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1
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Tonnerre P. [Hepatitis C virus chronic infection: Exhausted T cells remain dysfunctional after cure]. Med Sci (Paris) 2022; 38:640-642. [PMID: 36094230 DOI: 10.1051/medsci/2022093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Pierre Tonnerre
- Université Paris Cité, Inserm, Immunologie humaine, physiopathologie et immunothérapie (HIPI), Paris, France
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2
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Zhao S, Si M, Deng X, Wang D, Kong L, Zhang Q. HCV inhibits M2a, M2b and M2c macrophage polarization via HCV core protein engagement with Toll‑like receptor 2. Exp Ther Med 2022; 24:522. [PMID: 35837038 PMCID: PMC9257937 DOI: 10.3892/etm.2022.11448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/25/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Shixing Zhao
- Department of Intensive Care Unit, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Meng Si
- Department of Foreign Languages, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Xianpei Deng
- Department of Gastroenterology, Digestive Diseases Hospital of Shandong First Medical University, Shandong Institute of Parasitic Diseases, Shandong First Medical University and Shandong Academy of Medical Sciences, Jining, Shandong 272000, P.R. China
| | - Dengqin Wang
- College of Clinical Medicine, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Lingbin Kong
- College of Clinical Medicine, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Qianqian Zhang
- College of Clinical Medicine, Jining Medical University, Jining, Shandong 272000, P.R. China
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3
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Modified E2 Glycoprotein of Hepatitis C Virus Enhances Proinflammatory Cytokines and Protective Immune Response. J Virol 2022; 96:e0052322. [PMID: 35612312 DOI: 10.1128/jvi.00523-22] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatitis C virus (HCV) is characterized by a high number of chronic cases owing to an impairment of innate and adaptive immune responses. CD81 on the cell surface facilitates HCV entry by interacting with the E2 envelope glycoprotein. In addition, CD81/E2 binding on immunity-related cells may also influence host response outcome to HCV infection. Here, we performed site-specific amino acid substitution in the front layer of E2 sequence to reduce CD81 binding and evaluate the potential of the resulting immunogen as an HCV vaccine candidate. The modified sE2 protein (F442NYT), unlike unmodified sE2, exhibited a significant reduction in CD81 binding, induced higher levels of proinflammatory cytokines, repressed anti-inflammatory response in primary monocyte-derived macrophages as antigen-presenting cells, and stimulated CD4+ T cell proliferation. Immunization of BALB/c mice with an E1/sE2F442NYT nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccine resulted in improved IgG1-to-IgG2a isotype switching, an increase in neutralizing antibodies against HCV pseudotype virus, a B and T cell proliferative response to antigens, and improved protection against infection with a surrogate recombinant vaccinia virus-expressing HCV E1-E2-NS2aa134-966 challenge model compared to E1/unmodified sE2 mRNA-LNP vaccine. Further investigation of the modified E2 antigen may provide helpful information for HCV vaccine development. IMPORTANCE Hepatitis C virus (HCV) E2-CD81 binding dampens protective immune response. We have identified that an alteration of amino acids in the front layer of soluble E2 (sE2) disrupts CD81 interaction and alters the cytokine response. Immunization with modified sE2F442NYT (includes an added potential N-linked glycosylation site and reduces CD81 binding activity)-mRNA-LNP candidate vaccine generates improved proinflammatory response and protective efficacy against a surrogate HCV vaccinia challenge model in mice. The results clearly suggested that HCV E2 exhibits immunoregulatory activity that inhibits induction of robust protective immune responses. Selection of engineered E2 antigen in an mRNA-LNP platform amenable to nucleic acid sequence alterations may open a novel approach for multigenotype HCV vaccine development.
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4
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Singh N, Ma M, Montano-Loza AJ, Bhanji RA. Learning from a rare phenomenon — spontaneous clearance of chronic hepatitis C virus post-liver transplant: A case report. World J Hepatol 2022; 14:456-463. [PMID: 35317181 PMCID: PMC8891670 DOI: 10.4254/wjh.v14.i2.456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/26/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) can lead to chronic liver damage resulting in cirrhosis and hepatocellular carcinoma. Spontaneous clearance of HCV has been documented after an acute infection in 20%-45% of individuals. However, spontaneously resolved chronic hepatitis C following liver transplant (LT) is rare and has been documented only in a few case reports. The phenomenon of spontaneous clearance of chronic hepatitis C occurs together with other meaningful events, which are typically associated with significant changes in the host immunity.
CASE SUMMARY We report three cases of spontaneous resolution of chronic hepatitis C following liver transplantation. These patients either failed or had no HCV treatment prior to transplant, but had spontaneous resolution of HCV post-LT as documented by undetectable polymerase chain reaction (PCR). Diagnosis of HCV was based on viremia through PCR or liver biopsy. All three patients currently undergo surveillance and have no recurrence of HCV.
CONCLUSION Examining each patient’s clinical course, we learned about many viral, host and cellular-factors that may have enhanced the host’s immunity leading to spontaneous clearance of HCV. Though HCV treatment has excellent cure rates, understanding this mechanism may provide clinicians with insights regarding timing and duration of treatment.
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Affiliation(s)
- Noreen Singh
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton T6G 2X8, Alberta, Canada
| | - Mang Ma
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton T6G 2X8, Alberta, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton T6G 2X8, Alberta, Canada
| | - Rahima A Bhanji
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton T6G 2X8, Alberta, Canada
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5
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Démoulins T, Baron ML, Gauchat D, Kettaf N, Reed SJ, Charpentier T, Kalinke U, Lamarre A, Ahmed R, Sékaly RP, Sarkar S, Kalia V. Induction of thymic atrophy and loss of thymic output by type-I interferons during chronic viral infection. Virology 2022; 567:77-86. [PMID: 35032866 DOI: 10.1016/j.virol.2021.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 11/30/2021] [Accepted: 12/20/2021] [Indexed: 01/30/2023]
Abstract
Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/β expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαβR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers.
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Affiliation(s)
- Thomas Démoulins
- Institute of Virology and Immunology, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | | | - Dominique Gauchat
- Centre Hospitalier de l'Université de Montréal (CHUM), 1000, rue Saint-Denis, Montréal, Québec, H2X 0C1, Canada
| | - Nadia Kettaf
- Laboratoire d'immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Saint-Luc, Montréal, QC, H2X 1P1, Canada
| | - Steven James Reed
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA
| | - Tania Charpentier
- Centre INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval, Québec, H7V 1B7, Canada
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Alain Lamarre
- Centre INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval, Québec, H7V 1B7, Canada
| | - Rafi Ahmed
- Department of Microbiology & Immunology, School of Medicine, Emory University, 1510 Clifton Road, Atlanta, GA, USA
| | - Rafick-Pierre Sékaly
- Department of Pathology, Emory University Winship Cancer Center, Atlanta, GA, USA
| | - Surojit Sarkar
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA; Department of Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Pediatrics, Division of Hematology and Oncology, University of Washington, Seattle, WA, 98195, USA.
| | - Vandana Kalia
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA; Department of Pediatrics, Division of Hematology and Oncology, University of Washington, Seattle, WA, 98195, USA.
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6
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Senff T, Menne C, Cosmovici C, Lewis-Ximenez LL, Aneja J, Broering R, Kim AY, Westendorf AM, Dittmer U, Scherbaum N, Lauer GM, Timm J. Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C. JCI Insight 2021; 7:155432. [PMID: 34905514 PMCID: PMC8855829 DOI: 10.1172/jci.insight.155432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022] Open
Abstract
Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry. In a longitudinal analysis during acute HCV infection, frequencies of activated CD38+ iNKT cells reproducibly declined in spontaneously resolving patients, whereas they were persistently elevated in patients progressing to chronic infection. During the first year of infection, the frequency of activated CD38+ or CD69+ iNKT cells strongly correlated with alanine transaminase levels with particularly pronounced correlations in spontaneously resolving patients. Increased frequencies of activated iNKT cells in chronic HCV infection were confirmed in cross-sectional analyses of PWID with chronic or spontaneously resolved HCV infection; however, no apparent functional differences were observed with various stimulation protocols. Our data suggest that iNKT cells are activated during acute hepatitis C and that activation is sustained in chronic infection. The correlation between the frequency of activated iNKT cells and alanine transaminase may point toward a role of iNKT cells in liver damage.
