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Hepatitis C virus vaccine design: focus on the humoral immune response. J Biomed Sci 2020; 27:78. [PMID: 32631318 PMCID: PMC7338099 DOI: 10.1186/s12929-020-00669-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the recent development of safe and highly effective direct-acting antivirals, hepatitis C virus (HCV) infection remains a significant health problem. In 2016, the World Health Organization set out to reduce the rate of new HCV infections by 90% by 2030. Still, global control of the virus does not seem to be achievable in the absence of an effective vaccine. Current approaches to the development of a vaccine against HCV include the production of recombinant proteins, synthetic peptides, DNA vaccines, virus-like particles, and viral vectors expressing various antigens. In this review, we focus on the development of vaccines targeting the humoral immune response against HCV based on the cumulative evidence supporting the important role of neutralizing antibodies in protection against HCV infection. The main targets of HCV-specific neutralizing antibodies are the glycoproteins E1 and E2. Recent advances in the knowledge of HCV glycoprotein structure and their epitopes, as well as the possibility of getting detailed information on the human antibody repertoire generated by the infection, will allow rational structure-based antigen design to target specific germline antibodies. Although obtaining a vaccine capable of inducing sterilizing immunity will be a difficult task, a vaccine that prevents chronic hepatitis C infections, a more realistic goal in the short term, would have a considerable health impact.
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2
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Olbrich A, Wardemann H, Böhm S, Rother K, Colpitts CC, Wrensch F, Baumert TF, Berg T, Benckert J. Repertoire and Neutralizing Activity of Antibodies Against Hepatitis C Virus E2 Peptide in Patients With Spontaneous Resolution of Hepatitis C. J Infect Dis 2020; 220:1209-1218. [PMID: 31165162 DOI: 10.1093/infdis/jiz274] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 06/03/2019] [Indexed: 12/15/2022] Open
Abstract
Neutralizing antibodies can prevent hepatitis C virus (HCV) infection, one of the leading causes of cirrhosis and liver cancer. Here, we characterized the immunoglobulin repertoire of memory B-cell antibodies against a linear epitope in the central front layer of the HCV envelope (E2; amino acids 483-499) in patients who were infected in a single-source outbreak. A reverse transcription polymerase chain reaction-based immunoglobulin gene cloning and recombinant expression approach was used to express monoclonal antibodies from HCV E2 peptide-binding immunoglobulin G-positive memory B cells. We identified highly mutated antibodies with a neutralizing effect in vitro against different genotype isolates sharing similar gene features. Our data confirm the importance of VH1-69 use for neutralizing activity. The data offer a promising basis for vaccine research and the use of anti-E2 antibodies as a means of passive immunization.
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Affiliation(s)
- Anne Olbrich
- Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Hedda Wardemann
- Division of B Cell Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Stephan Böhm
- Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.,Max von Pettenkofer Institute, Munich, Germany
| | - Karen Rother
- Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Che C Colpitts
- Inserm U1110, University of Strasbourg, France.,Division of Infection and Immunity, University College London, United Kingdom
| | - Florian Wrensch
- Clinic for Hepatology and Gastroenterology, Charité, CVK, Berlin, Germany
| | - Thomas F Baumert
- Clinic for Hepatology and Gastroenterology, Charité, CVK, Berlin, Germany
| | - Thomas Berg
- Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Julia Benckert
- Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.,Inserm U1110, University of Strasbourg, France
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3
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Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
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Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
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Hepatitis C virus may have an entero-hepatic cycle which could be blocked with ezetimibe. Med Hypotheses 2017; 102:51-55. [PMID: 28478831 DOI: 10.1016/j.mehy.2017.03.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/08/2017] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus can lead to chronic infection, cirrhosis and hepatocellular carcinoma. With more than 170 million people infected worldwide, eradication remains a challenge even with the revolutionary current direct antiviral agents (DAAs). The risk of resistance, the safety profile in some populations, the genotype specificity and the high price of current DAAs explain why there is still interest in developing host targeting agents (HTA) that may help overcome some of these difficulties. Specifically, targeting the entry of HCV to the cell seems like a promising strategy. Recently it has been shown that the cholesterol transporter NPC1L1, a protein located in the small bowel epithelium and in the canalicular membrane of the hepatocyte is also an HCV receptor. Just as this protein is key in the entero-hepatic cycle of cholesterol, we hypothesize that there is an entero-hepatic cycle of HCV that could be disrupted by blocking NPC1L1 with ezetimibe, an already approved and readily available safe drug. Ezetimibe, either alone or in combination with DAAs, could decrease relapse rates, reduce resistance and even make treatments cheaper.
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Monrroy H, Angulo J, Pino K, Labbé P, Miquel JF, López-Lastra M, Soza A. Detection of high biliary and fecal viral loads in patients with chronic hepatitis C virus infection. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 40:339-347. [PMID: 28249699 DOI: 10.1016/j.gastrohep.2017.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The life cycle of the hepatitis C virus (HCV) is closely associated with lipid metabolism. Recently, NPC1L1 (a cholesterol transporter) has been reported to function as an HCV receptor. This receptor is expressed in the hepatocyte canalicular membrane and in the intestine; serving as a key transporter for the cholesterol enterohepatic cycle. OBJECTIVES We hypothesized that HCV might have a similar cycle, so we aimed to study the presence of HCV in bile and stools of infected patients. MATERIALS AND METHODS Blood, feces, and duodenal bile samples were collected from patients infected with HCV. The biliary viral load was normalized to the bile salt concentration of each sample and the presence of HCV core protein was also evaluated. A total of 12 patients were recruited. HCV RNA was detected in the bile from ten patients. RESULTS The mean viral load was 2.5log10IU/60mg bile salt. In the stool samples, HCV RNA was detected in ten patients (mean concentration 2.7log10IU/g of feces). CONCLUSIONS HCV RNA is readily detectable and is present at relatively high concentrations in the bile and stool samples of infected patients. This may be relevant as a source of infection in men who have sex with men. Biliary HCV secretion may perhaps play a role in the persistence of viral infection via an enterohepatic cycle of the virus or intrahepatic spread.
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Affiliation(s)
- Hugo Monrroy
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Chile
| | - Jenniffer Angulo
- Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
| | - Karla Pino
- Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
| | - Pilar Labbé
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Chile
| | | | - Marcelo López-Lastra
- Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
| | - Alejandro Soza
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Chile.
