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Dibo M, Battocchio EC, dos Santos Souza LM, da Silva MDV, Banin-Hirata BK, Sapla MM, Marinello P, Rocha SP, Faccin-Galhardi LC. Antibody Therapy for the Control of Viral Diseases: An Update. Curr Pharm Biotechnol 2019; 20:1108-1121. [DOI: 10.2174/1389201020666190809112704] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 04/22/2019] [Accepted: 08/01/2019] [Indexed: 12/29/2022]
Abstract
The epidemiological impact of viral diseases, combined with the emergence and reemergence of some viruses, and the difficulties in identifying effective therapies, have encouraged several studies to develop new therapeutic strategies for viral infections. In this context, the use of immunotherapy for the treatment of viral diseases is increasing. One of the strategies of immunotherapy is the use of antibodies, particularly the monoclonal antibodies (mAbs) and multi-specific antibodies, which bind directly to the viral antigen and bring about activation of the immune system. With current advancements in science and technology, several such antibodies are being tested, and some are already approved and are undergoing clinical trials. The present work aims to review the status of mAb development for the treatment of viral diseases.
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Affiliation(s)
- Miriam Dibo
- Department of Microbiology, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Eduardo C. Battocchio
- Department of Microbiology, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Lucas M. dos Santos Souza
- Department of Microbiology, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | | | - Bruna K. Banin-Hirata
- Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Milena M.M. Sapla
- Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Poliana Marinello
- Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Sérgio P.D. Rocha
- Department of Microbiology, Biological Sciences Center, State University of Londrina, Parana, Brazil
| | - Lígia C. Faccin-Galhardi
- Department of Microbiology, Biological Sciences Center, State University of Londrina, Parana, Brazil
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5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl)methyl]-L-proline Inhibits Hepatitis C Virus Entry. Sci Rep 2019; 9:7288. [PMID: 31086268 PMCID: PMC6514212 DOI: 10.1038/s41598-019-43783-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/30/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) is the major causative agent of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. The recent development of highly effective direct-acting antivirals (DAAs) has revolutionized the treatment of HCV patients. However, these DAAs are exorbitantly expensive for the majority of HCV patients worldwide. Moreover, these drugs still show genotypic difference in cure rate and have some resistant-associated variants. Tylophorine, a natural compound derived from Tylophora indica plants, is known to have anti-inflammatory and anti-cancerous growth activities. In the present study, we showed that two tylophorine intermediates, 5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl) methyl]-L-proline (O859585) and 2,3,6,7-tetramethoxy-9-phenanthrenecarboxylic acid (T298875), displayed anti-HCV activity with an EC50 of 38.25 µM for T298875 and 29.11~35.3 µM for O859585 in various HCV genotypes. We demonstrated that O859585 efficiently blocked HCV attachment by neutralizing free viral particles without affecting other stages of the HCV life cycle and interferon stimulation. O859585 interrupted binding between HCV E2 and CD81. Of note, co-treatment of O859585 with either interferon alpha (IFNα) or sofosbuvir exerted either an additive or synergistic antiviral activity in HCV-infected cells with no measurable effect on cell viability. Most importantly, O859585 in combination with IFNα and sofosbuvir exhibited synergistic effects on anti-HCV activity in primary human hepatocytes. Collectively, these data suggest that O859585 may be a novel antiviral agent for HCV therapy.
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3
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Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant 2019; 33:e13514. [DOI: 10.1111/ctr.13514] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Helen Te
- Center for Liver Diseases, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago Illinois
| | - Karen Doucette
- Division of Infectious Diseases University of Alberta Edmonton Alberta Canada
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Underwood AP, Walker MR, Brasher NA, Eltahla AA, Maher L, Luciani F, Lloyd AR, Bull RA. Understanding the Determinants of BnAb Induction in Acute HCV Infection. Viruses 2018; 10:E659. [PMID: 30469363 PMCID: PMC6266478 DOI: 10.3390/v10110659] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/31/2018] [Accepted: 11/16/2018] [Indexed: 12/16/2022] Open
Abstract
Despite recent advances in curative therapy, hepatitis C virus (HCV) still remains a global threat. In order to achieve global elimination, a prophylactic vaccine should be considered high priority. Previous immunogens used to induce broad neutralising antibodies (BnAbs) have been met with limited success. To improve immunogen design, factors associated with the early development of BnAbs in natural infection must first be understood. In this study, 43 subjects identified with acute HCV were analysed longitudinally using a panel of heterogeneous HCV pseudoparticles (HCVpp), to understand the emergence of BnAbs. Compared to those infected with a single genotype, early BnAb development was associated with subjects co-infected with at least 2 HCV subtypes during acute infection. In those that were mono-infected, BnAbs were seen to emerge with increasing viral persistence. If subjects acquired a secondary infection, nAb breadth was seen to boost upon viral re-exposure. Importantly, this data highlights the potential for multivalent and prime-boost vaccine strategies to induce BnAbs against HCV in humans. However, the data also indicate that the infecting genotype may influence the development of BnAbs. Therefore, the choice of antigen will need to be carefully considered in future vaccine trials.
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Affiliation(s)
- Alexander P Underwood
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Melanie R Walker
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Nicholas A Brasher
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Auda A Eltahla
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Lisa Maher
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Fabio Luciani
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Andrew R Lloyd
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
| | - Rowena A Bull
- School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
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5
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Rodríguez‐Perálvarez M, Guerrero‐Misas M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011639. [PMID: 28362060 PMCID: PMC6464256 DOI: 10.1002/14651858.cd011639.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. FUNDING 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. AUTHORS' CONCLUSIONS Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
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Affiliation(s)
- Manuel Rodríguez‐Perálvarez
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Marta Guerrero‐Misas
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
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6
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Tawar RG, Heydmann L, Bach C, Schüttrumpf J, Chavan S, King BJ, McClure CP, Ball JK, Pessaux P, Habersetzer F, Bartenschlager R, Zeisel MB, Baumert TF. Broad neutralization of hepatitis C virus-resistant variants by Civacir hepatitis C immunoglobulin. Hepatology 2016; 64:1495-1506. [PMID: 27531416 PMCID: PMC7615276 DOI: 10.1002/hep.28767] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/19/2016] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV)-induced end-stage liver disease is the major indication for liver transplantation (LT). However, reinfection of the liver graft is still common, especially in patients with detectable viral load at the time of LT. Limited data are available on direct-acting antivirals in the transplant setting for prevention of graft infection. The human hepatitis C immunoglobulin (HCIG) Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing its safety and efficacy at preventing HCV recurrence after liver transplantation (LT) in the United States. Using well-characterized patient-derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles (HCVpp) and cell culture-derived HCV (HCVcc) containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after LT. The human hepatitis C immune globulin Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing safety and efficacy to prevent HCV recurrence after LT in the United States. Using well-characterized patient-derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles and cell culture-derived HCV containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after liver transplantation. Additionally, we studied neutralization of different HCV genotypes and of direct-acting antiviral-resistant viruses. Our results indicate that Civacir potently, broadly, and dose-dependently neutralizes all tested patient variants in HCV pseudoparticles and cell culture-derived HCV assays including variants displaying resistance to host neutralizing antibodies and antiviral monoclonal antibodies. The half-maximal inhibitory concentrations were independent of the phenotype of the viral variant, indicating that virus neutralization by Civacir is not affected by viral selection. Furthermore, Civacir is equally active against tested direct-acting antiviral-resistant HCV isolates in cell culture. CONCLUSION Collectively, these results demonstrate broad neutralizing activity of Civacir against resistant viruses, likely due to synergy between anti-HCV antibodies derived from different plasma donors, and support its further clinical development for prevention of liver graft infection. (Hepatology 2016;64:1495-1506).
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Affiliation(s)
- Rajiv G Tawar
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
| | - Laura Heydmann
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
| | - Charlotte Bach
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
| | | | | | - Barnabas J King
- School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - C Patrick McClure
- School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Jonathan K Ball
- School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Patrick Pessaux
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Institut Hospitalo-universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - François Habersetzer
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Institut Hospitalo-universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Ralf Bartenschlager
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
- German Center for Infection Research, Heidelberg University, Heidelberg, Germany
| | - Mirjam B Zeisel
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- University of Strasbourg, Strasbourg, France
| | - Thomas F Baumert
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
- University of Strasbourg, Strasbourg, France.