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Affiliation(s)
- Tina Senff
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christopher Menne
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christine Cosmovici
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | | | - Jasneet Aneja
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
| | - Arthur Y Kim
- Department of Medicine, Massachusetts General Hospital, Boston, United States of America
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Norbert Scherbaum
- Department for Addiction Medicine and Addictive Behavior, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Georg M Lauer
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Jörg Timm
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
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Abstract
Liver cancer is a global problem and hepatocellular carcinoma (HCC) accounts for about 85% of this cancer. In the USA, etiologies and risk factors for HCC include chronic hepatitis C virus (HCV) infection, diabetes, non-alcoholic steatohepatitis (NASH), obesity, excessive alcohol drinking, exposure to tobacco smoke, and genetic factors. Chronic HCV infection appears to be associated with about 30% of HCC. Chronic HCV infection induces multistep changes in liver, involving metabolic disorders, steatosis, cirrhosis and HCC. Liver carcinogenesis requires initiation of neoplastic clones, and progression to clinically diagnose malignancy. Tumor progression associates with profound exhaustion of tumor-antigen-specific CD8+T cells, and accumulation of PD-1hi CD8+T cells and Tregs. In this chapter, we provide a brief description of HCV and environmental/genetic factors, immune regulation, and highlight mechanisms of HCV associated HCC. We also underscore HCV treatment and recent paradigm of HCC progression, highlighted the current treatment and potential future therapeutic opportunities.
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Rezaee N, Babaeekhou L, Ghane M. Hepatitis C virus in Iran; transmission routes, growth in 3a genotype distribution, and lack of liver marker relation with genotypes. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2020; 25:96. [PMID: 33273941 PMCID: PMC7698380 DOI: 10.4103/jrms.jrms_482_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 02/24/2020] [Accepted: 05/27/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND The hepatitis C virus (HCV) outbreak in Iran is increasing. This study investigated the dissemination and transmission routes of HCV genotypes in different regions of Iran. The relationship between serum biochemical markers and viral genotypes was also assessed to find whether liver enzymes level can be considered as the markers for HCV genotypes. MATERIALS AND METHODS HCV-infected patients from different provinces of Iran (from August 2017 to March 2019) were enrolled. Nested reverse transcriptase polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR were used to discover the genotypes. The infection transmission routes in the study population were investigated and recorded. Serum samples with equal viral loud from the patients without other liver disorders were recruited to explore the association between the genotypes and the liver biochemical markers. RESULTS One thousand serum samples positive for the HCV genome were recruited. Genotype 3a was the most prevalent in the north, while genotype 1a was dominant at the center. In total, genotype 3a was the dominant genotype closely followed by 1a. Needle sharing by addicts was the most common transmission way of infection in Iran. This way was also the most for genotype 3a dissemination, and genotype 1a was transmitted mostly between family members. No significant association (P > 0.05) was observed between biochemical marker titers and HCV genotypes. CONCLUSION A shift in the distribution profile of HCV genotypes, related to the transmission routes, has happened over time. Public awareness of the main routes of HCV transmission can break the cycle of transmission. Liver enzyme values in HCV-infected patients showed no relation with genotypes and only represented hepatocellular dysfunction.
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Affiliation(s)
- Nastaran Rezaee
- Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
| | - Laleh Babaeekhou
- Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
| | - Maryam Ghane
- Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
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9
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Gidea CG, Narula N, Reyentovich A, Fargnoli A, Smith D, Pavone J, Lewis T, Karpe H, Stachel M, Rao S, Moreira A, Saraon T, Raimann J, Kon Z, Moazami N. Increased early acute cellular rejection events in hepatitis C-positive heart transplantation. J Heart Lung Transplant 2020; 39:1199-1207. [PMID: 32739334 DOI: 10.1016/j.healun.2020.06.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs). METHODS In this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs. RESULTS A total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (<56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT- recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT- group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8-45) in the NAT+ group vs 65 (IQR: 44-84) days in the NAT-. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004). CONCLUSIONS Transient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.
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Affiliation(s)
| | | | | | | | | | | | - Tyler Lewis
- Pharmacy, NYU Langone Medical Center, New York, New York
| | - Hannah Karpe
- Medical School, New York University School of Medicine, New York, New York
| | | | - Shaline Rao
- Division of Cardiology, Department of Medicine
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10
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Medel MLH, Reyes GG, Porras LM, Bernal AR, Luna JS, Garcia AP, Cordova J, Parra A, Mummidi S, Kershenobich D, Hernández J. Prolactin Induces IL-2 Associated TRAIL Expression on Natural Killer Cells from Chronic Hepatitis C Patients In vivo and In vitro. Endocr Metab Immune Disord Drug Targets 2020; 19:975-984. [PMID: 30520386 DOI: 10.2174/1871530319666181206125545] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/15/2018] [Accepted: 11/16/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Natural killer cells (NKC) are a major component of the innate immune response to HCV, mediating their effects through TRAIL and IFN-γ. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC. OBJECTIVE The study aims to explore if hyperprolactinemia can activate NKC in HCVp. METHODS We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-γ levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls. RESULTS The treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-γ. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained the viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls. CONCLUSION Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1-type cytokine profile. Also, an increase in TRAIL and IL-2 was associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp.
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Affiliation(s)
- Maria L H Medel
- Infectology Service, General Hospital of Mexico Dr. "Eduardo Liceaga", Mexico City, Mexico
| | - Gabriela G Reyes
- Liver, Pancreas and Motility Laboratory (HIPAM) - Experimental Medicine Research Unit, Faculty of Medicine, Mexico City, Mexico
| | - Luz M Porras
- Liver, Pancreas and Motility Laboratory (HIPAM) - Experimental Medicine Research Unit, Faculty of Medicine, Mexico City, Mexico
| | - Arturo R Bernal
- Directorate of Research, General Hospital of Mexico Dr. Eduardo Liceaga ", Mexico City, Mexico
| | - Jesús S Luna
- Department of Cell Biology, IPN Research and Advanced Studies Center, Mexico City, Mexico
| | - Adolfo P Garcia
- Liver, Pancreas and Motility Laboratory (HIPAM) - Experimental Medicine Research Unit, Faculty of Medicine, Mexico City, Mexico
| | - Jacqueline Cordova
- Directorate of Research, General Hospital of Mexico Dr. Eduardo Liceaga ", Mexico City, Mexico
| | - Adalberto Parra
- Department of Endocrinology, National Institute of Perinatology "Isidro Espinosa de los Reyes ", Mexico City, Mexico
| | - Srinivas Mummidi
- South Texas Diabetes & Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas, United States
| | - David Kershenobich
- National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Mexico City, Mexico
| | - Joselín Hernández
- Liver, Pancreas and Motility Laboratory (HIPAM) - Experimental Medicine Research Unit, Faculty of Medicine, Mexico City, Mexico.,South Texas Diabetes & Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas, United States.,Clinical Pharmacology Unit, General Hospital of Mexico Dr. "Eduardo Liceaga", Mexico City, Mexico
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11
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Echevarria D, Gutfraind A, Boodram B, Layden J, Ozik J, Page K, Cotler SJ, Major M, Dahari H. Modeling indicates efficient vaccine-based interventions for the elimination of hepatitis C virus among persons who inject drugs in metropolitan Chicago. Vaccine 2019; 37:2608-2616. [PMID: 30962092 DOI: 10.1016/j.vaccine.2019.02.081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/07/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Persons who inject drugs (PWID) are at highest risk for acquiring and transmitting hepatitis C (HCV) infection. The recent availability of oral direct-acting antiviral (DAA) therapy with reported cure rates >90% can prevent HCV transmission, making HCV elimination an attainable goal among PWID. The World Health Organization (WHO) recently proposed a 90% reduction in HCV incidence as a key objective. However, given barriers to the use of DAAs in PWID, including cost, restricted access to DAAs, and risk of reinfection, combination strategies including the availability of effective vaccines are needed to eradicate HCV as a public health threat. This study aims to model the cost and efficacy of a dual modality approach using HCV vaccines combined with DAAs to reduce HCV incidence by 90% and prevalence by 50% in PWID populations. METHODS We developed a mathematical model that represents the HCV epidemic among PWID and calibrated it to empirical data from metropolitan Chicago, Illinois. Four medical interventions were considered: vaccination of HCV naive PWID, DAA treatment, DAA treatment followed by vaccination, and, a combination of vaccination and DAA treatment. RESULTS The combination of vaccination and DAAs is the lowest cost-expensive intervention for achieving the WHO target of 90% incidence reduction. The use of DAAs without a vaccine is much less cost-effective with the additional risk of reinfection after treatment. Vaccination of naïve PWID alone, even when scaled-up to all reachable PWID, cannot achieve 90% reduction of incidence in high-prevalence populations due to infections occurring before vaccination. Similarly, the lowest cost-expensive way to halve prevalence in 15 years is through the combination of vaccination and DAAs. CONCLUSIONS The modeling results underscore the importance of developing an effective HCV vaccine and augmenting DAAs with vaccines in HCV intervention strategies in order to achieve efficient reductions in incidence and prevalence.
