-Ceramide and Upregulates Sphingosine and Sphinganine Serum Levels

Author

Grammatikos, Georgios, primary, Dietz, Julia, additional, Ferreiros, Nerea, additional, Koch, Alexander, additional, Dultz, Georg, additional, Bon, Dimitra, additional, Karakasiliotis, Ioannis, additional, Lutz, Thomas, additional, Knecht, Gaby, additional, Gute, Peter, additional, Herrmann, Eva, additional, Zeuzem, Stefan, additional, Mavromara, Penelope, additional, Sarrazin, Christoph, additional, and Pfeilschifter, Josef, additional

Published
2016
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26. Novel indole–flutimide heterocycles with activity against influenza PA endonuclease and hepatitis C virus

Author

Zoidis, Grigoris, primary, Giannakopoulou, Erofili, additional, Stevaert, Annelies, additional, Frakolaki, Efseveia, additional, Myrianthopoulos, Vassilios, additional, Fytas, George, additional, Mavromara, Penelope, additional, Mikros, Emmanuel, additional, Bartenschlager, Ralf, additional, Vassilaki, Niki, additional, and Naesens, Lieve, additional

Published
2016
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27. Relationship between antibodies to hepatitis C virus core+1 protein and treatment outcome.

Author

Mylopoulou, Theodora, Papadopoulos, Vasileios, Kassela, Katerina, Karakasiliotis, Ioannis, Souvalidou, Fani, Mimidis, Panagiotis, Veletza, Stavroula, Mavromara, Penelope, and Mimidis, Konstantinos

Subjects
IMMUNOGLOBULINS, HEPATITIS C virus, LIVER cancer
Abstract

Background It has been suggested that hepatitis C virus (HCV) core+1 protein plays a crucial role in the viral life cycle, potentially affecting liver cirrhosis and the development of hepatocellular carcinoma. Methods To investigate its relationship with the outcome of HCV standard combination therapy with peginterferon-a plus ribavirin, we screened 139 consecutive HCV patients (119 with chronic HCV infection and 20 who spontaneously cleared HCV) for the presence of anti-core+1 antibodies (Abs). In addition, liver fibrosis was determined by FibroScan in all but one patients. Results Twenty-nine patients were cirrhotic (stiffness >12.5 kPa, F4 METAVIR), all of them with mild liver cirrhosis (Child-Pugh score A). Eighty-six of 139 patients were treatment-experienced with standard combination therapy. Fifty of them had achieved a sustained virological response, while 36 were non-responders. The prevalence of anti-core+1 Abs in patients with chronic HCV infection was 22.69% (27/119 patients): 18% (9/50 patients) in responders and 36.11% (13/36 patients) in non-responders (P=0.050). Five (17.24%) of the 29 cirrhotic patients and 22 (24.72%) of the 89 non-cirrhotic patients were positive for anti-core+1 Abs (P=0.405). Furthermore, the presence of anti-core+1 Abs correlated with the poor response interleukin (IL) 28B genotype TT (P=0.040). No correlation between spontaneous clearance and anti-core+1 Abs was observed (P=0.088). Conclusion The presence of anti-core+1 Abs might be correlated with the poor response IL28B TT genotype and may negatively affect the outcome of standard combination treatments in HCV patients, suggesting that core+1 may play a biological role in the course of HCV infection. [ABSTRACT FROM AUTHOR]

Published
2018
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28. Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase

Author

Serti, Elisavet Doumba, Polyxeni P. Thyphronitis, George and Tsitoura, Panagiota Katsarou, Konstantina Foka, Pelagia and Konstandoulakis, Manousos M. Koskinas, John Mavromara, Penelope and Georgopoulou, Urania

Abstract

Hepatitis C virus (HCV) has been shown to actively replicate in cells of the immune system, altering both their function and cytokine expression. Naked nucleocapsids have been reported in the serum of infected patients. We investigated interference of recombinant non-enveloped capsid-like particles with signaling pathways in T cells. HCV non-enveloped particles (HCVne) internalization was verified in Jurkat and Hut 78 T cells, as well as primary human peripheral blood and intrahepatic mononuclear cells. HCVne uptake leads to activation of the MAPKs-p38 signaling pathway. Using specific phosphoantibodies, signaling pathways inhibitors, and chemical agents, it was demonstrated that p38 activation in T cells correlated with IL-2 transcriptional activation and was accompanied by a parallel increase of IL-2 cytokine secretion. c-fos and egr-1, two transcription factors, essential for IL-2 promoter activity, were also found to be elevated. We propose that HCVne uptake by T lymphocytes results in increased MAPKs-p38 activity and IL-2 expression, thus altering the host immune response.