- Institut Hospitalo-universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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7
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State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization. J Immunol Res 2016; 2016:1412840. [PMID: 27843956 PMCID: PMC5098088 DOI: 10.1155/2016/1412840] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/09/2016] [Accepted: 09/20/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) still represents a major public health threat, with a dramatic burden from both epidemiological and clinical points of view. New generation of direct-acting antiviral agents (DAAs) has been recently introduced in clinical practice promising to cure HCV and to overcome the issues related to the interferon-based therapies. However, the emergence of drug resistance and the suboptimal activity of DAAs therapies against diverse HCV genotypes have been observed, determining treatment failure and hampering an effective control of HCV spread worldwide. Moreover, these treatments remain poorly accessible, particularly in low-income countries. Finally, effective screening strategy is crucial to early identifying and treating all HCV chronically infected patients. For all these reasons, even though new drugs may contribute to impacting HCV spread worldwide a preventive HCV vaccine remains a cornerstone in the road to significantly reduce the HCV spread globally, with the ultimate goal of its eradication. Advances in molecular vaccinology, together with a strong financial, political, and societal support, will enable reaching this fundamental success in the coming years. In this comprehensive review, the state of the art about these major topics in the fight against HCV and the future of research in these fields are discussed.
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8
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Desombere I, Fafi-Kremer S, Van Houtte F, Pessaux P, Farhoudi A, Heydmann L, Verhoye L, Cole S, McKeating JA, Leroux-Roels G, Baumert TF, Patel AH, Meuleman P. Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. Hepatology 2016; 63:1120-34. [PMID: 26710081 PMCID: PMC7613414 DOI: 10.1002/hep.28428] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 12/04/2015] [Accepted: 12/23/2015] [Indexed: 01/01/2023]
Abstract
UNLABELLED End-stage liver disease (ESLD) caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation, the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct-acting antiviral therapies have reduced efficacy in patients with ESLD and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study, we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct, but overlapping, epitope in the viral E2 glycoprotein to protect humanized mice from a patient-derived HCV challenge. Their neutralizing activity was assessed using the HCV pseudoparticles and cell-culture-derived HCV systems expressing multiple patient-derived envelopes and a human-liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient-derived HCV genotype 1b isolate, whereas 3 of 4 AP33-treated mice were completely protected. In contrast, only one of four 3/11-treated mice remained HCV-RNA negative throughout the observation period, whereas the other 3 had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro. CONCLUSIONS Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo. Given that mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and reinfected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition, our data are valuable for the design of a prophylactic vaccine.
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Affiliation(s)
| | - Samira Fafi-Kremer
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques,Université de Strasbourg, Strasbourg, France,Laboratoire de Virologie
| | | | - Patrick Pessaux
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques,Université de Strasbourg, Strasbourg, France,Laboratoire de Virologie
| | - Ali Farhoudi
- Center for Vaccinology, Ghent University, Ghent, Belgium
| | - Laura Heydmann
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques,Université de Strasbourg, Strasbourg, France
| | - Lieven Verhoye
- Center for Vaccinology, Ghent University, Ghent, Belgium
| | - Sarah Cole
- MRC – University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
| | - Jane A. McKeating
- Viral Hepatitis Research Group, Centre for Human Virology, University of Birmingham, Birmingham, UK
| | | | - Thomas F. Baumert
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques,Université de Strasbourg, Strasbourg, France,Laboratoire de Virologie,corresponding authors; Contact information: Prof. Philip Meuleman, PhD, Center for Vaccinology - Ghent University, University Hospital Ghent, Building A, 1st floor, De Pintelaan 185, B-9000 Gent, Belgium, Phone: +32 (0)9 332 02 05 (direct); Phone: +32 (0)9 332 36 58 (office administrator), Fax: +32 (0)9 332 63 11; , Thomas F. Baumert: , Arvind H. Patel:
| | - Arvind H. Patel
- MRC – University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK,corresponding authors; Contact information: Prof. Philip Meuleman, PhD, Center for Vaccinology - Ghent University, University Hospital Ghent, Building A, 1st floor, De Pintelaan 185, B-9000 Gent, Belgium, Phone: +32 (0)9 332 02 05 (direct); Phone: +32 (0)9 332 36 58 (office administrator), Fax: +32 (0)9 332 63 11; , Thomas F. Baumert: , Arvind H. Patel:
| | - Philip Meuleman
- Center for Vaccinology, Ghent University, Ghent, Belgium,corresponding authors; Contact information: Prof. Philip Meuleman, PhD, Center for Vaccinology - Ghent University, University Hospital Ghent, Building A, 1st floor, De Pintelaan 185, B-9000 Gent, Belgium, Phone: +32 (0)9 332 02 05 (direct); Phone: +32 (0)9 332 36 58 (office administrator), Fax: +32 (0)9 332 63 11; , Thomas F. Baumert: , Arvind H. Patel:
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9
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Rowe IA, Tully DC, Armstrong MJ, Parker R, Guo K, Barton D, Morse GD, Venuto CS, Ogilvie CB, Hedegaard DL, McKelvy JF, Wong-Staal F, Allen TM, Balfe P, McKeating JA, Mutimer. DJ. Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation. Liver Transpl 2016; 22:287-97. [PMID: 26437376 PMCID: PMC4901184 DOI: 10.1002/lt.24349] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 08/26/2015] [Accepted: 09/08/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1-infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.
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Affiliation(s)
- Ian A Rowe
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK,NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | | | - Matthew J Armstrong
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Richard Parker
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Kathy Guo
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK
| | - Darren Barton
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Cancer Research UK Clinical Trials Unit, University of Birmingham, UK
| | - Gene D Morse
- School of Pharmacy and Pharmaceutical Sciences and NYS Centre of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, NY, US
| | - Charles S Venuto
- Center for Human Experimental Therapeutics, University of Rochester School of Medicine, Rochester, NY, US
| | | | - Ditte L Hedegaard
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | | | | | - Todd M Allen
- Ragon Institute of MGH, MIT and Harvard, Harvard, US
| | - Peter Balfe
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | - Jane A McKeating
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK,NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK
| | - David J Mutimer.
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK
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10
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O’Shea D, Law J, Egli A, Douglas D, Lund G, Forester S, Lambert J, Law M, Burton D, Tyrrell D, Houghton M, Humar A, Kneteman N. Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. Liver Transpl 2016; 22:324-32. [PMID: 26389583 PMCID: PMC4769112 DOI: 10.1002/lt.24344] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 09/01/2015] [Indexed: 01/13/2023]
Abstract
The anti-hepatitis C virus (HCV) activity of a novel monoclonal antibody (mAb; AR4A) and epigallocatechin gallate (EGCG) were studied in vitro using a HCV cell culture system and in vivo using a humanized liver mouse model capable of supporting HCV replication. Alone, both exhibit reliable cross-genotype HCV inhibition in vitro, and combination therapy completely prevented HCV infection. In vitro AR4A mAb (alone and combined with EGCG) robustly protects against the establishment of HCV genotype 1a infection. EGCG alone fails to reliably protect against an HCV challenge. In conclusion, AR4A mAb represents a safe and efficacious broadly neutralizing antibody against HCV applicable to strategies to safely prevent HCV reinfection following liver transplantation, and it lends further support to the concept of HCV vaccine development. The poor bioavailability of EGCG limits HCV antiviral activity in vitro.