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Affiliation(s)
- Desarae Echevarria
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA
| | - Alexander Gutfraind
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA; Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Basmattee Boodram
- Community Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Jennifer Layden
- Health Protection Office, Illinois Department of Public Health, Chicago, IL, USA
| | - Jonathan Ozik
- Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA; Decision and Infrastructure Sciences, Argonne National Laboratory, Argonne, IL, USA
| | - Kimberly Page
- Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA
| | - Marian Major
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA.
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13
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Reinfection by hepatitis C virus following effective all-oral direct-acting antiviral drug therapy in HIV/hepatitis C virus coinfected individuals. AIDS 2019; 33:685-689. [PMID: 30829744 DOI: 10.1097/qad.0000000000002103] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES We analysed hepatitis C virus (HCV) reinfection among participants in a prospective registry of HIV/HCV-coinfected patients treated with all-oral direct-acting antiretroviral (DAA)-based therapy in the region of Madrid. DESIGN An observational cohort study. METHODS The study period started on the date sustained viral response (SVR) was confirmed. The censoring date was 31 December 2017. SVR was defined as negative HCV-RNA 12 weeks after completion of treatment. Reinfection was defined as a positive HCV-RNA test result after achievement of SVR. RESULTS Reinfections were detected in 17 of 2359 HIV/HCV-coinfected patients (0.72%) overall, in 12 out of 177 (6.78%) MSM and in five out of 1459 (0.34%) people who inject drugs (PWID). The incidence of reinfection [95% confidence interval (95% CI)] per 100 person-years was 0.48 (0.30-0.77) overall, 5.93 (3.37-10.44) for MSM and 0.21 (0.09-0.52) for PWID. Reinfections were detected a median of 15 weeks (interquartile range 13-26) after SVR. In 10 (58.82%) patients, the reinfection was caused by a different HCV genotype. All 12 MSM with reinfection acknowledged unprotected anal intercourse with several partners, seven used chemsex, six reported fisting and four practiced slamming. A concomitant STI was detected in five patients. Four IDU with reinfection reported injecting drugs following SVR. CONCLUSION HCV reinfection is a matter of concern in HIV-positive MSM treated with all-oral DAA therapy in the region of Madrid. Our data suggest that prevention strategies and frequent testing with HCV-RNA should be applied following SVR in MSM who engage in high-risk practices.
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14
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Ray RB, Ray R. Hepatitis C Virus Manipulates Humans as its Favorite Host for a Long-Term Relationship. Hepatology 2019; 69:889-900. [PMID: 30102776 PMCID: PMC6351149 DOI: 10.1002/hep.30214] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus (HCV) infection-associated liver disease is a global health problem. HCV often causes silent disease, and eventually progresses to end-stage liver disease. HCV infects hepatocytes; however, initial manifestation of liver disease is mostly displayed in hepatic stellate cells (HSCs), causing fibrosis/cirrhosis, and is believed to occur from inflammation in the liver. It remains unclear why HCV is not spontaneously cleared from infected liver in the majority of individuals and develops chronic infection with progressive liver disease. Direct-acting antivirals (DAAs) show excellent results in controlling viremia, although beneficial consequence in advanced liver disease remains to be understood. In this review, we highlight the current knowledge that has contributed to our understanding of the role of HCV in inflammation, immune evasion, metabolic disorders, liver pathogeneses, and efforts in vaccine development.
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Affiliation(s)
- Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, Missouri 63104, USA,Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri 63104, USA
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri 63104, USA
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15
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Hart GR, Ferguson AL. Computational design of hepatitis C virus immunogens from host-pathogen dynamics over empirical viral fitness landscapes. Phys Biol 2018; 16:016004. [PMID: 30484433 DOI: 10.1088/1478-3975/aaeec0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) afflicts 170 million people and kills 700 000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic, but despite 25 years of research, no vaccine is available. A major obstacle is HCV's extreme genetic variability and rapid mutational escape from immune pressure. Coupling maximum entropy inference with population dynamics simulations, we have employed a computational approach to translate HCV sequence databases into empirical landscapes of viral fitness and simulate the intrahost evolution of the viral quasispecies over these landscapes. We explicitly model the coupled host-pathogen dynamics by combining agent-based models of viral mutation with stochastically-integrated coupled ordinary differential equations for the host immune response. We validate our model in predicting the mutational evolution of the HCV RNA-dependent RNA polymerase (protein NS5B) within seven individuals for whom longitudinal sequencing data is available. We then use our approach to perform exhaustive in silico evaluation of putative immunogen candidates to rationally design tailored vaccines to simultaneously cripple viral fitness and block mutational escape within two selected individuals. By systematically identifying a small number of promising vaccine candidates, our empirical fitness landscapes and host-pathogen dynamics simulator can guide and accelerate experimental vaccine design efforts.
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Affiliation(s)
- Gregory R Hart
- Department of Physics, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL 61801, United States of America. Present address: Department of Therapeutic Radiology, Yale University, 202 LLCI, 15 York Street, New Haven, CT 96510, United States of America
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16
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Li Z, Liu Q. Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. J Gen Virol 2017; 99:44-61. [PMID: 29235977 DOI: 10.1099/jgv.0.000987] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease actively involved in regulating lipid homeostasis. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, the underlying mechanisms have not been thoroughly characterized. Moreover, whether PCSK9 regulates HCV translation and assembly/secretion has not been determined. We therefore further studied the effects of PCSK9 on the HCV life cycle. We showed that PCSK9 did not affect HCV translation or assembly/secretion. Overexpression of PCSK9 inhibited HCV replication in HCV genomic replicon cells in a dose-dependent manner and after cell culture-derived HCV (HCVcc) infection. Knocking down PCSK9 increased HCV replication. The gain-of-function (D374Y) or loss-of-function (Δaa. 31-52) PCSK9 mutants for low-density lipoprotein receptor (LDLR) degradation had no effect on HCV replication, suggesting that HCV replication inhibition by PCSK9 was not due to LDLR degradation. The uncleaved ProPCSK9, but not cleaved PCSK9, down-regulated HCV replication, suggesting that the auto-cleavage of PCSK9 affected HCV replication. We also found that PCSK9 interacted with NS5A through NS5A aa. 95-215, and this region played an important role in NS5A dimerization, NS5A-RNA binding and was essential for HCV replication. More importantly, NS5A dimerization and NS5A-RNA binding were suppressed by PCSK9 upon interaction. These results suggested that PCSK9 inhibited HCV replication through interaction with NS5A. Our study should help optimize anti-HCV treatment regimen in patients with abnormal lipid profiles.