Published
2011

32. Novel tumour-specific promoters for transcriptional targeting of hepatocellular carcinoma by herpes simplex virus vectors

Author

Foka, Pelagia Pourchet, Aldo Hernandez-Alcoceba, Ruben and Doumba, Polyxeni P. Pissas, George Kouvatsis, Vlassis and Dalagiorgou, Georgia Kazazi, Dorothea Marconi, Peggy and Foschini, Mariagiovanna Manservigi, Roberto Konstadoulakis, Manousos M. Koskinas, John Epstein, Alberto L. Mavromara, Penelope

Subjects
digestive system diseases
Abstract

Background Hepatocellular carcinoma (HCC) is a cancer of poor prognosis, with limited success in patient treatment, which it makes an excellent target for gene therapy and viral oncolysis. Accordingly, herpes virus simplex type-1 (HSV-1) is one of the most promising viral platforms for transferring therapeutic genes and the development of oncolytic vectors that can target, multiply in, and eradicate hepatoma cells via their lytic cycle. Enhanced efficacy and specificity of HSV-1-based vectors towards HCC may be achieved by using HCC-specific gene promoters to drive selective viral gene expression and accomplish conditional replication and/or to control the expression of therapeutic genes. However, careful verification of promoter function in the context of the replication-competent HSV-1 vectors is required. The present study aimed to identify novel HCC-specific promoters that could efficiently direct transgene expression to HCC cells and maintain their activity during active viral replication. Methods Publicly available microarray data from human HCC biopsies were analysed in order to detect novel candidate genes induced primarily in HCC compared to normal liver. HCC specificity and promoter activity were evaluated by RT-PCR and chromatin immunoprecipitation. Additionally, transcriptional activity of promoters was further evaluated in the context of HSV-1 genome, using luciferase assays in cultured cells and animal models. Results Eight HCC-specific genes were characterised in this study: Angiopoietin-like-3, Cytochrome P450, family 2, subfamily C, polypeptide 8, Vitronectin, Alcohol dehydrogenase 6-class V, Apolipoprotein B, Fibrinogen beta chain, Inter-alpha-globulin-inhibitor H3 and Inter-alpha-globulin-inhibitor H1. Specific HCC expression and active gene transcription were confirmed in human liver and non-liver cell lines and further evaluated in primary neoplastic cells from hepatitis C and B virus (HCV-and HBV)-associated HCC patients. High promoter activity and specificity in the presence of HSV-1 infection and from within the viral genome, was validated, both in vitro and in vivo. Conclusions We identified and experimentally characterized novel hepatoma-specific promoters, which were valuable for cancer-specific gene therapy, using HSV-1 vectors. Copyright (c) 2010 John Wiley & Sons, Ltd.

Published
2010

35. Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3 gene expression by repressing HNF-1α activity

Author

Foka, Pelagia, primary, Karamichali, Eirini, additional, Dalagiorgou, Georgia, additional, Serti, Elisavet, additional, Doumba, Polyxeni P., additional, Pissas, George, additional, Kakkanas, Athanassios, additional, Kazazi, Dorothea, additional, Kochlios, Emmanouil, additional, Gaitanou, Maria, additional, Koskinas, John, additional, Georgopoulou, Urania, additional, and Mavromara, Penelope, additional

Published
2014
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37. Correction: Synonymous Mutations in the Core Gene Are Linked to Unusual Serological Profile in Hepatitis C Virus Infection

Author

Budkowska, Agata, primary, Kakkanas, Athanassios, additional, Nerrienet, Eric, additional, Kalinina, Olga, additional, Maillard, Patrick, additional, Horm, Srey Viseth, additional, Dalagiorgou, Geena, additional, Vassilaki, Niki, additional, Georgopoulou, Urania, additional, Martinot, Michelle, additional, Sall, Amadou Alpha, additional, and Mavromara, Penelope, additional

Published
2011
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38. Synonymous Mutations in the Core Gene Are Linked to Unusual Serological Profile in Hepatitis C Virus Infection

Author

Budkowska, Agata, primary, Kakkanas, Athanassios, additional, Nerrienet, Eric, additional, Kalinina, Olga, additional, Maillard, Patrick, additional, Horm, Srey Viseth, additional, Dalagiorgou, Geena, additional, Vassilaki, Niki, additional, Georgopoulou, Urania, additional, Martinot, Michelle, additional, Sall, Amadou Alpha, additional, and Mavromara, Penelope, additional

Published
2011
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40. Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase

Author

Serti, Elisavet, primary, Doumba, Polyxeni P., additional, Thyphronitis, George, additional, Tsitoura, Panagiota, additional, Katsarou, Konstantina, additional, Foka, Pelagia, additional, Konstandoulakis, Manousos M., additional, Koskinas, John, additional, Mavromara, Penelope, additional, and Georgopoulou, Urania, additional

Published
2010
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41. Hepatitis C Virus Controls Interferon Production through PKR Activation

Author

Arnaud, Noëlla, primary, Dabo, Stéphanie, additional, Maillard, Patrick, additional, Budkowska, Agata, additional, Kalliampakou, Katerina I., additional, Mavromara, Penelope, additional, Garcin, Dominique, additional, Hugon, Jacques, additional, Gatignol, Anne, additional, Akazawa, Daisuke, additional, Wakita, Takaji, additional, and Meurs, Eliane F., additional

Published
2010
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44. Green fluorescent protein – Tagged HCV non-enveloped capsid like particles: Development of a new tool for tracking HCV core uptake

Author

Katsarou, Konstantina, primary, Serti, Elisavet, additional, Tsitoura, Panagiota, additional, Lavdas, Alexandros A., additional, Varaklioti, Agoritsa, additional, Pickl-Herk, Angela-Maria, additional, Blaas, Dieter, additional, Oz-Arslan, Devrim, additional, Zhu, Rong, additional, Hinterdorfer, Peter, additional, Mavromara, Penelope, additional, and Georgopoulou, Urania, additional

Published
2009
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