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Affiliation(s)
- D. O’Shea
- Transplant Infectious Diseases, Alberta Transplant Institute, Department of Medicine, University of Alberta,Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada,To whom correspondence should be addressed: Daire O’Shea, Consultant in Infectious Diseases, Regional Infectious Diseases Unit, Crewe Road, Edinburgh EH4 2XU, Scotland, UK, Tel: +441315372862, Fax: +441315372878,
| | - J Law
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - A Egli
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - D Douglas
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - G Lund
- KMT Hepatech, University of Alberta, Edmonton, Alberta, Canada
| | - S Forester
- Dept. of Food Science, Pennsylvania State University, PA
| | - J Lambert
- Dept. of Food Science, Pennsylvania State University, PA
| | - M Law
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA 92037, USA
| | - D.R. Burton
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA 92037, USA,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
| | - D.L.J. Tyrrell
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - M. Houghton
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - A. Humar
- Toronto General Hospital, University Health Network, Multi-Organ Transplant Program Toronto, Ontario, Canada
| | - N Kneteman
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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11
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A Diverse Panel of Hepatitis C Virus Glycoproteins for Use in Vaccine Research Reveals Extremes of Monoclonal Antibody Neutralization Resistance. J Virol 2015; 90:3288-301. [PMID: 26699643 PMCID: PMC4794667 DOI: 10.1128/jvi.02700-15] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 12/11/2015] [Indexed: 02/07/2023] Open
Abstract
Despite significant advances in the treatment of hepatitis C virus (HCV) infection, the need to develop preventative vaccines remains. Identification of the best vaccine candidates and evaluation of their performance in preclinical and clinical development will require appropriate neutralization assays utilizing diverse HCV isolates. We aimed to generate and characterize a panel of HCV E1E2 glycoproteins suitable for subsequent use in vaccine and therapeutic antibody testing. Full-length E1E2 clones were PCR amplified from patient-derived serum samples, cloned into an expression vector, and used to generate viral pseudoparticles (HCVpp). In addition, some of these clones were used to generate cell culture infectious (HCVcc) clones. The infectivity and neutralization sensitivity of these viruses were then determined. Bioinformatic and HCVpp infectivity screening of approximately 900 E1E2 clones resulted in the assembly of a panel of 78 functional E1E2 proteins representing distinct HCV genotypes and different stages of infection. These HCV glycoproteins differed markedly in their sensitivity to neutralizing antibodies. We used this panel to predict antibody efficacy against circulating HCV strains, highlighting the likely reason why some monoclonal antibodies failed in previous clinical trials. This study provides the first objective categorization of cross-genotype patient-derived HCV E1E2 clones according to their sensitivity to antibody neutralization. It has shown that HCV isolates have clearly distinguishable neutralization-sensitive, -resistant, or -intermediate phenotypes, which are independent of genotype. The panel provides a systematic means for characterization of the neutralizing response elicited by candidate vaccines and for defining the therapeutic potential of monoclonal antibodies. IMPORTANCE Hepatitis C virus (HCV) has a global burden of more than 170 million people, many of whom cannot attain the new, expensive, direct-acting antiviral therapies. A safe and effective vaccine that generates both T cell responses and neutralizing antibodies is required to eradicate the disease. Regions within the HCV surface glycoproteins E1 and E2 are essential for virus entry and are targets for neutralizing antibodies. Screening of vaccine candidates requires suitable panels of glycoproteins that represent the breadth of neutralization resistance. Use of a standard reference panel for vaccine studies will ensure comparability of data sets, as has become routine for HIV-1. Here, we describe a large panel of patient-derived HCV glycoproteins with an assessment of their neutralization sensitivity to defined monoclonal antibodies, which has enabled us to predict their likely efficacy in the wider HCV-infected population. The panel could also be important for future selection of additional therapeutic antibodies and for vaccine design.
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12
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Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME. Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine-induced neutralizing activity. Hepatology 2015; 62:1670-82. [PMID: 26251214 PMCID: PMC4681649 DOI: 10.1002/hep.28108] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 08/03/2015] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P ≤ 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003). CONCLUSION These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.
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Affiliation(s)
- Alla Kachko
- Division of Viral ProductsCBER/FDASilver SpringMD
| | - Sharon E. Frey
- Division of Infectious Diseases, Allergy and ImmunologySaint Louis University School of MedicineSt LouisMO
| | - Lev Sirota
- Division of Biostatistics, Office of Biostatistics and EpidemiologyCBER/FDASilver SpringMD
| | - Ranjit Ray
- Division of Infectious Diseases, Allergy and ImmunologySaint Louis University School of MedicineSt LouisMO
| | | | | | - Pei Zhang
- Division of HematologyCBER/FDASilver SpringMD
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13
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Kim H, Lee KW, Yi NJ, Lee HW, Choi Y, Suh SW, Jeong J, Suh KS. Response-Guided Therapy for Hepatitis C Virus Recurrence Based on Early Protocol Biopsy after Liver Transplantation. J Korean Med Sci 2015; 30:1577-83. [PMID: 26539000 PMCID: PMC4630472 DOI: 10.3346/jkms.2015.30.11.1577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 07/29/2015] [Indexed: 11/20/2022] Open
Abstract
Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and progressive. Here, we report recent results of response-guided therapy for HCV recurrence based on early protocol biopsy after LT. We reviewed patients who underwent LT for HCV related liver disease between 2010 and 2012. Protocol biopsies were performed at 3, 6, and 12 months after LT in HCV recurrence (positive HCV-RNA). For any degree of fibrosis, ≥ moderate inflammation on histology or HCV hepatitis accompanying with abnormal liver function, we treated with pegylated interferon and ribavirin. We adjusted treatment period according to individual response to treatment. Among 41 HCV related recipients, 25 (61.0%) who underwent protocol biopsies more than once were enrolled in this study. The mean follow-up time was 43.1 (range, 23-55) months after LT. Genotype 1 and 2 showed in 56.0% and 36.0% patients, respectively. Of the 25 patients, 20 (80.0%) started HCV treatment after LT. Rapid or early virological response was observed in 20 (100%) patients. Fifteen (75.0%) patients finished the treatment with end-of-treatment response. Sustained virological response (SVR) was in 11 (55.0%) patients, including 5 (41.7%) of 12 genotype 1 and 6 (75.0%) of 8 non-genotype 1 (P = 0.197). Only rapid or complete early virological response was a significant predictor for HCV treatment response after LT (100% in SVR group vs. 55.6% in non-SVR group, P = 0.026). Overall 3-yr survival rate was 100%. In conclusion, response-guided therapy for HCV recurrence based on early protocol biopsy after LT shows encouraging results.
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Affiliation(s)
- Hyeyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Suk-Won Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jaehong Jeong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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14
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Paciello R, Urbanowicz RA, Riccio G, Sasso E, McClure CP, Zambrano N, Ball JK, Cortese R, Nicosia A, De Lorenzo C. Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb. J Gen Virol 2015; 97:82-94. [PMID: 26519290 DOI: 10.1099/jgv.0.000330] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross-competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination.
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Affiliation(s)
- Rolando Paciello
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
| | - Richard A Urbanowicz
- School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
- NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
| | - Gennaro Riccio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
| | - Emanuele Sasso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
| | - C Patrick McClure
- School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
- NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
| | - Nicola Zambrano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
| | - Jonathan K Ball
- School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
- NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
| | | | - Alfredo Nicosia
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
| | - Claudia De Lorenzo
- Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy
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15
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Schweitzer CJ, Liang TJ. Border Control in Hepatitis C Virus Infection: Inhibiting Viral Entry. ACS Infect Dis 2015; 1:416-9. [PMID: 27617924 DOI: 10.1021/acsinfecdis.5b00060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A new era has begun in the treatment of hepatitis C virus (HCV) infection with powerful yet expensive therapies. New treatments are emerging that target the entry step of HCV and could potentially block reinfection after liver transplant. These treatments include antibodies, which target the virus or host receptors required by HCV. Additionally, several new and previously approved small-molecule compounds have been described that target unique aspects of HCV entry. Overall, the blocking entry represents an attractive strategy that could yield powerful combination therapies to combat HCV.
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Affiliation(s)
- Cameron J. Schweitzer
- Liver Diseases
Branch, National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States
| | - T. Jake Liang
- Liver Diseases
Branch, National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States
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16
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Barsa JE, Branch AD, Schiano TD. A pleasant dilemma to have: to treat the HCV patient on the waiting list or to treat post-liver transplantation? Clin Transplant 2015; 29:859-65. [DOI: 10.1111/ctr.12596] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2015] [Indexed: 12/13/2022]
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Abstract
PURPOSE OF REVIEW Hepatitis C virus (HCV) infection remains the leading indication for liver transplant, and viral eradication prior to liver transplant to prevent disease recurrence has traditionally been challenging because of the poor tolerability and efficacy of available therapies. However, with the recent introduction of potent interferon (IFN)-free direct acting antiviral regimens, viral eradication prior to liver transplant is now possible. RECENT FINDINGS Although data are limited, several proof of concept studies have now shown high rates of safety and efficacy in patients with compensated as well as mild-to-moderately decompensated cirrhosis. Although, treatment on the liver transplant waiting list can safely prevent postliver transplant recurrence in selected patients, the ideal regimen and treatment duration have yet to be determined. SUMMARY Although IFN-free therapies represent a tremendous advance in our ability to cure this previously difficult to treat population, additional data on the safety of these regimens, particularly in patients with severely decompensated cirrhosis, the consequences of virologic failure and the impact of viral eradication on short- and long-term liver function are urgently needed.