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Comprehensive mapping of antigen specific T cell responses in hepatitis C virus infected patients with or without spontaneous viral clearance. PLoS One 2017; 12:e0171217. [PMID: 28170421 PMCID: PMC5295680 DOI: 10.1371/journal.pone.0171217] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 01/18/2017] [Indexed: 12/28/2022] Open
Abstract
Elucidating protective immunity against HCV is important for the development of a preventative vaccine. We hypothesize that spontaneous resolution of acute HCV infection offers clue to protective immune responses, and that DAA therapy affects the quality and quantity of HCV-specific T cell responses. To test these hypotheses, we performed T cell epitope mapping in 111 HCV-infected individuals including 61 chronically HCV-1b (CHC-1b) infected, 24 chronically HCV-2a (CHC-2a) infected and 26 spontaneously recovered (SPR) patients with 376 overlapping peptides covering the entire HCV polyprotein. Selected T cell epitopes were then used to evaluate T cell responses in another 22 chronically HCV-1b infected patients on DAA therapy. Results showed that SPR had better HCV-specific T cell responses than CHC, as manifested by higher response rate, greater magnitude and broader epitope coverage. In addition, SPR recognized novel epitopes in Core, E1, E2, NS4B, NS5A regions that were not present in the CHC. Furthermore, during the first 24 weeks of DAA therapy, there was no functional immune reconstitution of HCV-specific T cells. These results indicate that T cell responses may be a correlate of protection. Therefore, effective preventative vaccines should elicit a robust T cell response. Although various DAA regimens efficiently cleared viruses from the blood of HCV-infected patients, there was no contemporaneous early T cell immune reconstitution, suggesting that early treatment is needed for preserving the functions of HCV-specific T cells.
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Abdel-Hady KM, Gutierrez AH, Terry F, Desrosiers J, De Groot AS, Azzazy HME. Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development. Hum Vaccin Immunother 2015; 10:2366-77. [PMID: 25424944 DOI: 10.4161/hv.29177] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
With over 150 million people chronically infected worldwide and millions more infected annually, hepatitis C continues to pose a burden on the global healthcare system. The standard therapy of hepatitis C remains expensive, with severe associated side effects and inconsistent cure rates. Vaccine development against the hepatitis C virus has been hampered by practical and biological challenges posed by viral evasion mechanisms. Despite these challenges, HCV vaccine research has presented a number of candidate vaccines that progressed to phase II trials. However, those efforts focused mainly on HCV genotypes 1 and 2 as vaccine targets and barely enough attention was given to genotype 4, the variant most prevalent in the Middle East and central Africa. We describe herein the in silico identification of highly conserved and immunogenic T-cell epitopes from the HCV genotype 4 proteome, using the iVAX immunoinformatics toolkit, as targets for an epitope-driven vaccine. We also describe a fast and inexpensive approach for results validation using the empirical data on the Immune Epitope Database (IEDB) as a reference. Our analysis identified 90 HLA class I epitopes of which 20 were found to be novel and 19 more had their binding predictions retrospectively validated; empirical data for the remaining 51 epitopes was insufficient to validate their binding predictions. Our analysis also identified 14 HLA class II epitopes, of which 8 had most of their binding predictions validated. Further investigation is required regarding the efficacy of the identified epitopes as vaccine targets in populations where HCV genotype 4 is most prevalent.
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Affiliation(s)
- Karim M Abdel-Hady
- a Department of Chemistry; School of Sciences and Engineering; The American University in Cairo; New Cairo, Egypt
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8
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Characterization of hepatitis C virus interaction with heparan sulfate proteoglycans. J Virol 2015; 89:3846-58. [PMID: 25609801 DOI: 10.1128/jvi.03647-14] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) entry involves binding to cell surface heparan sulfate (HS) structures. However, due to the lipoprotein-like structure of HCV, the exact contribution of virion components to this interaction remains controversial. Here, we investigated the relative contribution of HCV envelope proteins and apolipoprotein E in the HS-binding step. Deletion of hypervariable region 1, a region previously proposed to be involved in HS binding, did not alter HCV virion binding to HS, indicating that this region is not involved in this interaction in the context of a viral infection. Patient sera and monoclonal antibodies recognizing different regions of HCV envelope glycoproteins were also used in a pulldown assay with beads coated with heparin, a close HS structural homologue. Although isolated HCV envelope glycoproteins could interact with heparin, none of these antibodies was able to interfere with the virion-heparin interaction, strongly suggesting that at the virion surface, HCV envelope glycoproteins are not accessible for HS binding. In contrast, results from kinetic studies, heparin pulldown experiments, and inhibition experiments with anti-apolipoprotein E antibodies indicated that this apolipoprotein plays a major role in HCV-HS interaction. Finally, characterization of the HS structural determinants required for HCV infection by silencing of the enzymes involved in the HS biosynthesis pathway and by competition with modified heparin indicated that N- and 6-O-sulfation but not 2-O-sulfation is required for HCV infection and that the minimum HS oligosaccharide length required for HCV infection is a decasaccharide. Together, these data indicate that HCV hijacks apolipoprotein E to initiate its interaction with specific HS structures. IMPORTANCE Hepatitis C is a global health problem. Hepatitis C virus (HCV) infects approximately 130 million individuals worldwide, with the majority of cases remaining undiagnosed and untreated. In most infected individuals, the virus evades the immune system and establishes a chronic infection. As a consequence, hepatitis C is the leading cause of cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. Virus infection is initiated by entry of the virus into the host cell. In this study, we provide new insights into the viral and cellular determinants involved in the first step of HCV entry, the binding of the virus to host cells. We show that apolipoprotein E is likely responsible for virus binding to heparan sulfate and that N- and 6-O-sulfation of the heparan sulfate proteoglycans is required for HCV infection. In addition, the minimal HS length unit required for HCV infection is a decasaccharide.
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Larrubia JR, Moreno-Cubero E, Lokhande MU, García-Garzón S, Lázaro A, Miquel J, Perna C, Sanz-de-Villalobos E. Adaptive immune response during hepatitis C virus infection. World J Gastroenterol 2014; 20:3418-3430. [PMID: 24707125 PMCID: PMC3974509 DOI: 10.3748/wjg.v20.i13.3418] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 09/28/2013] [Accepted: 11/29/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.
