Special Issue "Hepatitis C Pathology"

Guest Editor
Dr. Birke Bartosch
Centre de recherche en cancérologie de Lyon, UMR 5286, UMR_S 1052, Equipe 15, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France
E-Mail: birke.bartosch@inserm.fr
Phone: +33 472681975
Fax: +33 472681971
Interests: flavivirus; hepatitis C virus; hepatitis B virus; virus-host cell interactions; hepatology; liver physiopathology; antivirals

Worldwide approximately 130 million people are thought to be infected with hepatitis C virus (HCV). HCV frequently induces chronic liver disease and on the long term cirrhosis and hepatocellular carcinoma. The major clinical manifestations of chronic hepatitis C comprise steatosis, insulin resistance and type 2 diabetes. Mounting evidence suggests that HCV reprograms it’s host metabolism and modulates immune responses. These alterations contribute to the establishment of a liver microenvironment that is favorable for persistent viral replication, but that is also characterized by increased levels of oxidative stress, altered cytokine patterns and inflammatory responses that can trigger auto-immunity as well as fibrosis and ultimately hepatocarcinogenesis. Unraveling the interactions between HCV and its host and the consequential effects on the liver microenvironment and disease progression is an important task in the field. Understanding these events will help to improve therapy and patient care.

Investigators are invited to contribute original research articles or reviews that help us to understand the molecular pathology of chronic hepatitis C with a particular focus on disease progression in respect to:

Type of Paper: Article
Title: Hepatitis C Virus NS5A Protein Induces Suppression Of p21: A Possible Mechanism for HCV-Mediated HCC Progression
Authors: Manal A. Eid ¹, Azza M. Abdu Allah ^2,*, Kawthar I. Mohammed ³, Sahar El Adawy ⁴, Seham Sabry ⁴ and Sahar A.F. Hammoudah ¹
Affiliations: ¹ Department of Clinical Pathology, Tanta University, Egypt; E-Mail: manaleid@hotmail.com
² Department of Medical Biochemistry, Faculty of Medicine, Menoufya University, Egypt; E-Mail: ommiar_2003@hotmail.com
³ Department of Medical Microbiology and Immunology, Faculty of Medicine, Ain Shams University. Egypt. E-Mail: Kawthar_75@yahoo.com
⁴ Department of Internal Medicine, Faculty of Medicine, Al Azhar University, Egypt; E-Mail: drsahar25@yahoo.com
⁴ Department of Internal Medicine, Faculty of Medicine, Al Azhar University, Egypt; E-Mail: drseham4@yahoo.com
¹ Department of Clinical Pathology, Tanta University, Egypt; E-Mail: saharfathi2011@yahoo.com
* Author to whom correspondence should be addressed; E-Mail: ommiar_2003@hotmail.com Tel.: 009665560875954-0020483670876.
Abstract: Development of chronic hepatitis and a potential for disease progression to hepatocellular carcinoma are important clinical features of HCV infection. Recent studies suggested that hepatitis C virus NS5A protein plays an important role in promoting cell growth. NS5A is likely to exert its activity in concert with p53 and p21 genes as well as other cellular transcription factors. Therefore, we investigated the effect of chronic HCV infection on p53 and p21 protein expression. Our study was conducted on 102 patients with chronic HCV infection and 22 reference controls. The results demonstrated that hepatitis C virus transcriptionally represses p21/Waf1 gene. Western analysis revealed decreased p21 protein in chronic HCV infection. However, no change in p53 protein level was observed. Further immunopricipitation analysis suggested that HCV-induced repression of p21 could be mediated by inactivation of p53 function through direct physical association with NS5A viral protein. Together, our work highlight the possibility that persistent perturbation of p53/p21 activity by HCV NS5A protein during chronic infection may have a critical consequence in HCV pathogenesis.
Keywords: HCV; p21;p53;HCC

Type of Paper: Review
Title: The B Cell-disorders in Patients with Chronic Hepatitis C
Authors: Takayoshi Ito, Momoko Inokuchi, Yuu Shimozuma, Manabu Uchikoshi, Miyuki Miyashita, Jun Arai, Kenichi Morikawa, Hisako Nozawa, Tomoe Shimazaki and Michio Imawari
Affiliations: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
Abstract: Hepatitis C virus (HCV) infection induces not only liver diseases but also the variety of B cell-disorders, such as lymphoproliferative disorders and autoimmune diseases. Detail mechanism to develop these disorders has not been fully clarified, but recently infection and/or association with B cells were demonstrated to lead to the abnormal B cell activation and development of such B cell-disorders. HCV RNA is detected in B cells from 64.0% of patients with chronic hepatitis C, and negative-strand HCV RNA in 5.3% of these patients. These results indicate that B cell-tropic HCV exists and may play an important role in the immunological dysfunction of B cells. Furthermore, this immune perturbation is in turn associated with the resistance of HCV against host immune systems and viral persistence. Here, we review the evidence of B cell-disorders in patients with chronic hepatitis C and discuss the possibility that this B cell-disorders affect the viral persistence and efficacy of antiviral therapy.

Type of Paper: Review
Title: Hepatitis C Virus, Cholesterol and Lipoproteins - Impact for the Viral Life Cycle and Pathogenesis of Liver Disease
Authors: Daniel J. Felmlee ^1,2, Mohamed-Lamine Hafirassou ^1,2, Thomas F. Baumert ^1,2,3, Catherine Schuster ^1,2
Affiliations: ¹ Inserm, U748, Strasbourg, France, ² Université de Strasbourg, Strasbourg, France, ³Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Abstract: Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles.  Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement and cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
Keywords: Hepatitis C virus, lipoproteins, apolipoproteins, apoE, apoB, cholesterol, triglyceride, viral attachment, entry, assembly, secretion, viral immune escape, lipid disorder.