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18
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Tarr AW, Khera T, Hueging K, Sheldon J, Steinmann E, Pietschmann T, Brown RJP. Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design. Viruses 2015; 7:3995-4046. [PMID: 26193307 PMCID: PMC4517138 DOI: 10.3390/v7072809] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/19/2015] [Accepted: 07/08/2015] [Indexed: 12/13/2022] Open
Abstract
In the 26 years since the discovery of Hepatitis C virus (HCV) a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA) regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design.
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Affiliation(s)
- Alexander W Tarr
- School of Life Sciences, Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Tanvi Khera
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Kathrin Hueging
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Julie Sheldon
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Eike Steinmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Thomas Pietschmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig 38124, Germany.
| | - Richard J P Brown
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
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19
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de Jong YP, Dorner M, Mommersteeg MC, Xiao JW, Balazs AB, Robbins JB, Winer BY, Gerges S, Vega K, Labitt RN, Donovan BM, Giang E, Krishnan A, Chiriboga L, Charlton MR, Burton DR, Baltimore D, Law M, Rice CM, Ploss A. Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 2015; 6:254ra129. [PMID: 25232181 DOI: 10.1126/scitranslmed.3009512] [Citation(s) in RCA: 175] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs-AR3A, AR3B, and AR4A-delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.
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Affiliation(s)
- Ype P de Jong
- Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA. Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
| | - Marcus Dorner
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Michiel C Mommersteeg
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Jing W Xiao
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | | | - Justin B Robbins
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Benjamin Y Winer
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Sherif Gerges
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Kevin Vega
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Rachael N Labitt
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Bridget M Donovan
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Erick Giang
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Anuradha Krishnan
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Luis Chiriboga
- Department of Pathology, New York University Medical Center, New York, NY 10016, USA
| | - Michael R Charlton
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Dennis R Burton
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - David Baltimore
- Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
| | - Mansun Law
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Charles M Rice
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Alexander Ploss
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
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20
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Ji C, Liu Y, Pamulapati C, Bohini S, Fertig G, Schraeml M, Rubas W, Brandt M, Ries S, Ma H, Klumpp K. Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody. Hepatology 2015; 61:1136-44. [PMID: 25417967 DOI: 10.1002/hep.27603] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 11/13/2014] [Indexed: 01/01/2023]
Abstract
UNLABELLED CD81 is a required receptor for hepatitis C virus (HCV) infection of human hepatocytes in vitro. We generated several high-affinity anti-human CD81 monoclonal antibodies (mAbs) that demonstrated potent, specific, and cross-genotype inhibition of HCV entry. One of these mAbs, K04, was administered to human liver chimeric mice before or after HCV infection to determine its ability to prevent HCV infection or spread of HCV infection, respectively. All vehicle control mice established HCV infection, reaching steady-state levels of serum HCV RNA by day 21. Pretreatment of mice with K04 prevented HCV infection in all mice (n = 5). Treatment of mice with mAb K04 every 3 days for 21 days, starting at 6 hours postinfection, resulted in effective inhibition of virus spread. In 3 mice that were sacrificed on day 24, serum HCV levels remained detectable, below the limit of quantification (LOQ), indicating that infection was established, but virus spread was blocked, by the anti-CD81 mAb. In 5 additional mice that were followed for a longer time, virus remained detectable, below LOQ, until days 24 and 30 in 4 of 5 mice. In the fifth mouse, viral load was quantifiable, but reduced to 64-fold below the mean viral load in vehicle control at day 24. In addition, 2 of 5 mice cleared the infection by day 30 and 1 mouse had undetectable virus load from day 6 onward. CONCLUSION These results demonstrate that CD81 is required for HCV infection and virus spread in vivo, and that anti-CD81 antibodies such as K04 may have potential as broad-spectrum antiviral agents for prevention and treatment of HCV infection.
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21
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Kong L, Jackson KN, Wilson IA, Law M. Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design. Curr Opin Virol 2015; 11:148-57. [PMID: 25932568 PMCID: PMC4507806 DOI: 10.1016/j.coviro.2015.04.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 04/08/2015] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus infects nearly 3% of the world's population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and hepatocellular carcinoma in endemic countries. Although antiviral drugs are now available, they are not readily accessible to marginalized social groups and developing nations that are disproportionally impacted by HCV. To stop the HCV pandemic, a vaccine is needed. Recent advances in HCV research have provided new opportunities for studying HCV neutralizing antibodies and their subsequent use for rational vaccine design. It is now recognized that neutralizing antibodies to conserved antigenic sites of the virus can cross-neutralize diverse HCV genotypes and protect against infection in vivo. Structural characterization of the neutralizing epitopes has provided valuable information for design of candidate immunogens.
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Affiliation(s)
- Leopold Kong
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Kelli N Jackson
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Ian A Wilson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Mansun Law
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
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22
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Lin LT, Chung CY, Hsu WC, Chang SP, Hung TC, Shields J, Russell RS, Lin CC, Li CF, Yen MH, Tyrrell DLJ, Lin CC, Richardson CD. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry. J Hepatol 2015; 62:541-548. [PMID: 25450204 DOI: 10.1016/j.jhep.2014.10.040] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 10/07/2014] [Accepted: 10/22/2014] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS A vaccine against hepatitis C virus (HCV) is unavailable and cost-effective antivirals that prevent HCV infection and re-infection, such as in the transplant setting, do not exist. In a search for novel and economical prophylactic agents, we examined the antiviral activity of saikosaponins (SSa, SSb2, SSc, and SSd) from Bupleurum kaoi root (BK) as entry inhibitors against HCV infection. METHODS Infectious HCV culture systems were used to examine the effect of saikosaponins on the complete virus life cycle (entry, RNA replication/translation, and particle production). Antiviral activity against various HCV genotypes, clinical isolates, and infection of primary human hepatocytes were also evaluated. RESULTS BK and the saikosaponins potently inhibited HCV infection at non-cytotoxic concentrations. These natural agents targeted early steps of the viral life cycle, while leaving replication/translation, egress, and spread relatively unaffected. In particular, we identified SSb2 as an efficient inhibitor of early HCV entry, including neutralization of virus particles, preventing viral attachment, and inhibiting viral entry/fusion. Binding analysis, using soluble viral glycoproteins, demonstrated that SSb2 acted on HCV E2. Moreover, SSb2 inhibited infection by several genotypic strains and prevented binding of serum-derived HCV onto hepatoma cells. Finally, treatment with the compound blocked HCV infection of primary human hepatocytes. CONCLUSIONS Due to its potency, SSb2 may be of value for development as an antagonist of HCV entry and could be explored as prophylactic treatment during the course of liver transplantation.
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Affiliation(s)
- Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chueh-Yao Chung
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Chan Hsu
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shun-Pang Chang
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ting-Chun Hung
- Department of Clinical Pathology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Justin Shields
- Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada
| | - Rodney S Russell
- Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Chih-Chan Lin
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chien-Feng Li
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Ming-Hong Yen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Chun-Ching Lin
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Christopher D Richardson
- Department of Pediatrics and Canadian Center for Vaccinology, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
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23
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Vercauteren K, Mesalam AA, Leroux-Roels G, Meuleman P. Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization. World J Gastroenterol 2014; 20:15975-91. [PMID: 25473151 PMCID: PMC4239485 DOI: 10.3748/wjg.v20.i43.15975] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/09/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infections represent a major global health problem. End-stage liver disease caused by chronic HCV infection is a major indication for liver transplantation. However, after transplantation the engrafted liver inevitably becomes infected by the circulating virus. Direct acting antivirals are not yet approved for use in liver transplant patients, and limited efficacy and severe side effects hamper the use of pegylated interferon combined with ribavirin in a post-transplant setting. Therefore, alternative therapeutic options need to be explored. Viral entry represents an attractive target for such therapeutic intervention. Understanding the mechanisms of viral entry is essential to define the viral and cellular factors involved. The HCV life cycle is dependent of and associated with lipoprotein physiology and the presence of lipoproteins has been correlated with altered antiviral efficacy of entry inhibitors. In this review, we summarise the current knowledge on how lipoprotein physiology influences the HCV life cycle. We focus especially on the influence of lipoproteins on antibodies that target HCV envelope proteins or antibodies that target the cellular receptors of the virus. This information can be particularly relevant for the prevention of HCV re-infection after liver transplantation.