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Different requirements for scavenger receptor class B type I in hepatitis C virus cell-free versus cell-to-cell transmission. J Virol 2013; 87:8282-93. [PMID: 23698298 DOI: 10.1128/jvi.01102-13] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is believed to initially infect the liver through the basolateral side of hepatocytes, where it engages attachment factors and the coreceptors CD81 and scavenger receptor class B type I (SR-BI). Active transport toward the apical side brings the virus in close proximity of additional entry factors, the tight junction molecules claudin-1 and occludin. HCV is also thought to propagate via cell-to-cell spread, which allows highly efficient virion delivery to neighboring cells. In this study, we compared an adapted HCV genome, clone 2, characterized by superior cell-to cell spread, to its parental genome, J6/JFH-1, with the goal of elucidating the molecular mechanisms of HCV cell-to-cell transmission. We show that CD81 levels on the donor cells influence the efficiency of cell-to-cell spread and CD81 transfer between neighboring cells correlates with the capacity of target cells to become infected. Spread of J6/JFH-1 was blocked by anti-SR-BI antibody or in cells knocked down for SR-BI, suggesting a direct role for this receptor in HCV cell-to-cell transmission. In contrast, clone 2 displayed a significantly reduced dependence on SR-BI for lateral spread. Mutations in E1 and E2 responsible for the enhanced cell-to-cell spread phenotype of clone 2 rendered cell-free virus more susceptible to antibody-mediated neutralization. Our results indicate that although HCV can lose SR-BI dependence for cell-to-cell spread, vulnerability to neutralizing antibodies may limit this evolutionary option in vivo. Combination therapies targeting both the HCV glycoproteins and SR-BI may therefore hold promise for effective control of HCV dissemination.
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Habersetzer F, Leboeuf C, Doffoël M, Zeisel MB, Baumert TF. Synthetic anti-lipopolysaccharide peptides and hepatitis C virus infection. Expert Opin Investig Drugs 2013; 22:853-62. [PMID: 23634817 DOI: 10.1517/13543784.2013.794218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges. AREAS COVERED This article focuses and comments on the recent development of synthetic anti-lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity. EXPERT OPINION SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology.
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New insights in recurrent HCV infection after liver transplantation. Clin Dev Immunol 2013; 2013:890517. [PMID: 23710205 PMCID: PMC3655463 DOI: 10.1155/2013/890517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 03/17/2013] [Accepted: 03/31/2013] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome.
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Shi C, Ploss A. Hepatitis C virus vaccines in the era of new direct-acting antivirals. Expert Rev Gastroenterol Hepatol 2013; 7:171-85. [PMID: 23363265 DOI: 10.1586/egh.12.72] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is a major global health problem as it has a high propensity for establishing chronicity. Chronic HCV carriers are at risk of developing severe liver disease including fibrosis, cirrhosis and liver cancer. While treatment has considerably improved over the years, therapy is still only partially effective, and is plagued by side effects, which contribute to treatment failure and is expensive to manage. The drug development pipeline contains several compounds that hold promise to achieve the goal of a short and more tolerable therapy, and are also likely to improve treatment response rates. It remains to be seen, however, how potent antiviral drug cocktails will affect the hepatitis C burden worldwide. In resource-poor environments, considerable costs, inadequate infrastructure for medical supervision and distribution may diminish the impact of future therapies. Consequently, development of novel therapeutic and prophylactic strategies is imperative to contain HCV infection globally.
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Affiliation(s)
- Chao Shi
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
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14
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FOFANA ISABEL, FAFI–KREMER SAMIRA, CAROLLA PATRIC, FAUVELLE CATHERINE, ZAHID MUHAMMADNAUMAN, TUREK MARINE, HEYDMANN LAURA, CURY KARINE, HAYER JULIETTE, COMBET CHRISTOPHE, COSSET FRANÇOIS, PIETSCHMANN THOMAS, HIET MARIE, BARTENSCHLAGER RALF, HABERSETZER FRANÇOIS, DOFFOËL MICHEL, KECK ZHEN, FOUNG STEVENKH, ZEISEL MIRJAMB, STOLL–KELLER FRANÇOISE, BAUMERT THOMASF. Mutations that alter use of hepatitis C virus cell entry factors mediate escape from neutralizing antibodies. Gastroenterology 2012; 143:223-233.e9. [PMID: 22503792 PMCID: PMC5295797 DOI: 10.1053/j.gastro.2012.04.006] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 03/14/2012] [Accepted: 04/06/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion. METHODS We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture-derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors. RESULTS By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus-antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general. CONCLUSIONS We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines.
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Affiliation(s)
- ISABEL FOFANA
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - SAMIRA FAFI–KREMER
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
,Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - PATRIC CAROLLA
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - CATHERINE FAUVELLE
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | | | - MARINE TUREK
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - LAURA HEYDMANN
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - KARINE CURY
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - JULIETTE HAYER
- Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086, Centre National de la Recherche Scientifique, Université de Lyon, Institut de Biologie et Chimie des Proteines, Lyon, France
| | - CHRISTOPHE COMBET
- Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086, Centre National de la Recherche Scientifique, Université de Lyon, Institut de Biologie et Chimie des Proteines, Lyon, France
| | - FRANÇOIS–LOÏC COSSET
- Université de Lyon, Université Claude Bernard Lyon1, IFR 128, Inserm U758; Ecole Normale Supérieure de Lyon, 69364 Lyon, France
| | - THOMAS PIETSCHMANN
- Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - MARIE–SOPHIE HIET
- The Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - RALF BARTENSCHLAGER
- The Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - FRANÇOIS HABERSETZER
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
,Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - MICHEL DOFFOËL
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
,Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - ZHEN–YONG KECK
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - STEVEN K. H. FOUNG
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - MIRJAM B. ZEISEL
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
| | - FRANÇOISE STOLL–KELLER
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
,Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - THOMAS F. BAUMERT
- Inserm, U748, Strasbourg, France
,Université de Strasbourg, Strasbourg, France
,Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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15
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Thimme R, Binder M, Bartenschlager R. Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol Rev 2012; 36:663-83. [PMID: 22142141 DOI: 10.1111/j.1574-6976.2011.00319.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/07/2011] [Accepted: 11/25/2011] [Indexed: 12/24/2022] Open
Affiliation(s)
- Robert Thimme
- Department of Medicine II, University Medical Center Freiburg, Freiburg, Germany
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16
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Di Lorenzo C, Angus AGN, Patel AH. Hepatitis C virus evasion mechanisms from neutralizing antibodies. Viruses 2011; 3:2280-2300. [PMID: 22163345 PMCID: PMC3230852 DOI: 10.3390/v3112280] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 10/28/2011] [Accepted: 11/07/2011] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) represents a major public health problem, affecting 3% of the world's population. The majority of infected individuals develop chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. To date, a vaccine is not available and current therapy is limited by resistance, adverse effects and high costs. Although it is very well established that cell-mediated immunity is necessary for viral clearance, the importance of host antibodies in clearing HCV infection is being increasingly recognized. Indeed, recent studies indicate that neutralizing antibodies are induced in the early phase of infection by patients who subsequently clear viral infection. Conversely, patients who do not clear the virus develop high titers of neutralizing antibodies during the chronic stage. Surprisingly, these antibodies are not able to control HCV infection. HCV has therefore developed mechanisms to evade immune elimination, allowing it to persist in the majority of infected individuals. A detailed understanding of the mechanisms by which the virus escapes immune surveillance is therefore necessary if novel preventive and therapeutic treatments have to be designed. This review summarizes the current knowledge of the mechanisms used by HCV to evade host neutralizing antibodies.