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Affiliation(s)
- Zhubing Li
- VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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17
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Ghoma Linguissi LS, Nkenfou CN. Epidemiology of viral hepatitis in the Republic of Congo: review. BMC Res Notes 2017; 10:665. [PMID: 29197421 PMCID: PMC5712139 DOI: 10.1186/s13104-017-2951-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023] Open
Abstract
Objective Considered an endemic zone, Republic of Congo has a high seroprevalence rate of hepatitis B and C virus. To know the extent of hepatitis infection as a public health problem, we reviewed published literature and other sources for reports of these viral infections in the country. Results High seroprevalence of HBV and HCV carriage in blood donors were observed in studies confirming Congo’s place in the hyperendemic area of HBV and HCV infection. These prevalence were compared by Chi square test. We compared the prevalence of three studies conducted in 1996, 2015 and 2016. The statistical results were very significant. HBV genotype E was most prevalent. Very few studies were done on pregnant women. Difficulties in the care and management of patients were also noted because of the high cost of often unavailable treatments. Difficulties arise, however, when an attempt was made to implement the National Hepatitis Control Program. Despite studies conducted on hepatitis prevalence, health interventions are still needed to care and manage these patients and the need to implement the national hepatitis control is more pressing in the Congo.
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Affiliation(s)
| | - Celine Nguefeu Nkenfou
- Chantal Biya International Reference Centre for Research on Prevention and Management on HIV and AIDS, Yaounde, Cameroon.,Higher Teachers Training College, University of Yaounde I, Yaounde, Cameroon
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18
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Li D, Wang X, von Schaewen M, Tao W, Zhang Y, Heller B, Hrebikova G, Deng Q, Sun Q, Ploss A, Zhong J, Huang Z. Immunization With a Subunit Hepatitis C Virus Vaccine Elicits Pan-Genotypic Neutralizing Antibodies and Intrahepatic T-Cell Responses in Nonhuman Primates. J Infect Dis 2017; 215:1824-1831. [PMID: 28398489 DOI: 10.1093/infdis/jix180] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 04/07/2017] [Indexed: 12/22/2022] Open
Abstract
Background The global control of hepatitis C virus (HCV) infection remains a great burden, owing to the high prices and potential drug resistance of the new direct-acting antivirals (DAAs), as well as the risk of reinfection in DAA-cured patients. Thus, a prophylactic vaccine for HCV is of great importance. We previously reported that a single recombinant soluble E2 (sE2) vaccine produced in insect cells was able to induce broadly neutralizing antibodies (NAbs) and prevent HCV infection in mice. Here the sE2 vaccine was evaluated in non-human primates. Methods Rhesus macaques were immunized with sE2 vaccine in combination with different adjuvants. Vaccine-induced NAbs in antisera were tested for neutralization activities against a panel of cell culture-derived HCV (HCVcc), while T-cell responses were evaluated in splenocytes, peripheral blood mononuclear cells, and hepatic lymphocytes. Results sE2 is able to elicit NAbs against HCVcc harboring structural proteins from multiple HCV genotypes in rhesus macaques. Moreover, sE2-immunized macaques developed systemic and intrahepatic memory T cells specific for E2. A significant correlation between the sE2-specific immunoglobulin G titers and neutralization spectrum was observed, highlighting the essential role of sE2 immunogenicity on achieving broad NAbs. Conclusions sE2 is a promising HCV vaccine candidate that warrants further preclinical and clinical development.
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Affiliation(s)
- Dapeng Li
- Unit of Vaccinology and Antiviral Strategies.,Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai
| | - Xuesong Wang
- Unit of Vaccinology and Antiviral Strategies.,Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai
| | | | - Wanyin Tao
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai
| | | | - Brigitte Heller
- Department of Molecular Biology, Princeton University, New Jersey
| | | | - Qiang Deng
- Unit of Vaccinology and Antiviral Strategies
| | - Qiang Sun
- Key Laboratory of Primate Neurobiology, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai.,Suzhou Nonhuman Primate Facility, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Suzhou, China
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, New Jersey
| | - Jin Zhong
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai
| | - Zhong Huang
- Unit of Vaccinology and Antiviral Strategies
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19
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Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans.
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Affiliation(s)
- Jijing Shi
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | - Yuanyuan Li
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | | | - Xuexiu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 460000, China
| | - Fu-Sheng Wang
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
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20
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Das S, Mullick R, Kumar A, Tandon H, Bose M, Gouthamchandra K, Chandra M, Ravishankar B, Khaja MN, Srinivasan N, Das S, Melkote Subbarao S, Karande AA. Identification of a novel epitope in the C terminus of hepatitis C virus-E2 protein that induces potent and cross-reactive neutralizing antibodies. J Gen Virol 2017; 98:962-976. [PMID: 28221101 DOI: 10.1099/jgv.0.000735] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis, but an effective vaccine is still not available to prevent infection. Use of neutralizing antibodies could be a potential therapeutic option. In this study, the presence of anti-HCV antibodies in HCV-infected patients was assessed from 50 patients and the presence of neutralizing antibodies was examined using 'hepatitis C virus-like particles'. Antibodies from two samples exhibited significant inhibitory activity, suggesting that these may neutralize viral infection. Antigenic determinants generating the neutralizing antibodies from these two samples were delineated by epitope mapping using the core, E1 and E2 regions and a stretch of 45 amino acid peptide (E2C45) derived from the C-terminal region of HCV-E2 protein (aa 634-679) was designed. Results suggest that this hitherto uncharacterized region has the potential to generate neutralizing antibodies against HCV and thus be effective in preventing virus entry into liver cells. Computational analysis of the structure of the modelled peptide (E2C45) suggested high conformational entropy for this region. Furthermore, E2C45 peptide-generated antibodies could block virus entry and monoclonal antibodies generated against this peptide could also significantly reduce virus replication in a cell culture system. It is possible that the inhibition could be partly due to a conformational alteration of the CD81-binding region, preventing virus attachment to liver cells. In conclusion, this work focused on the discovery of a novel epitope at the C terminus of E2 that induces potent neutralizing antibodies in HCV-infected patients.
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Affiliation(s)
- Soma Das
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
| | - Ranajoy Mullick
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Anuj Kumar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Himani Tandon
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
| | - Mihika Bose
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
| | - K Gouthamchandra
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Madhavi Chandra
- Bioviz Technologies Pvt Ltd, Sagar Society, Road No. 2, Banjara Hills, Hyderabad 500 034, India
| | | | - M N Khaja
- Bioviz Technologies Pvt Ltd, Sagar Society, Road No. 2, Banjara Hills, Hyderabad 500 034, India
| | | | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Shaila Melkote Subbarao
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Anjali Anoop Karande
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
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21
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Preclinical evaluation of multi antigenic HCV DNA vaccine for the prevention of Hepatitis C virus infection. Sci Rep 2017; 7:43531. [PMID: 28266565 PMCID: PMC5339862 DOI: 10.1038/srep43531] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 01/25/2017] [Indexed: 02/07/2023] Open
Abstract
Direct-acting antiviral treatment for hepatitis C virus (HCV) infection is costly and does not protect from re-infection. For human and chimpanzees, recovery from acute HCV infection correlates with host CD4+ and CD8+ T cell responses. DNA plasmids targeting the HCV non-structural antigens NS3, NS4, and NS5, were previously reported to induce robust and sustained T cell responses in mice and primates. These plasmids were combined with a plasmid encoding cytokine IL-28B, together named as VGX-6150. The dose-dependent T cell response and safety of VGX-6150 administered intramuscularly and followed by electroporation was assessed in mice. Immune responses plateaued at 20 μg/dose with IL-28B demonstrating significant immunoadjuvant activity. Mice administered VGX-6150 at 40, 400, and 800 μg given either as a single injection or as 14 injections given bi-weekly over 26 weeks showed no vaccine related changes in any clinical parameter compared to placebo recipients. There was no evidence of VGX-6150 accumulation at the injection site or in any organ 1 month following the 14th vaccination. Based on these studies, the approximate lethal dose (ALD) exceeds 800 μg/dose and the NOAEL was 800 μg/dose in mouse. In conclusion, VGX-6150 appears safe and a promising preventive vaccine candidate for HCV infection.