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24
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Vercauteren K, Van Den Eede N, Mesalam AA, Belouzard S, Catanese MT, Bankwitz D, Wong-Staal F, Cortese R, Dubuisson J, Rice CM, Pietschmann T, Leroux-Roels G, Nicosia A, Meuleman P. Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents. Hepatology 2014; 60:1508-18. [PMID: 24797654 PMCID: PMC4211977 DOI: 10.1002/hep.27196] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023]
Abstract
UNLABELLED Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect. CONCLUSION HCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting.
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Affiliation(s)
- Koen Vercauteren
- Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium
| | - Naomi Van Den Eede
- Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium
| | - Ahmed Atef Mesalam
- Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium
| | - Sandrine Belouzard
- Institut Pasteur de Lille, Center for Infection & Immunity of Lille, Inserm U1019, CNRS UMR8204, Université Lille Nord de France
| | - Maria Teresa Catanese
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA,Department of Infectious Diseases, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, United Kingdom
| | - Dorothea Bankwitz
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | | | | | - Jean Dubuisson
- Institut Pasteur de Lille, Center for Infection & Immunity of Lille, Inserm U1019, CNRS UMR8204, Université Lille Nord de France
| | - Charles M. Rice
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA
| | - Thomas Pietschmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Geert Leroux-Roels
- Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium
| | - Alfredo Nicosia
- CEINGE, via Gaetano Salvatore 486, 80145, Naples, Italy,Department of Molecular Medicine and Medical Biotechnology, University of Naples Frederico II, Naples, Italy
| | - Philip Meuleman
- Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium,Corresponding author: Prof. Dr. Philip Meuleman, Center for Vaccinology – Ghent University, UZ Gent, Building A, 1st floor, De Pintelaan 185, B-9000 Gent, Belgium., Phone: +32 9 332 02 05, Fax: +32 9 332 63 11,
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25
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Bukong TN, Momen-Heravi F, Kodys K, Bala S, Szabo G. Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS Pathog 2014; 10:e1004424. [PMID: 25275643 PMCID: PMC4183590 DOI: 10.1371/journal.ppat.1004424] [Citation(s) in RCA: 335] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 08/26/2014] [Indexed: 12/11/2022] Open
Abstract
Antibodies targeting receptor-mediated entry of HCV into hepatocytes confer limited therapeutic benefits. Evidence suggests that exosomes can transfer genetic materials between cells; however, their role in HCV infection remains obscure. Here, we show that exosomes isolated from sera of chronic HCV infected patients or supernatants of J6/JFH1-HCV-infected Huh7.5 cells contained HCV RNA. These exosomes could mediate viral receptor-independent transmission of HCV to hepatocytes. Negative sense HCV RNA, indicative of replication competent viral RNA, was present in exosomes of all HCV infected treatment non-responders and some treatment-naïve individuals. Remarkably, HCV RNA was associated with Ago2, HSP90 and miR-122 in exosomes isolated from HCV-infected individuals or HCV-infected Huh7.5 cell supernatants. Exosome-loading with a miR-122 inhibitor, or inhibition of HSP90, vacuolar H+-ATPases, and proton pumps, significantly suppressed exosome-mediated HCV transmission to naïve cells. Our findings provide mechanistic evidence for HCV transmission by blood-derived exosomes and highlight potential therapeutic strategies.
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Affiliation(s)
- Terence N. Bukong
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Fatemeh Momen-Heravi
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- * E-mail:
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26
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Bunchorntavakul C, Reddy KR. Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances. J Clin Transl Hepatol 2014; 2:124-33. [PMID: 26357623 PMCID: PMC4521260 DOI: 10.14218/jcth.2014.00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/13/2014] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
Management of hepatitis C (HCV) in liver transplantation (LT) population presents unique challenges. Suboptimal graft survival in HCV+ LT recipients is attributable to universal HCV recurrence following LT. Although eradication of HCV prior to LT is ideal for the prevention of HCV recurrence it is often limited by adverse events, particularly in patients with advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCV antibodies is ineffective. Early antiviral therapy after LT has been investigated, but no clear benefit has been demonstrated. Protocol liver biopsy is generally recommended in HCV+ LT recipients, and antiviral therapy can be considered in those with severe/progressive HCV recurrence. Sustained virological response (SVR) can be achieved in approximately 30% of LT recipients with pegylated interferon/ribavirin (PEG-IFN/RBV) with survival benefit, but adverse effects are common. Favorable patient characteristics for response to therapy include non-1 genotype, previously untreated, low baseline HCV-RNA, and donor IL28B genotype CC. Direct acting antiviral (DAA)-based triple therapy is associated with higher rates of SVR, but with similar or slightly higher rates of side effects, and immunosuppressive regimens need to be closely monitored and adjusted during the treatment period. Notably, the safety and efficacy of HCV treatment are very likely to improve with newer generation DAA. The benefit of immunosuppressive strategy on the natural history HCV recurrence has not been well elucidated. Based upon available evidence, cyclosporine A (CSA), mycophenolate mofetil (MMF), and sirolimus appear to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms appear to impact the course and treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival probability.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
| | - K. Rajender Reddy
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
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27
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Ball JK, Tarr AW, McKeating JA. The past, present and future of neutralizing antibodies for hepatitis C virus. Antiviral Res 2014; 105:100-11. [PMID: 24583033 PMCID: PMC4034163 DOI: 10.1016/j.antiviral.2014.02.013] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 02/08/2014] [Accepted: 02/13/2014] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease and hepatocellular carcinoma worldwide. HCV establishes a chronic infection in the majority of cases. However, some individuals clear the virus, demonstrating a protective role for the host immune response. Although new all-oral drug combinations may soon replace traditional ribavirin-interferon therapy, the emerging drug cocktails will be expensive and associated with side-effects and resistance, making a global vaccine an urgent priority. T cells are widely accepted to play an essential role in clearing acute HCV infection, whereas the role antibodies play in resolution and disease pathogenesis is less well understood. Recent studies have provided an insight into viral neutralizing determinants and the protective role of antibodies during infection. This review provides a historical perspective of the role neutralizing antibodies play in HCV infection and discusses the therapeutic benefits of antibody-based therapies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Jonathan K Ball
- School of Life Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom
| | - Alexander W Tarr
- School of Life Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom
| | - Jane A McKeating
- Viral Hepatitis Research Group and Centre for Human Virology, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
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Gurusamy KS, Tsochatzis E, Toon CD, Davidson BR, Burroughs AK. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation. Cochrane Database Syst Rev 2013; 2013:CD006573. [PMID: 24297303 PMCID: PMC6599865 DOI: 10.1002/14651858.cd006573.pub3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND It is not clear whether prophylactic antiviral therapy is indicated to improve patient and graft survival in patients undergoing liver transplantation for chronic decompensated hepatitis C virus (HCV) infection. OBJECTIVES To compare the benefits and harms of different prophylactic antiviral therapies for patients undergoing liver transplantation for chronic HCV infection. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013. SELECTION CRITERIA Only randomised clinical trials irrespective of language, blinding, or publication status and comparing various prophylactic antiviral therapies (alone or in combination) in the prophylactic treatment of patients undergoing liver transplantation for chronic HCV infection. DATA COLLECTION AND ANALYSIS Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) or hazard ratio (HR) with 95% confidence intervals (CI) using the fixed-effect and the random-effects models based on available case analysis. MAIN RESULTS A total of 501 liver transplant recipients undergoing liver transplantation for chronic HCV infection were randomised in 12 trials to various experimental interventions and control interventions. The proportion of genotype I varied between 49% and 100% in the seven trials that reported the genotype. Only one or two trials were included under each comparison. All the trials were of high risk of bias. Ten trials including 441 liver transplant recipients provided data for this review.There were no significant differences in the 90-day mortality (1 trial; 81 participants; 5/35 (adjusted proportion: 14.2%) in interferon group versus 5/46 (10.9%) in control group; RR 1.31; 95% CI 0.41 to 4.19); mortality at maximal follow-up (2 trials; 105 participants; 7/47 (adjusted proportion: 14.8%) in interferon group versus 10/58 (17.2%) in control group; RR 0.86; 95% CI 0.36 to 2.08); long-term mortality (1 trial; 81 participants; HR 0.45; 95% CI 0.13 to 1.56); mortality at maximal follow-up (1 trial; 54 participants; 1/26 (3.9%) in pegylated interferon group versus 2/28 (7.1%) in control group; RR 0.54; 95% CI 0.05 to 5.59); 90-day mortality (1 trial; 115 participants; 5/55 (9.1%) in pegylated interferon plus ribavirin group versus 3/60 (5.0%) in control group; RR 1.82; 95% 0.46 to 7.25); 90-day mortality (3 trials; 53 participants; 3/37 (adjusted proportion: 4.3%) in HCV antibody group versus 1/16 (6.3%) in placebo group; RR 0.69; 95% CI 0.15 to 3.11); or 90-day mortality (2 trials; 31 participants; 2/14 (adjusted proportion: 16.2%) in HCV antibody high-dose group versus 1/17 (5.9%) in HCV antibody low-dose group; RR 2.75; 95% CI; 0.30 to 25.35). There were no significant differences in the retransplantation at maximal follow-up (2 trials; 105 participants; 2/47 (adjusted proportion: 4.0%) in interferon group versus 2/58 (3.4%) in control group; RR 1.17; 95% CI 0.22 to 6.2); 90-day retransplantation (1 trial; 18 participants; 1/12 (8.3%) in HCV antibody group versus 0/6 (0%) in control group; RR 1.71; 95% CI 0.09 to 32.93); or 90-day retransplantation (1 trial; 12 participants; 1/6 (17.7%) in HCV antibody high-dose group versus 0/6 (0%) in HCV antibody low-dose group; RR 3.00; 95% CI 0.15 to 61.74). There were no significant differences in serious adverse events, graft rejection, worsening of fibrosis, or HCV recurrence between intervention and control groups in any of the comparisons that reported these outcomes. None of the trials reported quality of life, liver decompensation, intensive therapy unit stay, or hospital stay. Life-threatening adverse events were not reported in either group in any of the comparisons. AUTHORS' CONCLUSIONS There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation. Further randomised clinical trials with adequate trial methodology and adequate duration of follow-up are necessary.
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Affiliation(s)
- Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free Hospital,Rowland Hill StreetLondonUKNW3 2PF
| | - Emmanuel Tsochatzis
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Clare D Toon
- West Sussex County CouncilPublic Health1st Floor, The GrangeTower StreetChichesterWest SussexUKPO19 1QT
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free Hospital,Rowland Hill StreetLondonUKNW3 2PF
| | - Andrew K Burroughs
- Royal Free Hampstead NHS Foundation TrustSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
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29
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Macarthur KL, Smolic R, Smolic MV, Wu CH, Wu GY. Update on the Development of Anti-Viral Agents Against Hepatitis C. J Clin Transl Hepatol 2013; 1:9-21. [PMID: 26357602 PMCID: PMC4521270 DOI: 10.14218/jcth.2013.007xx] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 05/14/2013] [Accepted: 05/14/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects nearly 170 million people worldwide and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The search for a drug regimen that maximizes efficacy and minimizes side effects is quickly evolving. This review will discuss a wide range of drug targets currently in all phases of development for the treatment of HCV. Direct data from agents in phase III/IV clinical trials will be presented, along with reported side-effect profiles. The mechanism of action of all treatments and resistance issues are highlighted. Special attention is given to available trial data supporting interferon-free treatment regimens. HCV has become an increasingly important public health concern, and it is important for physicians to stay up to date on the rapidly growing novel therapeutic options.
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Affiliation(s)
| | | | | | - Catherine H. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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30
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Ciria R, Pleguezuelo M, Khorsandi SE, Davila D, Suddle A, Vilca-Melendez H, Rufian S, de la Mata M, Briceño J, Cillero PL, Heaton N. Strategies to reduce hepatitis C virus recurrence after liver transplantation. World J Hepatol 2013; 5:237-50. [PMID: 23717735 PMCID: PMC3664282 DOI: 10.4254/wjh.v5.i5.237] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 11/16/2012] [Accepted: 12/01/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.
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Affiliation(s)
- Ruben Ciria
- Ruben Ciria, Shirin Elizabeth Khorsandi, Diego Davila, Abid Suddle, Hector Vilca-Melendez, Nigel Heaton, Institute of Liver Studies, King's College Hospital, London SE5 9RS, United Kingdom
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31
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Takebe Y, Saucedo CJ, Lund G, Uenishi R, Hase S, Tsuchiura T, Kneteman N, Ramessar K, Tyrrell DLJ, Shirakura M, Wakita T, McMahon JB, O'Keefe BR. Antiviral lectins from red and blue-green algae show potent in vitro and in vivo activity against hepatitis C virus. PLoS One 2013; 8:e64449. [PMID: 23700478 PMCID: PMC3660260 DOI: 10.1371/journal.pone.0064449] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 04/15/2013] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a significant public health problem with over 170,000,000 chronic carriers and infection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimated to result in ∼10,000 deaths in the United States in the year 2011. Current treatment options for HCV infection are limited to PEG-ylated interferon alpha (IFN-α), the nucleoside ribavirin and the recently approved HCV protease inhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the protein griffithsin, is readily bioavailable after subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV therapy and that these proteins should be studied further for their therapeutic potential.
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Affiliation(s)
- Yutaka Takebe
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Carrie J. Saucedo
- Molecular Targets Laboratory, SAIC-Frederick, Frederick, Maryland, United States of America
| | | | - Rie Uenishi
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Saiki Hase
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takayo Tsuchiura
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | | | - Koreen Ramessar
- Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America
| | | | | | - Takaji Wakita
- Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - James B. McMahon
- Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America
| | - Barry R. O'Keefe
- Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America
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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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Chung RT, Gordon FD, Curry MP, Schiano TD, Emre S, Corey K, Markmann J, Hertl M, Pomposelli JJ, Pomfret EA, Florman S, Schilsky M, Broering TJ, Finberg RW, Szabo G, Zamore PD, Khettry U, Babcock GJ, Ambrosino DM, Leav B, Leney M, Smith HL, Molrine DC. Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study. Am J Transplant 2013; 13:1047-1054. [PMID: 23356386 PMCID: PMC3618536 DOI: 10.1111/ajt.12083] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 11/20/2012] [Accepted: 12/04/2012] [Indexed: 01/25/2023]
Abstract
Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.
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Affiliation(s)
- R. T. Chung
- Massachusetts General Hospital, Boston, MA, United States
| | - F. D. Gordon
- Lahey Clinic Medical Center, Burlington, MA, United States
| | - M. P. Curry
- Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - T. D. Schiano
- Mount Sinai Medical Center, New York, NY, United States
| | - S. Emre
- Yale New Haven Hospital, New Haven, CT, United States
| | - K. Corey
- Massachusetts General Hospital, Boston, MA, United States
| | - J. Markmann
- Massachusetts General Hospital, Boston, MA, United States
| | - M. Hertl
- Massachusetts General Hospital, Boston, MA, United States
| | | | - E. A. Pomfret
- Lahey Clinic Medical Center, Burlington, MA, United States
| | - S. Florman
- Mount Sinai Medical Center, New York, NY, United States
| | - M. Schilsky
- Yale New Haven Hospital, New Haven, CT, United States
| | - T. J. Broering
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - R. W. Finberg
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - G. Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - P. D. Zamore
- Howard Hughes Medical Institute and Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, United States
| | - U. Khettry
- Lahey Clinic Medical Center, Burlington, MA, United States
| | - G. J. Babcock
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - D. M. Ambrosino
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - B. Leav
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - M. Leney
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - H. L. Smith
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
| | - D. C. Molrine
- MassBiologics, University of Massachusetts Medical School, Boston, MA, United States
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Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. J Hepatol 2013; 58:421-6. [PMID: 23073223 DOI: 10.1016/j.jhep.2012.10.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 10/01/2012] [Accepted: 10/08/2012] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.