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Affiliation(s)
- Caterina Di Lorenzo
- MRC - University of Glasgow Centre for Virus Research, Church Street, Glasgow, G11 5JR, UK; E-Mails: (C.D.L.); (A.G.N.A.)
| | - Allan G. N. Angus
- MRC - University of Glasgow Centre for Virus Research, Church Street, Glasgow, G11 5JR, UK; E-Mails: (C.D.L.); (A.G.N.A.)
| | - Arvind H. Patel
- MRC - University of Glasgow Centre for Virus Research, Church Street, Glasgow, G11 5JR, UK; E-Mails: (C.D.L.); (A.G.N.A.)
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17
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Helle F, Duverlie G, Dubuisson J. The hepatitis C virus glycan shield and evasion of the humoral immune response. Viruses 2011; 3:1909-32. [PMID: 22069522 PMCID: PMC3205388 DOI: 10.3390/v3101909] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 09/28/2011] [Accepted: 10/01/2011] [Indexed: 12/14/2022] Open
Abstract
Despite the induction of effective immune responses, 80% of hepatitis C virus (HCV)-infected individuals progress from acute to chronic hepatitis. In contrast to the cellular immune response, the role of the humoral immune response in HCV clearance is still subject to debate. Indeed, HCV escapes neutralizing antibodies in chronically infected patients and reinfection has been described in human and chimpanzee. Studies of antibody-mediated HCV neutralization have long been hampered by the lack of cell-culture-derived virus and the absence of a small animal model. However, the development of surrogate models and recent progress in HCV propagation in vitro now enable robust neutralization assays to be performed. These advances are beginning to shed some light on the mechanisms of HCV neutralization. This review summarizes the current state of knowledge of the viral targets of anti-HCV-neutralizing antibodies and the mechanisms that enable HCV to evade the humoral immune response. The recent description of the HCV glycan shield that reduces the immunogenicity of envelope proteins and masks conserved neutralizing epitopes at their surface constitutes the major focus of this review.
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Affiliation(s)
- François Helle
- Laboratory of Virology, EA4294, Jules Verne University of Picardie, Amiens 80000, France; E-Mail:
| | - Gilles Duverlie
- Laboratory of Virology, EA4294, Jules Verne University of Picardie, Amiens 80000, France; E-Mail:
- Virology Department, Amiens University Hospital Center, South Hospital, Amiens 80000, France
| | - Jean Dubuisson
- Inserm U1019, CNRS UMR8204, Center for Infection and Immunity of Lille (CIIL), Institut Pasteur de Lille, Université Lille Nord de France, Lille 59021, France; E-Mail:
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18
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Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, Davis C, Mee CJ, Turek M, Gorke S, Royer C, Fischer B, Zahid MN, Lavillette D, Fresquet J, Cosset FL, Rothenberg SM, Pietschmann T, Patel AH, Pessaux P, Doffoël M, Raffelsberger W, Poch O, Mckeating JA, Brino L, Baumert TF. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 2011; 17:589-95. [PMID: 21516087 PMCID: PMC3938446 DOI: 10.1038/nm.2341] [Citation(s) in RCA: 567] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 03/03/2011] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.
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Affiliation(s)
- Joachim Lupberger
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Mirjam B. Zeisel
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Fei Xiao
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Christine Thumann
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Isabel Fofana
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Laetitia Zona
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Christopher Davis
- Hepatitis C Research Group
University of BirminghamDivision of Immunity and InfectionEdgbaston, Birmingham B15 2TT, GB
| | - Christopher J. Mee
- Hepatitis C Research Group
University of BirminghamDivision of Immunity and InfectionEdgbaston, Birmingham B15 2TT, GB
| | - Marine Turek
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Sebastian Gorke
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
- Department of Medicine II
University of FreiburgFahnenbergplatz, 79085 Freiburg im Breisgau, DE
| | - Cathy Royer
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Benoit Fischer
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire
INSERM : U964CNRS : UMR7104Université de StrasbourgParc D'Innovation - 1 Rue Laurent Fries - BP 10142 - 67404 Illkirch Cedex, FR
| | - Muhammad N. Zahid
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
| | - Dimitri Lavillette
- Virologie Humaine
INSERM : U758IFR128École Normale Supérieure - Lyon46, Allee D'Italie 69364 Lyon Cedex 07, FR
| | - Judith Fresquet
- Virologie Humaine
INSERM : U758IFR128École Normale Supérieure - Lyon46, Allee D'Italie 69364 Lyon Cedex 07, FR
| | - François-Loïc Cosset
- Virologie Humaine
INSERM : U758IFR128École Normale Supérieure - Lyon46, Allee D'Italie 69364 Lyon Cedex 07, FR
| | - S Michael Rothenberg
- Massachusetts General Hospital Cancer Center
Howard Hughes Medical InstituteHarvard Medical School55 Fruit St, Boston, MA 02114, US
| | - Thomas Pietschmann
- TWINCORE, Division of Experimental Virology
Centre for Experimental and Clinical Infection Research HannoverMedical School Hannover (MHH)Helmholtz Centre for Infection Research (HZI)Feodor-Lynen-Straße 7 D-30625 Hannover, DE
| | - Arvind H. Patel
- MRC Virology Unit
University of Glasgow - Institute of VirologyGlasgow, Glasgow City G12 8QQ, GB
| | - Patrick Pessaux
- Service d'Hépato-Gastroentérologie
Nouvel Hôpital CivilHôpitaux Universitaires de Strasbourg (HUS)1 Place de l'Hôpital 67000 Strasbourg, FR
| | - Michel Doffoël
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
- Service d'Hépato-Gastroentérologie
Nouvel Hôpital CivilHôpitaux Universitaires de Strasbourg (HUS)1 Place de l'Hôpital 67000 Strasbourg, FR
| | - Wolfgang Raffelsberger
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire
INSERM : U964CNRS : UMR7104Université de StrasbourgParc D'Innovation - 1 Rue Laurent Fries - BP 10142 - 67404 Illkirch Cedex, FR
| | - Olivier Poch
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire
INSERM : U964CNRS : UMR7104Université de StrasbourgParc D'Innovation - 1 Rue Laurent Fries - BP 10142 - 67404 Illkirch Cedex, FR
| | - Jane A. Mckeating
- Hepatitis C Research Group
University of BirminghamDivision of Immunity and InfectionEdgbaston, Birmingham B15 2TT, GB
| | - Laurent Brino
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire
INSERM : U964CNRS : UMR7104Université de StrasbourgParc D'Innovation - 1 Rue Laurent Fries - BP 10142 - 67404 Illkirch Cedex, FR
| | - Thomas F. Baumert
- Interaction Virus-Hôte et Maladies du Foie
INSERM : U748Université de Strasbourg - Faculté de Médecine 3 Rue Koeberle 67000 Strasbourg, FR
- Service d'Hépato-Gastroentérologie
Nouvel Hôpital CivilHôpitaux Universitaires de Strasbourg (HUS)1 Place de l'Hôpital 67000 Strasbourg, FR
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19
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Zeisel MB, Fofana I, Fafi-Kremer S, Baumert TF. Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies. J Hepatol 2011; 54:566-76. [PMID: 21146244 DOI: 10.1016/j.jhep.2010.10.014] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 10/12/2010] [Accepted: 10/14/2010] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Preventive modalities are absent and the current antiviral treatment is limited by resistance, toxicity, and high costs. Viral entry is required for initiation, spread, and maintenance of infection, and thus is a promising target for antiviral therapy. HCV entry is a highly orchestrated process involving viral and host cell factors. These include the viral envelope glycoproteins E1 and E2, CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Recent studies in preclinical models and HCV-infected patients have demonstrated that the virus has developed multiple strategies to escape host immune responses during viral entry. These include evasion from neutralizing antibodies and viral spread by cell-cell transmission. These challenges have to be taken into account for the design of efficient antiviral strategies. Thus, a detailed understanding of the mechanisms of viral entry and escape is a prerequisite to define viral and cellular targets and develop novel preventive and therapeutic antivirals. This review summarizes the current knowledge about the molecular mechanisms of HCV entry into hepatocytes, highlights novel targets and reviews the current preclinical and clinical development of compounds targeting entry. Proof-of-concept studies suggest that HCV entry inhibitors are a novel and promising class of antivirals widening the preventive and therapeutic arsenal against HCV infection.