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22
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Spontaneous Elimination of Hepatitis C Virus Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1039:45-54. [PMID: 29164488 DOI: 10.1007/5584_2017_76] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus (HCV) is the etiological agent of chronic hepatitis C and a major cause of liver cirrhosis and hepatocellular carcinoma. Only a minority of infected individuals can clear the virus spontaneously. The knowledge of the determinants of virus clearance would allow the development of effective methods preventing its further spread and optimizing treatment regimens. Viral factors associated with spontaneous virus clearance in the acute phase of infection, such as HCV genotype, virus heterogeneity, and the impact of viral proteins on the immune system have been characterized. Likewise, host genetic markers, such as the interleukin genotypes, HLA alleles, and factors affecting the T lymphocyte response appear to play an important role. Studies have revealed that natural clearance of HCV infection in the chronic phase is rare and its mechanisms are not well understood. In this review, we present the state-of-the art knowledge on the viral and host factors affecting the spontaneous elimination of HCV infection.
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23
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Zhang Q, Wang Y, Zhai N, Song H, Li H, Yang Y, Li T, Guo X, Chi B, Niu J, Crispe IN, Su L, Tu Z. HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway. Sci Rep 2016; 6:36160. [PMID: 27786268 PMCID: PMC5082373 DOI: 10.1038/srep36160] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 10/11/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection.
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Affiliation(s)
- Qianqian Zhang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jining Medical University, Jining, China
| | - Yang Wang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Naicui Zhai
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Hongxiao Song
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Haijun Li
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Tianyang Li
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
| | - Xiaolin Guo
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Baorong Chi
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
| | - Ian Nicholas Crispe
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Lishan Su
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Zhengkun Tu
- Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, China
- Department of Hepatobiliary and Pancreatic Diseases, the First Hospital of Jilin University, Changchun, China
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24
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Fauvelle C, Colpitts CC, Keck ZY, Pierce BG, Foung SKH, Baumert TF. Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies. Expert Rev Vaccines 2016; 15:1535-1544. [PMID: 27267297 DOI: 10.1080/14760584.2016.1194759] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION With more than 150 million chronically infected people, hepatitis C virus (HCV) remains a substantial global health burden. Direct-acting antivirals have dramatically improved viral cure. However, limited access to therapy, late stage detection of infection and re-infection following cure illustrate the need for a vaccine for global control of infection. Vaccines with induction of neutralizing antibodies (nAbs) have been shown to protect successfully against infections by multiple viruses and are currently developed for HCV. Areas covered: Here we review the progress towards the development of vaccines aiming to confer protection against chronic HCV infection by inducing broadly nAbs. The understanding or viral immune evasion in infected patients, the development of novel model systems and the recent structural characterization of viral envelope glycoprotein E2 has markedly advanced our understanding of the molecular mechanisms of virus neutralization with the concomitant development of several vaccine candidates. Expert commentary: While HCV vaccine development remains challenged by the high viral diversity and immune evasion, marked progress in HCV research has advanced vaccine design. Several vaccine candidates have shown robust induction of nAbs in animal models and humans. Randomized clinical trials are the next step to assess their clinical efficacy for protection against chronic infection.
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Affiliation(s)
- Catherine Fauvelle
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France
| | - Che C Colpitts
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France
| | - Zhen-Yong Keck
- c Department of Pathology , Stanford University School of Medicine , Stanford , CA , USA
| | - Brian G Pierce
- d Institute for Bioscience and Biotechnology Research , University of Maryland , Rockville , MD , USA
| | - Steven K H Foung
- c Department of Pathology , Stanford University School of Medicine , Stanford , CA , USA
| | - Thomas F Baumert
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France.,e Institut Hospitalo-Universitaire, Pôle Hépato-digestif , Hôpitaux Universitaires de Strasbourg , Strasbourg , France
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25
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Li H, Stoddard MB, Wang S, Giorgi EE, Blair LM, Learn GH, Hahn BH, Alter HJ, Busch MP, Fierer DS, Ribeiro RM, Perelson AS, Bhattacharya T, Shaw GM. Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification. J Virol 2016; 90:152-66. [PMID: 26468546 PMCID: PMC4702571 DOI: 10.1128/jvi.02156-15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/02/2015] [Indexed: 01/06/2023] Open
Abstract
UNLABELLED Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequence lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences. IMPORTANCE Despite the recent development of highly effective, interferon-sparing anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and the development of an effective vaccine, which could be facilitated by a precise molecular identification of transmitted/founder (T/F) viral genomes and their progeny. We used single-genome sequencing to show that inferred HCV T/F sequences in recipients were identical to viral sequences in their respective donors and that viral genomes generally evolved early in infection according to a simple model of random sequence evolution. Altogether, the findings validate T/F genome inferences and illustrate how T/F sequence identification can illuminate studies of HCV transmission, immunopathogenesis, drug resistance development, and vaccine protection, including sieving effects on breakthrough virus strains.
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Affiliation(s)
- Hui Li
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Mark B Stoddard
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shuyi Wang
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elena E Giorgi
- T-Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Lily M Blair
- T-Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA Department of Biology, Stanford University, Stanford, California, USA
| | - Gerald H Learn
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Beatrice H Hahn
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Harvey J Alter
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael P Busch
- Blood Systems Research Institute, University of California San Francisco, San Francisco, California, USA
| | - Daniel S Fierer
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ruy M Ribeiro
- T-Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Tanmoy Bhattacharya
- T-Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA Santa Fe Institute, Santa Fe, New Mexico, USA
| | - George M Shaw
- Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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26
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Abstract
UNLABELLED Hepatitis C virus (HCV) afflicts 170 million people worldwide, 2%-3% of the global population, and kills 350 000 each year. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic in the developing world where expensive drug therapies are not available. Despite 20 years of research, the high mutability of the virus and lack of knowledge of what constitutes effective immune responses have impeded development of an effective vaccine. Coupling data mining of sequence databases with spin glass models from statistical physics, we have developed a computational approach to translate clinical sequence databases into empirical fitness landscapes quantifying the replicative capacity of the virus as a function of its amino acid sequence. These landscapes explicitly connect viral genotype to phenotypic fitness, and reveal vulnerable immunological targets within the viral proteome that can be exploited to rationally design vaccine immunogens. We have recovered the empirical fitness landscape for the HCV RNA-dependent RNA polymerase (protein NS5B) responsible for viral genome replication, and validated the predictions of our model by demonstrating excellent accord with experimental measurements and clinical observations. We have used our landscapes to perform exhaustive in silico screening of 16.8 million T-cell immunogen candidates to identify 86 optimal formulations. By reducing the search space of immunogen candidates by over five orders of magnitude, our approach can offer valuable savings in time, expense, and labor for experimental vaccine development and accelerate the search for a HCV vaccine. ABBREVIATIONS HCV-hepatitis C virus, HLA-human leukocyte antigen, CTL-cytotoxic T lymphocyte, NS5B-nonstructural protein 5B, MSA-multiple sequence alignment, PEG-IFN-pegylated interferon.
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Affiliation(s)
- Gregory R Hart
- Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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27
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Zhang C, Lu Y, Zhou H, Lu H, Qian X, Liu X, Wang X, Ding Z, Zhang F, Lu L. Acquiring Kupffer cells in mice using a MACS-based method. Transplant Proc 2015; 47:553-7. [PMID: 25769606 DOI: 10.1016/j.transproceed.2015.01.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 01/09/2015] [Accepted: 01/28/2015] [Indexed: 12/27/2022]
Abstract
OBJECTIVE This study sought to establish a new method to isolate Kupffer cells (KCs) by magnetic activated cell sorting (MACS). METHODS Nonparenchymal cells were acquired from C57BL/6 mice livers by a perfusion system in vivo and then stained with F4/80(+) fluorescein isothiocyanate and CD11c(-) phycoerythrin antibodies. After incubating with immunomagnetic beads, F4/80(+)CD11c(-) KCs were obtained by MACS selection. The purity was evaluated by flow cytometry, and the morphological features and vitality were analyzed in in vitro cultures. RESULTS Compared with traditional methods, acquiring KCs by MACS was characterized by economy, efficiency, and high purity. The F4/80(+)CD11c(-) KCs cultured in vitro also showed the typical adherent shape and excellent phagocytic ability. CONCLUSIONS With the 2-step method using immunomagnetic beads, we provide a new method by which KCs can be obtained from mouse liver with high purity and distinct phenotype of F4/80(+) CD.