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Mutimer D. Understanding the switchbacks: the impact of direct antivirals on the minimization of hepatitis C virus recurrence after transplantation. Liver Transpl 2012; 18 Suppl 2:S47-51. [PMID: 22887985 DOI: 10.1002/lt.23533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
1. Interferon (IFN) and ribavirin can be used in select patients before or after liver transplantation, and they can reduce the risk of recurrence or effect a cure in these settings. 2. Currently licensed direct-acting antiviral drugs are used with IFN and ribavirin, so the safety and tolerability of triple therapy will be worse than those of double therapy in pretransplant and posttransplant settings. 3. Drug-drug interactions [exemplified by the interactions of protease inhibitors (PIs) with tacrolimus and cyclosporine] and the need for dose modifications (exemplified by the need to modify ribavirin doses in patients with renal dysfunction) challenge the safe use of antiviral drugs after transplantation. 4. Experience with the use of human immunodeficiency virus PIs and emerging data about hepatitis C virus (HCV) PIs show that this class of drugs can be used with care after transplantation. 5. Attempts to prevent HCV graft infections through the use of HCV immunoglobulin immediately after transplantation have been largely unsuccessful. 6. The blockade of cell surface HCV receptors with antibodies or small molecules appears to limit HCV cell entry in vivo and in a mouse model, and this may suggest a novel approach to limiting HCV recurrence at the time of transplantation.
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Affiliation(s)
- David Mutimer
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, United Kingdom.
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Chatel-Chaix L, Germain MA, Götte M, Lamarre D. Direct-acting and host-targeting HCV inhibitors: current and future directions. Curr Opin Virol 2012; 2:588-98. [PMID: 22959589 DOI: 10.1016/j.coviro.2012.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 08/07/2012] [Indexed: 02/07/2023]
Abstract
The inclusion of NS3 protease inhibitors to the interferon-containing standard of care improved sustained viral response rates in hepatitis C virus (HCV) infected patients. However, there is still an unmet medical need as this drug regimen is poorly tolerated and lacks efficacy, especially in difficult-to-treat patients. Intense drug discovery and development efforts have focused on direct-acting antivirals (DAA) that target NS3 protease, NS5B polymerase and the NS5A protein. DAA combinations are currently assessed in clinical trials. Alternative antivirals have emerged that target host machineries co-opted by HCV. Finally, continuous and better understanding of HCV biology allows speculating on the value of novel classes of DAA required in future personalized all-oral interferon-free combination therapy and for supporting global disease eradication.
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Affiliation(s)
- Laurent Chatel-Chaix
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Montréal, Québec H3T 1J4, Canada
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Morin TJ, Broering TJ, Leav BA, Blair BM, Rowley KJ, Boucher EN, Wang Y, Cheslock PS, Knauber M, Olsen DB, Ludmerer SW, Szabo G, Finberg RW, Purcell RH, Lanford RE, Ambrosino DM, Molrine DC, Babcock GJ. Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees. PLoS Pathog 2012; 8:e1002895. [PMID: 22952447 PMCID: PMC3431327 DOI: 10.1371/journal.ppat.1002895] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 07/23/2012] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412–423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5–1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation. The majority of individuals infected with hepatitis C virus (HCV) become chronically infected and many go on to develop liver failure requiring liver transplantation. Unfortunately, the transplanted liver becomes infected with HCV in nearly 100% of transplant patients. Current treatments for HCV are poorly tolerated after liver transplantation and graft health is compromised by infection. We have developed a monoclonal antibody called HCV1 that blocks HCV from infecting liver cells in culture. Using chimpanzees as a model for HCV infection, we demonstrate that HCV1 has the ability to prevent HCV infection. We also show that HCV1 can treat chimpanzees chronically infected with HCV and reduce plasma viral load to below the level of detection for a period of 7 to 21 days. The virus that reemerges in the treated chimpanzees was resistant to HCV1 neutralization demonstrating target engagement. Given the ability of HCV1 to protect chimpanzees from HCV infection, we speculate that HCV1 may be beneficial in HCV- infected patients undergoing liver transplant.
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Affiliation(s)
- Trevor J. Morin
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Teresa J. Broering
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Brett A. Leav
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Barbra M. Blair
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Kirk J. Rowley
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Elisabeth N. Boucher
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Yang Wang
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Peter S. Cheslock
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Michael Knauber
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - David B. Olsen
- Merck Research Laboratories, West Point, Pennsylvania, United States of America
| | - Steve W. Ludmerer
- Merck Research Laboratories, West Point, Pennsylvania, United States of America
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Robert W. Finberg
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Robert H. Purcell
- National Institutes of Health, Bethesda, Maryland, United States of America
| | - Robert E. Lanford
- Department of Virology and Immunology, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, Texas, United States of America
| | - Donna M. Ambrosino
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Deborah C. Molrine
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
| | - Gregory J. Babcock
- MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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Carbone M, Lenci I, Baiocchi L. Prevention of hepatitis C recurrence after liver transplantation: An update. World J Gastrointest Pharmacol Ther 2012; 3:36-48. [PMID: 22966482 PMCID: PMC3437445 DOI: 10.4292/wjgpt.v3.i4.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation, being associated with accelerated progression to cirrhosis, graft loss and death. Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus (HCV) infection compared to HCV-negative recipients. Many variables may impact on recurrent HCV liver disease. Overall, excess immunosuppression is believed to be a key factor; however, no immunosuppressive regimen has been identified to be more beneficial or less harmful. Donor age limitations, exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects. After transplantation, antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients. New findings in the field of immunotherapy and genomic medicine applied to this context are promising.
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Affiliation(s)
- Marco Carbone
- Marco Carbone, Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom
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40
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Abstract
Owing to the tremendous effort from both academia and industry, drug development for hepatitis C virus (HCV) infection has been flourishing, with a range of pipeline compounds at various stages of development. Although combination of the recently launched serine protease inhibitors will further improve the response rate of current interferon-based therapy, some intrinsic limitations of these compounds and the tendency of resistance development by the virus, urge the development of alternative or additional therapeutic strategies. In this article we provide an overview of different host and viral factors which have emerged as new potential targets for therapeutic intervention using state-of-the-art technologies.
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Akamatsu N, Sugawara Y. Liver transplantation and hepatitis C. Int J Hepatol 2012; 2012:686135. [PMID: 22900194 PMCID: PMC3412106 DOI: 10.1155/2012/686135] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 05/21/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Lacek K, Vercauteren K, Grzyb K, Naddeo M, Verhoye L, Słowikowski MP, Fafi-Kremer S, Patel AH, Baumert TF, Folgori A, Leroux-Roels G, Cortese R, Meuleman P, Nicosia A. Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice. J Hepatol 2012; 57:17-23. [PMID: 22414763 DOI: 10.1016/j.jhep.2012.02.018] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Revised: 01/09/2012] [Accepted: 02/01/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV)-induced end-stage liver disease is currently the major indication for liver transplantation in the Western world. After transplantation, the donor liver almost inevitably becomes infected by the circulating virus and disease progression is accelerated in immune suppressed transplant patients. The current standard therapy, based on pegylated interferon and ribavirin, induces severe side effects and is often ineffective in this population. Therefore, new strategies to prevent graft re-infection are urgently needed. We have previously shown that monoclonal antibodies (mAbs) against the HCV co-receptor scavenger receptor class B type I (SR-BI/Cla1) inhibit infection by different HCV genotypes in cell culture. METHODS Using phage display libraries, we have generated a large set of novel human mAbs against SR-BI and evaluated their effectiveness in preventing HCV infection and direct cell-to-cell spread in vitro and in vivo using uPA-SCID mice with a humanized liver. RESULTS Eleven human monoclonal antibodies were generated that specifically recognize SR-BI. Two antibodies, mAb8 and mAb151, displayed the highest binding and inhibitory properties and also interfered with direct cell-to-cell spread in vitro. Studies in humanized mice showed that both antibodies were capable of preventing HCV infection and could block intrahepatic spread and virus amplification when administered 3 days after infection. Interestingly, anti-SR-BI therapy was effective against an HCV variant that escaped the control of the adaptive immune response in a liver transplant patient. CONCLUSIONS The anti-SR-BI mAbs generated in this study may represent novel therapeutic tools to prevent HCV re-infection of liver allografts.