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20
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Angus AGN, Patel AH. Immunotherapeutic potential of neutralizing antibodies targeting conserved regions of the HCV envelope glycoprotein E2. Future Microbiol 2011; 6:279-94. [PMID: 21449840 DOI: 10.2217/fmb.11.9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
HCV is a major cause of chronic liver disease worldwide. There is no vaccine available and the current antiviral therapies fail to cure approximately half of treated patients. Liver disease caused by HCV infection is the most common indication for orthotopic liver transplantation. Unfortunately, reinfection of the new liver is universal and often results in an aggressive form of the disease leading to graft loss and the need for retransplantation. Immunotherapies using antibodies that potently inhibit HCV infection have the potential to control or even prevent graft reinfection. The virion envelope glycoproteins E1 and E2, which are involved in HCV entry into host cells, are the targets of neutralizing antibodies. To date, a number of monoclonal antibodies targeting conserved regions of E2 have been described that display outstanding neutralizing capabilities against HCV infection in both in vitro and in vivo systems. This article will summarize the current literature on these neutralizing anti-E2 antibodies and discuss their potential immunotherapeutic efficacy.
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Affiliation(s)
- Allan G N Angus
- MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Church Street, Glasgow, UK
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21
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Eksioglu EA, Bess J, Jones G, Dettloff J, Dangmeon P, Dong HJ, Zhu H, Firpi R, Xu Y, Nelson DR, Liu C. Characterization of Anti-HCV Antibodies in IL-10-Treated Patients. Viral Immunol 2011; 23:359-68. [PMID: 20712480 DOI: 10.1089/vim.2009.0095] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
There is limited information on the direct role of the neutralizing antibody responses against hepatitis C virus (HCV) infection or methodologies to study them. Previously we have demonstrated that interleukin-10 (IL-10) administered to chronic hepatitis patients led to a decrease in disease activity, but an increase in HCV viral burden. The mechanism behind this is unknown. The objective of this study was to examine the antibody response in IL-10-treated patients. To establish a neutralization antibody assay, HCV-positive and HCV-negative sera were collected and incubated with HCV strain JFH-1 particles before culture with Huh 7.5 cells. Viral replication was measured a week later by either indirect immunofluorescence assay (iIFA) or real-time reverse transcriptase polymerase chain reaction (RT-PCR). After validation of the methodology, the sera from 30 previously-described subjects of a group previously treated with IL-10 were tested for the neutralization capacity of their antibodies. The amount of total anti-HCV antibody in the sera was also measured by direct staining of HCV full-length replicon cells. With this validated neutralization assay for anti-HCV antibodies we found that HCV-neutralizing antibodies are universally present, but with significantly different titers. In patients who were treated with IL-10, the total anti-HCV antibody titers appear to be constant, but with significantly decreased antibody neutralization activity. Our study validates an assay to quantitatively determine the presence and strength of HCV-specific neutralizing antibodies. We have found that IL-10-treated patients have significantly lower HCV antibodies, but maintain the total anti-HCV antibody titer, suggesting a novel mechanism by which IL-10 treatment increases viral load in patients.
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Affiliation(s)
- Erika A Eksioglu
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
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22
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Syder AJ, Lee H, Zeisel MB, Grove J, Soulier E, Macdonald J, Chow S, Chang J, Baumert TF, McKeating JA, McKelvy J, Wong-Staal F. Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. J Hepatol 2011; 54:48-55. [PMID: 20932595 DOI: 10.1016/j.jhep.2010.06.024] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 06/10/2010] [Accepted: 06/14/2010] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS ITX 5061 is a clinical stage small molecule compound that promotes high-density lipoprotein (HDL) levels in animals and patients by targeting the scavenger receptor BI protein pathway. Since SR-BI is a known co-receptor for HCV infection, we evaluated these compounds for their effects on HCV entry. METHODS We obtained ITX 5061 and related compounds to characterize their interaction with SR-BI and effects on HCV entry and infection. RESULTS We confirmed that a tritium-labeled compound analog (ITX 7650) binds cells expressing SR-BI, and both ITX 5061 and ITX 7650 compete for HDL-mediated lipid transfer in an SR-BI dependent manner. Both molecules inhibit HCVcc and HCVpp infection of primary human hepatocytes and/or human hepatoma cell lines and have minimal effects on HCV RNA replication. Kinetic studies suggest that the compounds act at an early post-binding step. CONCLUSIONS These results suggest that the ITX compounds inhibit HCV infection with a mechanism of action distinct from other HCV therapies under development. Since ITX 5061 has already been evaluated in over 280 patients with good pharmacokinetic and safety profiles, it warrants proof-of-concept clinical studies in HCV infected patients.