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Affiliation(s)
- C Zhang
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Y Lu
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - H Zhou
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - H Lu
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - X Qian
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - X Liu
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - X Wang
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Z Ding
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - F Zhang
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - L Lu
- Translational Medicine Research Center of Jiangning Hospital and Liver Transplantation Center of First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
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28
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Walker CM, Grakoui A. Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? Curr Opin Immunol 2015; 35:137-43. [PMID: 26241306 DOI: 10.1016/j.coi.2015.06.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 06/23/2015] [Accepted: 06/23/2015] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus infection is now curable by antiviral therapy but the global burden of liver disease is unlikely to diminish without a vaccine to prevent transmission. The objective of HCV vaccination is not to induce sterilizing immunity, but instead to prevent persistent infection. One vaccine that incorporates only non-structural HCV proteins is now in phase I/II efficacy trials to test the novel concept that T cell priming alone is sufficient for protection. Evidence also suggests that antibodies contribute to infection resolution. Vaccines comprised of recombinant envelope glycoproteins targeted by neutralizing antibodies have been assessed in humans for immunogenicity. Here, we discuss current concepts in protective immunity and divergent approaches to vaccination against a highly mutable RNA virus.
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Affiliation(s)
- Christopher M Walker
- Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University School of Medicine, 700 Children's Drive, Columbus, OH 43004, United States.
| | - Arash Grakoui
- Yerkes National Primate Research Center, Emory Vaccine Center, Emory University, Atlanta, GA 30329, United States; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322, United States.
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29
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Obaid A, Ahmad J, Naz A, Awan FM, Paracha RZ, Tareen SHK, Anjum S, Raza A, Baumbach J, Ali A. Modeling and analysis of innate immune responses induced by the host cells against hepatitis C virus infection. Integr Biol (Camb) 2015; 7:544-559. [PMID: 25848650 DOI: 10.1039/c4ib00285g] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
An in-depth understanding of complex systems such as hepatitis C virus (HCV) infection and host immunomodulatory response is an open challenge for biologists. In order to understand the mechanisms involved in immune evasion by HCV, we present a simplified formalization of the highly dynamic system consisting of HCV, its replication cycle and host immune responses at the cellular level using hybrid Petri net (HPN). The approach followed in this study comprises of step wise simulation, model validation and analysis of host immune response. This study was performed with an objective of making correlations among viral RNA levels, interferon (IFN) production and interferon stimulated genes (ISGs) induction. The results correlate with the biological data verifying that the model is very useful in predicting the dynamic behavior of the signaling proteins in response to a stimulus. This study implicates that HCV infection is dependent upon several key factors of the host immune response. The effect of host proteins on limiting viral infection is effectively overruled by the viral pathogen. This study also analyzes activity levels of RNase L, miR-122, IFN, ISGs and PKR induction and inhibition of TLR3/RIG1 mediated pathways in response to targeted manipulation in the presence of HCV. The results are in complete agreement at the time of writing with the published expression studies and western blot experiments. Our model also provides some biological insights regarding the role of PKR in the acute infection of HCV. It might help to explain why many patients fail to clear acute HCV infection while others, with low ISG basal levels, clear HCV spontaneously. The described methodology can easily be reproduced, which suitably supports the study of other viral infections in a formal, automated and expressive manner. The Petri net-based modeling approach applied here may provide valuable insights for study design and analyses to evaluate other disease associated integrated pathways in biological systems.
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Affiliation(s)
- Ayesha Obaid
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, 44000 Pakistan.
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30
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Callendret B, Eccleston HB, Hall S, Satterfield W, Capone S, Folgori A, Cortese R, Nicosia A, Walker CM. T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee. Hepatology 2014; 60:1531-40. [PMID: 24975498 PMCID: PMC4242208 DOI: 10.1002/hep.27278] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/20/2014] [Indexed: 01/15/2023]
Abstract
UNLABELLED Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection. CONCLUSIONS The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.
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Affiliation(s)
- Benoit Callendret
- Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, OH
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31
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Cosgrove C, Berger CT, Kroy DC, Cheney PC, Ghebremichael M, Aneja J, Tomlinson M, Kim AY, Lauer GM, Alter G. Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver. PLoS One 2014; 9:e105950. [PMID: 25148254 PMCID: PMC4141847 DOI: 10.1371/journal.pone.0105950] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 07/29/2014] [Indexed: 12/31/2022] Open
Abstract
Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals. Baseline expression of activating and inhibitory receptors was assessed, as well as functional responses following stimulation through classic NK cell pathways. Independent of HCV infection, the liver was enriched for the immunoregulatory CD56bright NK cell population, which produced less IFNγ and CD107a but comparable levels of MIP1β, and was immunophenotypically distinct from their blood counterparts. This profile was mostly unaltered in chronic HCV infection, though different expression levels of NKp46 and NKG2D were associated with different grades of fibrosis. In contrast to the liver, chronic HCV infection associated with an enrichment of CD161lowperforinhigh NK cells in the blood correlated with increased AST and 2B4 expression. However, the association of relatively discrete changes in the NK cell phenotype in the liver with the fibrosis stage nevertheless suggests an important role for the NK response. Overall these data suggest that tissue localization has a more pervasive effect on NK cells than the presence of chronic viral infection, during which these cells might be mostly attuned to limiting immunopathology. It will be important to characterize NK cells during early HCV infection, when they should have a critical role in limiting infection.
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Affiliation(s)
- Cormac Cosgrove
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Christoph T. Berger
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Daniela C. Kroy
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Medical Department 3, RWTH Aachen University Hospital, Aachen, Germany
| | - Patrick C. Cheney
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Musie Ghebremichael
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Jasneet Aneja
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Michelle Tomlinson
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Arthur Y. Kim
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Georg M. Lauer
- Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Galit Alter
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America
- * E-mail:
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32
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Rodrigue-Gervais IG, Rigsby H, Jouan L, Willems B, Lamarre D. Intact dendritic cell pathogen-recognition receptor functions associate with chronic hepatitis C treatment-induced viral clearance. PLoS One 2014; 9:e102605. [PMID: 25033043 PMCID: PMC4102513 DOI: 10.1371/journal.pone.0102605] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/20/2014] [Indexed: 12/17/2022] Open
Abstract
Although studies have addressed the exhaustion of the host's immune response to HCV and its role in treatment, there is little information about the possible contribution of innate immunity to treatment-induced clearance. We hypothesized that because intact myeloid dendritic cell (MDC) pathogen sensing functions are associated with improved HCV-specific CD8+ T cell functionality in some chronically infected patients, it might enhance HCV clearance rate under standard interferon therapy. To investigate this hypothesis, TLR-induced MDC activation and HCV-specific CD8+ T cell response quality were monitored longitudinally at the single-cell level using polychromatic flow cytometry in chronically infected patients undergoing interferon therapy. We correlated the immunological, biochemical and virological data with response to treatment. We demonstrate that the clinical efficacy of interferon-induced viral clearance is influenced by the extent to which HCV inhibits MDC functions before treatment, rather than solely on a breakdown of the extrinsic T cell immunosuppressive environment. Thus, viral inhibition of MDC functions before treatment emerges as a co-determining factor in the clinical efficacy of interferon therapy during chronic HCV infection.