Type of Paper: Review
Title: Host Genetic Variants in the Pathogenesis of Hepatitis C
Authors: Monika, Rau ¹, Katharina Baur ², and Andreas, Geier ^1,2
Affiliations: ¹ Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Germany, ² Laboratory for Molecular Hepatology, Department of Gastroenterology and Hepatology, USZ, Zurich, Switzerland
Abstract: Direct-acting antiviral drugs are currently replacing antiviral therapy for hepatitis c infection. Treatment related side effects are even worsened and the emergence of resistant viruses must be avoided because of the direct-antiviral acting. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In the last years different genetic variants are published with a strong association to therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects such as hemolytic anemia associations to genetic variants of inosine triphosphatase (ITPA) are described and different SLC28 transporters for RBV-uptake are successfully analyzed. Fibrosis progression has been associated to a growing number of modifier genes including variants of vitamin d receptor and bile salt export pump (ABCB11). Especially cirrhotic patients have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review will focus on different host genetic variants in the pathogenesis and treatment response of hepatitis C at the beginning of a new treatment area.

Type of Paper: Review
Title: Hepatitis C Virus and natural compounds: a new antiviral approach?
Authors: Noémie Calland, Jean Dubuisson, Yves Rouillé and Karin Séron
Affiliations: Center for Infection and Immunity of Lille, Inserm U1019, CNRS UMR8204, Institut Pasteur de Lille, Université Lille Nord de France, F-59019 Lille, France
Abstract: Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading (?) to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based on pegylated interferon and ribavirin, was partially effective, and had negative side effects. With recent advances in the understanding of the HCV life cycle, the development of promising direct acting antivirals (DAAs) has been achieved. Their use in combination with the current treatment has led to encouraging results for HCV genotype 1 patients. However, this therapy is quite expensive and will probably not be accessible for all patients worldwide. For this reason, constant efforts are being made to identify new antiviral molecules. Recent reports about natural compounds highlight their antiviral activity against HCV. Here, we aim to review the natural molecules that interfere with the HCV life cycle and discuss their potential use in HCV therapy.

Type of Paper: Review
Title: Pathogenesis of Hepatitis C During Pregnancy and Childhood
Authors : Armelle Le Campion and Hugo Soudeyns
Affiliations: Unité d'immunopathologie virale, Centre de recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, local 6735, Montréal (Québec) H3T 1C5, Canada ; Tél.: +1 514 345-4931 x3907, Fax: +1 514 345-4794 ; E-Mail : hugo.soudeyns@recherche-ste-justine.qc.ca
Abstract: The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), the leading cause of pediatric HCV infection, takes place at a rate of approximately 5%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at present because both pegylated interferon alpha and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this situation may change with the recent introduction of direct acting antiviral agents. This review will summarize what is currently known about HCV infection during pregnancy and childhood.  Particular emphasis will be placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child.

Type of Paper: Article
Title: Hepatitis C Virus and hepatocyte polarity.
Authors: Benedicto I ^1,2, Molina-Jiménez F ¹, Gondar V ₁, López-Cabrera M ^2,3, Majano PL ^1,2
Affiliations: ¹Molecular Biology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid 28006, Spain. ²CIBERehd, Instituto de Salud Carlos III, Madrid 28029, Spain. ³Centro de Biología Molecular Severo Ochoa (CBM-SO), CSIC-UAM, Madrid 28049, Spain.
Abstract: Hepatocytes, the main target of hepatitis C virus (HCV), are highly polarized cells in which their basolateral and apical domains, separated by Tight junctions (TJs), are in contact with blood and bile, respectively. TJs are macromolecular complexes that enable the maintenance of structural and functional polarity in epithelial cells. In addition, they constitute the first defensive barrier that prevents the entry of most infectious agents into the body. However, some pathogens are able to use or modify these structures in order to enter the host cell, contributing to some aspects of the infection-associated pathology. It has been established a relationship between HCV and TJs, not only in terms of virus-induced cellular alterations but also regarding the usage of TJ-associated proteins as entry factors. However, it has been proposed that polarity itself restricts HCV infection. Herein, we summarize the current knowledge about the link among HCV, TJs and hepatocyte polarity, and hypothesize how cellular polarization may affect different phases of the viral cycle. A deep understanding of the complex relationship between cellular polarity and HCV infection is of considerable significance to both hepatocyte physiology and the pathogenesis of HCV-associated liver diseases.

Type of Paper: Review
Title: Hepatitis C Virus and Cellular Stress Response: Implications to Molecular Pathogenesis of Liver Diseases
Authors: Po-Yuan Ke¹ and Steve Chen²
Affiliations: _^1. Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
^2. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China
E-mail: schen@ibms.sinica.edu.tw
Abstract: Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of human population infected worldwide, HCV infection is a global public health challenge. The efficacy of current therapy is still limited in many patients infected with HCV, thus a greater understanding of pathogenesis in HCV infection is necessarily needed. Emerging lines of evidence indicate that HCV triggers a wide range of cellular stress response, including cell cycle arrest, apoptosis, endoplasmic reticulum stress/unfolded protein response, and autophagy. Also, recent studies suggest that these HCV-induced cellular responses may contribute to chronic liver diseases by modulating cell proliferation, altering lipid metabolism, and potentiating oncogenic pathways. However, the detailed molecular mechanism underlying HCV infection to the pathogenesis of chronic liver diseases still remain determined. Here, we review the known stress response activation in HCV infection from in vivo and in vitro models, and also explore the possible relationship of a variety of cellular responses with the pathogenecity of HCV-associated diseases. Comprehensive knowledge of HCV-mediated disease progression shall shed new insights into the discovery of novel therapeutic targets and the development of new intervention strategy.