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Affiliation(s)
- Andrew J Syder
- iTherX Pharmaceuticals, Inc., San Diego, CA 92191-0530, USA
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23
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Ndongo N, Berthillon P, Pradat P, Vieux C, Bordes I, Berby F, Maynard M, Zoulim F, Trépo C, Petit MA. Association of anti-E1E2 antibodies with spontaneous recovery or sustained viral response to therapy in patients infected with hepatitis C virus. Hepatology 2010; 52:1531-42. [PMID: 20890942 DOI: 10.1002/hep.23862] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED The monoclonal antibody (mAb) D32.10 recognizes a discontinuous epitope encompassing three regions E1 (amino acids 297-306), E2A (amino acids 480-494), and E2B (amino acids 613-621) juxtaposed on the surface of serum-derived hepatitis C virus (HCV) particles (HCVsp). The mAb D32.10 inhibits efficiently and specifically the binding of HCVsp to human hepatocytes. Therefore, we investigated the clinical relevance of anti-E1E2A,B response in the serum of patients infected with HCV. To this end, an enzyme-linked immunosorbent assay (ELISA) using synthetic E1-, E2A-, and E2B-derived peptides was used. The ELISA was validated in terms of sensitivity, specificity, and test efficiency. The detection of the anti-E1E2 D32.10 epitope-binding antibodies during natural HCV infection in more than 300 HCV-positive sera demonstrated significantly (P < 0.001) higher prevalence of these antibodies: (1) in patients who spontaneously cured HCV infection (46 of 52, 88.5%) showing high titers (70% ≥ 1/1000) compared to never-treated patients with chronic hepatitis C (7 of 50, 14%) who actively replicated the virus, and (2) in complete responders (20 of 52, 38.5%) who cleared virus following treatment and achieved a sustained viral response compared to nonresponders (4 of 40, 10%). Serum anti-E1E2 antibodies were monitored before, during, and after the current standard-of-care therapy (pegylated interferon plus ribavirin) in responder and nonresponder patients. Optimal cutoff values were assessed by receiver operating characteristic curve analysis. One month prior to therapy initiation, the threshold of 1131 (optical density × 1000) gave 100% and 86% positive and negative predictive values, respectively, for achieving or not achieving a sustained viral response. CONCLUSION The anti-E1E2 D32.10 epitope-binding antibodies are associated with control of HCV infection and may represent a new relevant prognostic marker in serum. This unique D32.10 mAb may also have immunotherapeutic potential.
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Affiliation(s)
- Ndiémé Ndongo
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 871, Molecular Physiopathology and New Therapies in Viral Hepatitis, Lyon, France
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24
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Pfeffer S, Baumert T. Impact of microRNAs for pathogenesis and treatment of hepatitis C virus infection. ACTA ACUST UNITED AC 2010; 34:431-5. [DOI: 10.1016/j.gcb.2010.04.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Accepted: 04/08/2010] [Indexed: 12/11/2022]
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25
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Fofana I, Krieger SE, Grunert F, Glauben S, Xiao F, Fafi-Kremer S, Soulier E, Royer C, Thumann C, Mee CJ, McKeating JA, Dragic T, Pessaux P, Stoll-Keller F, Schuster C, Thompson J, Baumert TF. Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes. Gastroenterology 2010; 139:953-64, 964.e1-4. [PMID: 20685314 DOI: 10.1053/j.gastro.2010.05.073] [Citation(s) in RCA: 133] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 05/12/2010] [Accepted: 05/24/2010] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell. METHODS Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes. RESULTS Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies. CONCLUSIONS Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.
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26
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Host and viral determinants for engraftment of virus permissive human hepatocytes into chimeric immunodeficient mice. J Hepatol 2010; 53:421-3. [PMID: 20561706 DOI: 10.1016/j.jhep.2010.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 05/11/2010] [Indexed: 02/06/2023]
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27
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Fafi-Kremer S, Fofana I, Soulier E, Carolla P, Meuleman P, Leroux-Roels G, Patel AH, Cosset FL, Pessaux P, Doffoël M, Wolf P, Stoll-Keller F, Baumert TF. Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation. J Exp Med 2010; 207:2019-31. [PMID: 20713596 PMCID: PMC2931157 DOI: 10.1084/jem.20090766] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Accepted: 07/08/2010] [Indexed: 12/12/2022] Open
Abstract
End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.
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Affiliation(s)
- Samira Fafi-Kremer
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
| | - Isabel Fofana
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
| | - Eric Soulier
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
| | - Patric Carolla
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
| | - Philip Meuleman
- Center for Vaccinology, Ghent University and Hospital, 9000 Ghent, Belgium
| | - Geert Leroux-Roels
- Center for Vaccinology, Ghent University and Hospital, 9000 Ghent, Belgium
| | - Arvind H. Patel
- Medical Research Council Centre for Virus Research, University of Glasgow, Glasgow G11 5JR, Scotland, UK
| | - François-Loïc Cosset
- Institut National de la Santé et de la Recherche Médicale, Unité 758, Institut Fédératif de Recherche 128, Ecole Normale Supérieure, Université Claude Bernard Lyon 1, Université de Lyon, F-69007 Lyon, France
| | - Patrick Pessaux
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
| | - Michel Doffoël
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
| | - Philippe Wolf
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
| | - Françoise Stoll-Keller
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
| | - Thomas F. Baumert
- Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
- Université de Strasbourg, F-67000 Strasbourg, France
- Laboratoire de Virologie, Pôle des Pathologies Digestives, Hépatiques et Transplantation, and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
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28
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Zeisel MB, Turek M, Baumert TF. Getting closer to the patient: upgrade of hepatitis C virus infection in primary human hepatocytes. J Hepatol 2010; 53:388-9. [PMID: 20546960 DOI: 10.1016/j.jhep.2010.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Revised: 04/07/2010] [Accepted: 04/07/2010] [Indexed: 12/16/2022]
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29
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Georgel P, Schuster C, Zeisel MB, Stoll-Keller F, Berg T, Bahram S, Baumert TF. Virus-host interactions in hepatitis C virus infection: implications for molecular pathogenesis and antiviral strategies. Trends Mol Med 2010; 16:277-86. [PMID: 20537953 DOI: 10.1016/j.molmed.2010.04.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 04/12/2010] [Accepted: 04/13/2010] [Indexed: 12/18/2022]
Abstract
With a global burden of 170 million chronically infected patients and a major cause of liver cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is a major public health challenge. Recent discoveries of viral and cellular factors mediating virus-host interactions have allowed scientists to uncover the key molecular mechanisms of viral infection and escape from innate and adaptive immune responses. These include the discovery of tight junction proteins as entry factors and microRNA-122, cyclophilins and lipoproteins as host factors for virus translation, replication and production. Furthermore, global genetic analyses have identified IL-28B as a genetic factor associated with the outcome of HCV infection. These discoveries markedly advance the understanding of the molecular pathogenesis of HCV infection and uncover novel targets for urgently needed antiviral strategies.