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Affiliation(s)
- Ian Gaël Rodrigue-Gervais
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Hawley Rigsby
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Loubna Jouan
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Bernard Willems
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
- Département de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Daniel Lamarre
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
- Département de Médecine, Université de Montréal, Montréal, Québec, Canada
- * E-mail:
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33
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Abdel-Hakeem MS, Shoukry NH. Protective immunity against hepatitis C: many shades of gray. Front Immunol 2014; 5:274. [PMID: 24982656 PMCID: PMC4058636 DOI: 10.3389/fimmu.2014.00274] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/27/2014] [Indexed: 12/11/2022] Open
Abstract
The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada ; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University , Cairo , Egypt
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Médecine, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada
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34
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Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 2014; 146:1193-207. [PMID: 24412289 DOI: 10.1053/j.gastro.2013.12.036] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/22/2013] [Accepted: 12/27/2013] [Indexed: 02/08/2023]
Abstract
The liver has unique immune regulatory functions that promote the induction of tolerance rather than responses to antigens encountered locally. These functions are mediated by local expression of coinhibitory receptors and immunosuppressive mediators that help prevent overwhelming tissue damage. Over the years, we have gained more insight into the local regulatory cues that determine the functional complexity of immune responses regulated locally in the liver. Both the unique hepatic microenvironment and the particular liver sinusoidal cell populations, in addition to hepatocytes, actively modulate immune responses locally in the liver and thereby determine the outcome of hepatic immune responses. This is of high biological and clinical relevance in hepatitis B virus and hepatitis C virus infections, which can cause acute and persistent infections associated with chronic inflammation in humans that eventually progress to cirrhosis and hepatocellular carcinoma. Here, we review current knowledge about the balance between immunity and tolerance in the liver and how this may affect our understanding of the determinants of hepatitis B virus and hepatitis C virus clearance, persistence, and virus-induced liver disease.
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Affiliation(s)
- Percy A Knolle
- Institute of Molecular Immunology, Technische Universität München and Institutes of Molecular Medicine and Experimental Immunology, Universität Bonn, Bonn.
| | - Robert Thimme
- Department of Medicine, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany
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35
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Mishra S, Losikoff PT, Self AA, Terry F, Ardito MT, Tassone R, Martin WD, De Groot AS, Gregory SH. Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells. Vaccine 2014; 32:3285-92. [PMID: 24721533 DOI: 10.1016/j.vaccine.2014.03.083] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 02/19/2014] [Accepted: 03/26/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease. Spontaneous resolution of infection is associated with broad, MHC class I- (CD8(+)) and class II-restricted (CD4(+)) T cell responses to multiple viral epitopes. Only 20% of patients clear infection spontaneously, however, most develop chronic disease. The response to chemotherapy varies; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success in clinical trials. Vector-mediated vaccination with multi-epitope-expressing DNA constructs provides an improved approach. Highly-conserved, HLA-A2-restricted HCV epitopes and HLA-DRB1-restricted immunogenic consensus sequences (ICS, each composed of multiple overlapping and highly conserved epitopes) were predicted using bioinformatics tools and synthesized as peptides. HLA binding activity was determined in competitive binding assays. Immunogenicity and the ability of each peptide to stimulate naïve human T cell recognition and IFN-γ production were assessed in cultures of total PBMCs and in co-cultures composed of peptide-pulsed dendritic cells (DCs) and purified T lymphocytes, cell populations derived from normal blood donors. Essentially all predicted HLA-A2-restricted epitopes and HLA-DRB1-restricted ICS exhibited HLA binding activity and the ability to elicit immune recognition and IFN-γ production by naïve human T cells. The ability of DCs pulsed with these highly-conserved HLA-A2- and -DRB1-restricted peptides to induce naïve human T cell reactivity and IFN-γ production ex vivo demonstrates the potential efficacy of a multi-epitope-based HCV vaccine targeted to dendritic cells.
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Affiliation(s)
- Sasmita Mishra
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States
| | - Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States
| | - Alyssa A Self
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States
| | | | | | | | | | - Anne S De Groot
- EpiVax, Inc., Providence, RI, United States; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States
| | - Stephen H Gregory
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 432 Pierre M. Galletti Building, 55 Claverick Street, Providence, RI 02903, United States.
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36
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Zeng QL, Yang B, Sun HQ, Feng GH, Jin L, Zou ZS, Zhang Z, Zhang JY, Wang FS. Myeloid-derived suppressor cells are associated with viral persistence and downregulation of TCR ζ chain expression on CD8(+) T cells in chronic hepatitis C patients. Mol Cells 2014; 37:66-73. [PMID: 24552712 PMCID: PMC3907002 DOI: 10.14348/molcells.2014.2282] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 12/01/2013] [Accepted: 12/03/2013] [Indexed: 12/17/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) play an important role in impairing the function of T cells. We characterized MDSCs in two chronic hepatitis C (CHC) cohorts: a cross-sectional group that included 61 treatment-naive patients with CHC, 14 rapid virologic response (RVR) cases and 22 early virologic response (EVR) cases; and a longitudinal group of 13 cases of RVR and 10 cases of EVR after pegylated-interferon-α/ribavirin treatment for genotype 1b HCV infection. Liver samples from 32 CHC patients and six healthy controls were subjected to immunohistochemical analysis. MDSCs frequency in treatment-naive CHC was significantly higher than in RVR, EVR, or healthy subjects and was positively correlated with HCV RNA. Patients infected with HCV genotype 2a had a significantly higher frequency of MDSCs than those infected with genotype 1b. Decreased T cell receptor (TCR) ζ expression on CD8(+) T cells was significantly associated with an increased frequency of MDSCs in treatment-naive CHC patients and was restored by L-arginine treatment in vitro. Increased numbers of liver arginase-1(+) cells were closely associated with the histological activity index in CHC. The TCR ζ chain was significantly downregulated on hepatic CD8(+) T cells in CHC. During antiviral follow up, MDSCs frequency in peripheral blood mononuclear cells was directly correlated with the HCV RNA load in the plasma and inversely correlated with TCR ζ chain expression in CD8(+) T cells in both RVR and EVR cases. Notably, the RVR group had a higher frequency of MDSCs at baseline than the EVR group. Collectively, this study provides evidence that MDSCs might be associated with HCV persistence and downregulation of CD8 ζ chain expression.
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Affiliation(s)
- Qing-Lei Zeng
- Research Center for Biological Therapy, Beijing 302 Hospital, Peking University Health Science Center, Beijing,
China
| | - Bin Yang
- Department of Interventional Radiology, Beijing 302 Hospital, Beijing,
China
| | - Hong-Qi Sun
- Department of Infectious Diseases, Zhengzhou Sixth People’s Hospital, Zhengzhou,
China
| | - Guo-Hua Feng
- Research Center for Biological Therapy, Beijing 302 Hospital, Peking University Health Science Center, Beijing,
China
| | - Lei Jin
- The Institute of Translational Hepatology, Beijing,
China
| | - Zheng-Sheng Zou
- Non-infectious Liver Disease Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing,
China
| | - Zheng Zhang
- The Institute of Translational Hepatology, Beijing,
China
| | - Ji-Yuan Zhang
- The Institute of Translational Hepatology, Beijing,
China
| | - Fu-Sheng Wang
- Research Center for Biological Therapy, Beijing 302 Hospital, Peking University Health Science Center, Beijing,
China
- The Institute of Translational Hepatology, Beijing,
China
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37
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Jin L, Zhang XX, Zeng QL, Feng GH, Zhang JY, Chen LM, Xu XS, Zhang Z, Wang FS. Increased myeloid-derived suppressor cells correlate with viral persistence in patients with chronic hepatitis C. Shijie Huaren Xiaohua Zazhi 2014; 22:1574. [DOI: 10.11569/wcjd.v22.i11.1574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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38
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Zingaretti C, De Francesco R, Abrignani S. Why is it so difficult to develop a hepatitis C virus preventive vaccine? Clin Microbiol Infect 2013; 20 Suppl 5:103-9. [PMID: 24829939 DOI: 10.1111/1469-0691.12493] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
With an estimated 3% of the world's population chronically infected, hepatitis C virus (HCV) represents a major health problem for which an efficient vaccination strategy would be highly desirable. Indeed, chronic hepatitis C is recognized as one of the major causes of cirrhosis, hepatocarcinoma and liver failure worldwide and it is the most common indication for liver transplantation, accounting for 40-50% of liver transplants. Much progress has been made in the prevention of HCV transmission and in therapeutic intervention. However, even if a new wave of directly acting antivirals promise to overcome the problems of low efficacy and adverse effects observed for the current standard of care, which include interferon-α and ribavirin, an effective vaccine would be the only means to definitively eradicate infection and to diminish the burden of HCV-related diseases at affordable costs. Although there is strong evidence that the goal of a prophylactic vaccine could be achieved, there are huge development issues that have impeded reaching this goal and that still have to be addressed. In this article we address the question of whether an HCV vaccine is needed, whether it will eventually be feasible, and why it is so difficult to produce.