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Vercauteren K, Leroux-Roels G, Meuleman P. Blocking HCV entry as potential antiviral therapy. Future Virol 2012. [DOI: 10.2217/fvl.12.47] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Laryea MA, Watt KD. Immunoprophylaxis against and prevention of recurrent viral hepatitis after liver transplantation. Liver Transpl 2012; 18:514-23. [PMID: 22315212 DOI: 10.1002/lt.23408] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The reinfection of the hepatic allograft with hepatitis B virus and hepatitis C virus can have important sequelae that result in poor long-term patient and graft survival. Although a response to treatment with antiviral medications can improve these outcomes, not all patients tolerate these medications or experience viral eradication. Avoiding reinfection of the graft is the most effective means of improving the long-term outcomes for these patient populations. This review is focused on the prevention of viral hepatitis reinfection after liver transplantation.
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Affiliation(s)
- Marie A Laryea
- Multi-Organ Transplant Program, Dalhousie University, Halifax, Nova Scotia, Canada
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Abstract
Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post-transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis.
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Affiliation(s)
- Bruno Roche
- Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France. France
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46
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Meuleman P, Catanese MT, Verhoye L, Desombere I, Farhoudi A, Jones CT, Sheahan T, Grzyb K, Cortese R, Rice CM, Leroux-Roels G, Nicosia A. A human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo. Hepatology 2012; 55:364-72. [PMID: 21953761 PMCID: PMC3262867 DOI: 10.1002/hep.24692] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 09/14/2011] [Indexed: 12/21/2022]
Abstract
UNLABELLED Endstage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate reinfection of the grafted donor liver by circulating virus is inevitable and liver disease progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients, whereas anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread by way of cell-cell contacts. We generated a human monoclonal antibody against scavenger receptor class B type I (SR-BI), monoclonal antibody (mAb)16-71, which can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 coculture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in "human liver urokinase-type plasminogen activator, severe combined immune deficiency (uPA-SCID) mice" (chimeric mice). A 2-week anti-SR-BI therapy that was initiated 1 day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day postexposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. CONCLUSION Using in vitro cell culture and human liver-chimeric mouse models, we show that a human mAb targeting the HCV coreceptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following antiviral therapy.
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Affiliation(s)
- Philip Meuleman
- Center for Vaccinology, Ghent University and Hospital, Gent, Belgium.
| | | | - Lieven Verhoye
- Center for Vaccinology, Ghent University and Hospital, Gent, Belgium
| | | | - Ali Farhoudi
- Center for Vaccinology, Ghent University and Hospital, Gent, Belgium
| | - Christopher T. Jones
- Center for the study of Hepatitis C, The Rockefeller University, New York, NY, USA
| | - Timothy Sheahan
- Center for the study of Hepatitis C, The Rockefeller University, New York, NY, USA
| | | | | | - Charles M Rice
- Center for the study of Hepatitis C, The Rockefeller University, New York, NY, USA
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47
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Naturally occurring antibodies that recognize linear epitopes in the amino terminus of the hepatitis C virus E2 protein confer noninterfering, additive neutralization. J Virol 2011; 86:2739-49. [PMID: 22171278 DOI: 10.1128/jvi.06492-11] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection can persist even in the presence of a broadly neutralizing antibody response. Various mechanisms that underpin viral persistence have been proposed, and one of the most recently proposed mechanisms is the presence of interfering antibodies that negate neutralizing responses. Specifically, it has been proposed that antibodies targeting broadly neutralizing epitopes located within a region of E2 encompassing residues 412 to 423 can be inhibited by nonneutralizing antibodies binding to a less conserved region encompassing residues 434 to 446. To investigate this phenomenon, we characterized the neutralizing and inhibitory effects of human-derived affinity-purified immunoglobulin fractions and murine monoclonal antibodies and show that antibodies to both regions neutralize HCV pseudoparticle (HCVpp) and cell culture-infectious virus (HCVcc) infection albeit with different breadths and potencies. Epitope mapping revealed the presence of overlapping but distinct epitopes in both regions, which may explain the observed differences in neutralizing phenotypes. Crucially, we failed to demonstrate any inhibition between these two groups of antibodies, suggesting that interference by nonneutralizing antibodies, at least for the region encompassing residues 434 to 446, does not provide a mechanism for HCV persistence in chronically infected individuals.
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48
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Edwards VC, Tarr AW, Urbanowicz RA, Ball JK. The role of neutralizing antibodies in hepatitis C virus infection. J Gen Virol 2011; 93:1-19. [PMID: 22049091 DOI: 10.1099/vir.0.035956-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Hepatitis C virus (HCV) is a blood-borne virus estimated to infect around 170 million people worldwide and is, therefore, a major disease burden. In some individuals the virus is spontaneously cleared during the acute phase of infection, whilst in others a persistent infection ensues. Of those persistently infected, severe liver diseases such as cirrhosis and primary liver cancer may develop, although many individuals remain asymptomatic. A range of factors shape the course of HCV infection, not least host genetic polymorphisms and host immunity. A number of studies have shown that neutralizing antibodies (nAb) arise during HCV infection, but that these antibodies differ in their breadth and mechanism of neutralization. Recent studies, using both mAbs and polyclonal sera, have provided an insight into neutralizing determinants and the likely protective role of antibodies during infection. This understanding has helped to shape our knowledge of the overall structure of the HCV envelope glycoproteins--the natural target for nAb. Most nAb identified to date target receptor-binding sites within the envelope glycoprotein E2. However, there is some evidence that other viral epitopes may be targets for antibody neutralization, suggesting the need to broaden the search for neutralization epitopes beyond E2. This review provides a comprehensive overview of our current understanding of the role played by nAb in HCV infection and disease outcome and explores the limitations in the study systems currently used. In addition, we briefly discuss the potential therapeutic benefits of nAb and efforts to develop nAb-based therapies.
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Affiliation(s)
- Victoria C Edwards
- School of Molecular Medical Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Alexander W Tarr
- School of Molecular Medical Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Richard A Urbanowicz
- School of Molecular Medical Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Jonathan K Ball
- School of Molecular Medical Sciences and The Nottingham Digestive Diseases Centre Biomedical Research Unit, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
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49
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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: 50] [Impact Index Per Article: 3.6] [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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50
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Abstract
Hepatitis C virus (HCV)-infected patients undergoing liver transplantation universally experience rapid reinfection of their new liver graft. Current treatment protocols do not prevent graft reinfection and, in addition, an accelerated disease progression is observed. In the present study, we have evaluated a novel strategy to prevent HCV infection using a lectin, griffithsin (GRFT) that specifically binds N-linked high-mannose oligosaccharides that are present on the viral envelope. The antiviral effect of GRFT was evaluated in vitro using the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems. We show here that preincubation of HCVpp and HCVcc with GRFT prevents infection of Huh-7 hepatoma cells. Furthermore, GRFT interferes with direct cell-to-cell transmission of HCV. GRFT acts at an early phase of the viral life cycle by interfering in a genotype-independent fashion with the interaction between the viral envelope proteins and the viral receptor CD81. The capacity of GRFT to prevent infection in vivo was evaluated using uPA(+/+)-SCID mice (uPA stands for urokinase-type plasminogen activator) that harbor human primary hepatocytes in their liver (chimeric mice). In this proof-of-concept trial, we demonstrated that GRFT can mitigate HCV infection of chimeric mice. Treated animals that did become infected demonstrated a considerable delay in the kinetics of the viral infection. Our data demonstrate that GRFT can prevent HCV infection in vitro and mitigate HCV infection in vivo. GRFT treatment of chronically infected HCV patients undergoing liver transplantation may be a suitable strategy to prevent infection of the liver allograft.
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