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Affiliation(s)
- Philippe Georgel
- Laboratoire d'Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
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30
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Krieger SE, Zeisel MB, Davis C, Thumann C, Harris HJ, Schnober EK, Mee C, Soulier E, Royer C, Lambotin M, Grunert F, Dao Thi VL, Dreux M, Cosset FL, McKeating JA, Schuster C, Baumert TF. Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology 2010; 51:1144-57. [PMID: 20069648 DOI: 10.1002/hep.23445] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED The tight junction protein claudin-1 (CLDN1) has been shown to be essential for hepatitis C virus (HCV) entry-the first step of viral infection. Due to the lack of neutralizing anti-CLDN1 antibodies, the role of CLDN1 in the viral entry process is poorly understood. In this study, we produced antibodies directed against the human CLDN1 extracellular loops by genetic immunization and used these antibodies to investigate the mechanistic role of CLDN1 for HCV entry in an infectious HCV cell culture system and human hepatocytes. Antibodies specific for cell surface-expressed CLDN1 specifically inhibit HCV infection in a dose-dependent manner. Antibodies specific for CLDN1, scavenger receptor B1, and CD81 show an additive neutralizing capacity compared with either agent used alone. Kinetic studies with anti-CLDN1 and anti-CD81 antibodies demonstrate that HCV interactions with both entry factors occur at a similar time in the internalization process. Anti-CLDN1 antibodies inhibit the binding of envelope glycoprotein E2 to HCV permissive cell lines in the absence of detectable CLDN1-E2 interaction. Using fluorescent-labeled entry factors and fluorescence resonance energy transfer methodology, we demonstrate that anti-CLDN1 antibodies inhibit CD81-CLDN1 association. In contrast, CLDN1-CLDN1 and CD81-CD81 associations were not modulated. Taken together, our results demonstrate that antibodies targeting CLDN1 neutralize HCV infectivity by reducing E2 association with the cell surface and disrupting CD81-CLDN1 interactions. CONCLUSION These results further define the function of CLDN1 in the HCV entry process and highlight new antiviral strategies targeting E2-CD81-CLDN1 interactions.
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Affiliation(s)
- Sophie E Krieger
- Institut National de la Santé et de la Recherche Médicale, U748, Strasbourg, France
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31
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Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes. J Virol 2010; 84:5751-63. [PMID: 20357091 DOI: 10.1128/jvi.02200-09] [Citation(s) in RCA: 176] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The variability of the hepatitis C virus (HCV), which likely contributes to immune escape, is most pronounced in hypervariable region 1 (HVR1) of viral envelope protein 2. This domain is the target for neutralizing antibodies, and its deletion attenuates replication in vivo. Here we characterized the relevance of HVR1 for virus replication in vitro using cell culture-derived HCV. We show that HVR1 is dispensable for RNA replication. However, viruses lacking HVR1 (Delta HVR1) are less infectious, and separation by density gradients revealed that the population of Delta HVR1 virions comprises fewer particles with low density. Strikingly, Delta HVR1 particles with intermediate density (1.12 g/ml) are as infectious as wild-type virions, while those with low density (1.02 to 1.08 g/ml) are poorly infectious, despite quantities of RNA and core similar to those in wild-type particles. Moreover, Delta HVR1 particles exhibited impaired fusion, a defect that was partially restored by an E1 mutation (I347L), which also rescues infectivity and which was selected during long-term culture. Finally, Delta HVR1 particles were no longer neutralized by SR-B1-specific immunoglobulins but were more prone to neutralization and precipitation by soluble CD81, E2-specific monoclonal antibodies, and patient sera. These results suggest that HVR1 influences the biophysical properties of released viruses and that this domain is particularly important for infectivity of low-density particles. Moreover, they indicate that HVR1 obstructs the viral CD81 binding site and conserved neutralizing epitopes. These functions likely optimize virus replication, facilitate immune escape, and thus foster establishment and maintenance of a chronic infection.
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32
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Adaptive immunity to hepatitis C virus. Viruses 2009; 1:276-97. [PMID: 21994550 PMCID: PMC3185498 DOI: 10.3390/v1020276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Revised: 08/14/2009] [Accepted: 08/25/2009] [Indexed: 12/23/2022] Open
Abstract
The precise role of adaptive immune responses in the clinical outcome of HCV infection is still only partially defined. Recent studies suggest that viral-host cell interactions during the acute phase of infection are essential for viral clearance or progression into chronic HCV infection. This review focuses on different aspects of the adaptive immune responses as determinants of the different outcomes of HCV infection, clearance or persistent infection, and outlines current concepts of HCV evasion strategies. Unravelling these important mechanisms of virus-host interaction will contribute to the development of novel strategies to prevent and control HCV infection.
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33
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Zeisel MB, Baumert TF. HCV entry and neutralizing antibodies: lessons from viral variants. Future Microbiol 2009; 4:511-7. [PMID: 19492962 PMCID: PMC2898794 DOI: 10.2217/fmb.09.34] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Evaluation of: Grove J, Nielsen S, Zhong J et al.: Identification of a residue in hepatitis C virus E2 glycoprotein that determines scavenger receptor BI and CD81 receptor dependency and sensitivity to neutralizing antibodies. J. Virol. 82 (24), 12020-12029 (2008). Recent data suggest that a strong, early, broad neutralizing antibody response may contribute to the control of HCV in the acute phase of infection. However, the majority of individuals fail to clear HCV during the first months following infection and develop chronic infection despite the presence of anti-HCV antibodies. A prerequisite of the understanding behind the mechanisms of viral escape from antibody-mediated neutralization is the identification of various host-entry factors mediating the first steps of viral infection - binding and entry of HCV is believed to be a multistep process involving HCV envelope glycoproteins E1 and E2 as well as several host-cell surface molecules such as CD81, scavenger receptor class B type I, members of the claudin family and occludin. In this article, Grove et al. describe a single mutation in the HCV envelope glycoprotein E2 that alters glycoprotein structure thereby modulating viral interaction with scavenger receptor class B type I and CD81, and increasing sensitivity to neutralizing antibodies. The results of this study highlight the importance of the characterization of the interplay between HCV particles and host-cell factors for the understanding of virus neutralization by host-immune responses and pathogenesis of HCV infection.