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Metz P, Reuter A, Bender S, Bartenschlager R. Interferon-stimulated genes and their role in controlling hepatitis C virus. J Hepatol 2013; 59:1331-41. [PMID: 23933585 DOI: 10.1016/j.jhep.2013.07.033] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 07/23/2013] [Accepted: 07/24/2013] [Indexed: 12/24/2022]
Abstract
Infections with the hepatitis C virus (HCV) are a major cause of chronic liver disease. While the acute phase of infection is mostly asymptomatic, this virus has the high propensity to establish persistence and in the course of one to several decades liver disease can develop. HCV is a paradigm for the complex interplay between the interferon (IFN) system and viral countermeasures. The virus induces an IFN response within the infected cell and is rather sensitive against the antiviral state triggered by IFNs, yet in most cases HCV persists. Numerous IFN-stimulated genes (ISGs) have been reported to suppress HCV replication, but in only a few cases we begin to understand the molecular mechanisms underlying antiviral activity. It is becoming increasingly clear that blockage of viral replication is mediated by the concerted action of multiple ISGs that target different steps of the HCV replication cycle. This review briefly summarizes the activation of the IFN system by HCV and then focuses on ISGs targeting the HCV replication cycle and their possible mode of action.
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Affiliation(s)
- Philippe Metz
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013; 19:7896-7909. [PMID: 24307784 PMCID: PMC3848138 DOI: 10.3748/wjg.v19.i44.7896] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 10/13/2013] [Indexed: 02/06/2023] Open
Abstract
This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.
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Yazdanian M, Memarnejadian A, Mahdavi M, Sadat SM, Motevali F, Vahabpour R, Khanahmad H, Siadat SD, Aghasadeghi MR, Roohvand F. Immunization of Mice by BCG Formulated HCV Core Protein Elicited Higher Th1-Oriented Responses Compared to Pluronic-F127 Copolymer. HEPATITIS MONTHLY 2013; 13:e14178. [PMID: 24348641 PMCID: PMC3842517 DOI: 10.5812/hepatmon.14178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 09/14/2013] [Accepted: 09/25/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND A supreme vaccine for Hepatitis C virus (HCV) infection should elicit strong Th1-oriented cellular responses. In the absence of a Th1-specific adjuvant, immunizations by protein antigens generally induce Th2-type and weak cellular responses. OBJECTIVES To evaluate the adjuvant effect of BCG in comparison with nonionic copolymer-Pluronic F127 (F127) as a classic adjuvant in the formulation of HCV core protein (HCVcp) as a candidate vaccine for induction of Th1 immune responses. MATERIALS AND METHODS Expression of N-terminally His-Tagged HCVcp (1-122) by pIVEX2.4a-core vector harboring the corresponding gene under the control of arabinose-inducible (araBAD) promoter was achieved in BL21-AI strain of E.coli and purified through application of nitrilotriacetic acid (Ni-NTA) chromatography. Mice were immunized subcutaneously (s.c.) in base of the tail with 100 μl of immunogen (F127+HCVcp or BCG+HCVcp; 5 μgHCVcp/mouse/dose) or control formulations (PBS, BCG, F127) at weeks 0, 3, 6. Total and subtypes of IgG, as well as cellular immune responses (Proliferation, In vivo CTL and IFN-γ/IL-4 ELISpot assays against a strong and dominant H2-d restricted, CD8+-epitopic peptide, core 39-48; RRGPRLGVRA of HCVcp) were compared in each group of immunized animals. RESULTS Expression and purification of core protein around the expected size (21 kDa) was confirmed by Western blotting. The HCVcp + BCG vaccinated mice showed significantly higher lymphocyte proliferation and IFN-γ production but lower levels of cell lysis (45% versus 62% in CTL assay) than the HCVcp+F127 immunized animals. "Besides, total anti-core IgG and IgG1 levels were significantly higher in HCVcp + F127 immunized mice as compared to HCVcp + BCG vaccinated animals, indicating relatively higher efficacy of F127 for the stimulation of humoral and Th2-oriented immune responses". CONCLUSIONS Results showed that HCVcp + BCG induced a moderate CTL and mixed Th1/Th2 immune responses with higher levels of cell proliferation and IFN-γ secretion, indicating that BCG may have a better outcome when formulated in HCVcp-based subunit vaccines.
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Affiliation(s)
- Maryam Yazdanian
- Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, IR Iran
| | | | - Mehdi Mahdavi
- Virology Department, Pasteur Institute of Iran, Tehran, IR Iran
| | - Seyed Mehdi Sadat
- Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, IR Iran
| | - Fatemeh Motevali
- Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, IR Iran
| | | | - Hossein Khanahmad
- BCG Research Center, Karaj Research and Production Complex, Pasteur Institute of Iran, Karaj, IR Iran
| | | | | | - Farzin Roohvand
- Virology Department, Pasteur Institute of Iran, Tehran, IR Iran
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Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie 2013; 95:2326-35. [PMID: 24036368 DOI: 10.1016/j.biochi.2013.09.003] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 09/02/2013] [Indexed: 12/25/2022]
Abstract
Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.
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Affiliation(s)
- Cheng-gui Miao
- School of Pharmacy, Institute for Liver Diseases of Anhui Medical University, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Mei Shan Road, Hefei 230032, Anhui Province, China; School of Food and Drug, Anhui Science and Technology University, Bengbu 233100, China
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Wen B, Deng Y, Chen H, Guan J, Chuai X, Ruan L, Kong W, Tan W. The novel replication-defective vaccinia virus (Tiantan strain)-based hepatitis C virus vaccine induces robust immunity in macaques. Mol Ther 2013; 21:1787-95. [PMID: 23774793 DOI: 10.1038/mt.2013.122] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/10/2013] [Indexed: 12/13/2022] Open
Abstract
The induction of a robust neutralizing antibody (nAb) response is likely to be as essential as specific cell-mediated immunity (CMI) against multiple antigens for the development of effective preventive and therapeutic vaccines against hepatitis C virus (HCV) infection in humans. To date, no data on the immunogenicity of the replication-defective vaccinia virus (derived from the Tiantan strain) (rNTV)-based HCV vaccine in primates have been reported. This study describes in detail the immunogenicity of various vaccine candidates in rhesus macaques, including rNTV-based and replication-defective recombinant adenoviral (rAd)-based HCV vaccines, as well as HCV pseudotyped virus-like particles (HCVpp). Our data showed that rAd-HCV vaccine boosting induced robust CMI, while priming or boosting with HCVpp enhanced the antigen-specific nAb response after rAd-HCV vaccination; however, CMI was not enhanced. Vaccination includes rNTV-HCV priming induced robust antigen-specific antibody, particularly nAbs, and CMI responses. Furthermore, more robust and longer-lasting CMI and higher cytokine levels (both Th1 and Th2 types, especially IFN-γ) resulted from boosting with rAd-HCV. We conclude that the rNTV-based HCV vaccine induces robust nAbs and CMI when combined with a heterogeneous primer-booster strategy, which shows promise for development of a human HCV vaccine.
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Affiliation(s)
- Bo Wen
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, China
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