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34
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Eyre NS, Baumert TF, Beard MR. Closing the gap: the tight junction protein occludin and hepatitis C virus entry. Hepatology 2009; 49:1770-2. [PMID: 19402114 DOI: 10.1002/hep.22935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nicholas S Eyre
- School of Molecular and Biomedical Science, University of Adelaide and Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia
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35
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Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF. Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 2009; 8:333-45. [PMID: 19249975 DOI: 10.1586/14760584.8.3.333] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Development of an effective vaccine against the hepatitis C virus (HCV) has long been defined as a difficult challenge due to the considerable variability of this RNA virus and the observation that convalescent humans and chimpanzees could be re-infected after re-exposure. On the other hand, progress in the understanding of antiviral immune responses in patients with viral clearance has elucidated key mechanisms playing a role in the control of viral infection. Studies investigating prophylactic vaccine approaches in chimpanzees have confirmed that the induction and maintenance of strong helper and cytotoxic T-cell immune responses against multiple viral epitopes is necessary for protection against viral clearance and chronic infection. A multispecific B-cell response, resulting in rapid induction of cross-neutralizing antibodies may assist cellular responses. Therapeutic vaccine formulations currently being evaluated in clinical trials are facing the fact that the immune system of chronic carriers is impaired and needs the restoration of T-cell functions to enhance their efficacy.
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Affiliation(s)
- Françoise Stoll-Keller
- Inserm, U748 et Laboratoire de Virologie des Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé 67000 Strasbourg, France.
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36
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Abstract
Two to three percent of the world's population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Among these molecules, the tetraspanin CD81 is essential for HCV entry. Here, we have identified a partner of CD81, EWI-2wint, which is expressed in several cell lines but not in hepatocytes. Ectopic expression of EWI-2wint in a hepatoma cell line susceptible to HCV infection blocked viral entry by inhibiting the interaction between the HCV envelope glycoproteins and CD81. This finding suggests that, in addition to the presence of specific entry factors in the hepatocytes, the lack of a specific inhibitor can contribute to the hepatotropism of HCV. This is the first example of a pathogen gaining entry into host cells that lack a specific inhibitory factor.
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37
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Haberstroh A, Schnober EK, Zeisel MB, Carolla P, Barth H, Blum HE, Cosset FL, Koutsoudakis G, Bartenschlager R, Union A, Depla E, Owsianka A, Patel AH, Schuster C, Stoll-Keller F, Doffoël M, Dreux M, Baumert TF. Neutralizing host responses in hepatitis C virus infection target viral entry at postbinding steps and membrane fusion. Gastroenterology 2008; 135:1719-1728.e1. [PMID: 18718838 DOI: 10.1053/j.gastro.2008.07.018] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Revised: 06/02/2008] [Accepted: 07/17/2008] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) is a leading cause of chronic hepatitis worldwide. Viral attachment and entry, representing the first steps of virus-host cell interactions, are major targets of adaptive host cell defenses. The mechanisms of antibody-mediated neutralization by host neutralizing responses in HCV infection are only poorly understood. Retroviral HCV pseudotypes (HCVpp) and recombinant cell culture-derived HCV (HCVcc) have been successfully used to study viral entry and antibody-mediated neutralization. METHODS In this study, we used these model systems to investigate the mechanism of antibody-mediated neutralization by monoclonal antienvelope antibodies and polyclonal anti-HCV immunoglobulins purified from HCV-infected patients. RESULTS Using a panel of monoclonal antienvelope antibodies, we identified an epitope within the E1 glycoprotein targeted by human neutralizing antibodies during postbinding events. Interestingly, we observed that host neutralizing responses in the majority of HCV-infected individuals include antibodies targeting HCV entry after binding of the virus to the target cell membrane. Using a kinetic assay based on HCVpp and HCVcc entry, we demonstrate that purified antiviral immunoglobulins derived from individual HCV-infected patients appear to inhibit HCV infection at an entry step closely linked to CD81 and scavenger receptor BI (SR-BI). CONCLUSIONS Our results indicate that host neutralizing responses in HCV-infected patients target viral entry after HCV binding most likely related to HCV-CD81, and HCV-SR-BI interactions, as well as membrane fusion. These findings have implications not only for the understanding of the pathogenesis of HCV infection but also for the design of novel immunotherapeutic and preventive strategies.
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MESH Headings
- Adult
- Aged
- Antibodies, Anti-Idiotypic/immunology
- Antibodies, Monoclonal/therapeutic use
- Antigens, CD/drug effects
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Cells, Cultured
- Hepacivirus/immunology
- Hepatitis C Antibodies/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Immunoenzyme Techniques
- Immunoglobulin G/immunology
- Membrane Fusion/drug effects
- Middle Aged
- Receptors, Virus
- Scavenger Receptors, Class B/drug effects
- Scavenger Receptors, Class B/immunology
- Scavenger Receptors, Class B/metabolism
- Tetraspanin 28
- Viral Envelope Proteins/drug effects
- Viral Envelope Proteins/immunology
- Viral Envelope Proteins/metabolism
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Affiliation(s)
- Anita Haberstroh
- Department of Medicine II, University of Freiburg, Freiburg, Germany
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38
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Barth H, Robinet E, Liang TJ, Baumert TF. Mouse models for the study of HCV infection and virus-host interactions. J Hepatol 2008; 49:134-42. [PMID: 18457898 PMCID: PMC2529177 DOI: 10.1016/j.jhep.2008.03.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2008] [Revised: 03/10/2008] [Accepted: 03/10/2008] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver disease including steatosis, cirrhosis and hepatocellular carcinoma. The development of transgenic mice expressing HCV proteins and the successful repopulation of SCID/Alb-uPA mice with human hepatocytes provides an important tool for unraveling virus-host interactions in vivo. Several of these mouse models exhibit aspects of HCV-related liver disease. Thus, these in vivo models play an important role to further understand the pathogenesis of HCV infection and to evaluate the pre-clinical safety and efficacy of new antiviral compounds against HCV. This review summarizes the most important mouse models currently used to study HCV pathogenesis and infection. Finally, the perspective of these models for future HCV research as well as the design of novel small animal models is discussed.
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Affiliation(s)
- Heidi Barth
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA
| | - Eric Robinet
- Inserm Unit 748, 3 rue Koeberlé, F-67000 Strasbourg, France
- Université Louis Pasteur, 3 rue Koeberlé, F-67000 Strasbourg, France
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA
| | - Thomas F. Baumert
- Inserm Unit 748, 3 rue Koeberlé, F-67000 Strasbourg, France
- Université Louis Pasteur, 3 rue Koeberlé, F-67000 Strasbourg, France
- Service d’Hépato-gastroentérologie, Centre Hospitalier Universitaire Strasbourg, Nouvel Hôpital Civil, 1 place de l’hôpital, F-67000 Strasbourg, France
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