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Liou JW, Mani H, Yen JH, Hsu HJ, Chang CC. Hepatitis C virus core protein: Not just a nucleocapsid building block, but an immunity and inflammation modulator. Tzu Chi Med J 2021; 34:139-147. [PMID: 35465281 PMCID: PMC9020238 DOI: 10.4103/tcmj.tcmj_97_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 03/12/2021] [Accepted: 06/02/2021] [Indexed: 11/13/2022] Open
Abstract
Coevolution occurs between viruses and their hosts. The hosts need to evolve means to eliminate pathogenic virus infections, and the viruses, for their own survival and multiplication, have to develop mechanisms to escape clearance by hosts. Hepatitis C virus (HCV) of Flaviviridae is a pathogen which infects human liver and causes hepatitis, a condition of liver inflammation. Unlike most of the other flaviviruses, HCV has an excellent ability to evade host immunity to establish chronic infection. The persistent liver infection leads to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), as well as extrahepatic HCV-related diseases. HCV genomic RNA only expresses 10 proteins, many of which bear functions, in addition to those involved in HCV life cycle, for assisting the virus to develop its persistency. HCV core protein is a structural protein which encapsulates HCV genomic RNA and assembles into nucleocapsids. The core protein is also found to exert functions to affect host inflammation and immune responses by altering a variety of host pathways. This paper reviews the studies regarding the HCV core protein-induced alterations of host immunity and inflammatory responses, as well as the involvements of the HCV core protein in pro- and anti-inflammatory cytokine stimulations, host cellular transcription, lipid metabolism, cell apoptosis, cell proliferations, immune cell differentiations, oxidative stress, and hepatocyte steatosis, which leads to liver fibrosis, cirrhosis, and HCC. Implications of roles played by the HCV core protein in therapeutic resistance are also discussed.
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Papasavvas E, Azzoni L, Yin X, Liu Q, Joseph J, Mackiewicz A, Ross B, Lynn KM, Jacobson JM, Mounzer K, Kostman JR, Montaner LJ. HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy-treated HIV/HCV-co-infected subjects. J Viral Hepat 2017; 24:865-876. [PMID: 28419653 PMCID: PMC5589504 DOI: 10.1111/jvh.12714] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 03/21/2017] [Indexed: 12/12/2022]
Abstract
The impact of hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viraemic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 ART-treated HIV/HCV genotype 1 co-infected) were studied. Clinical and liver enzyme measurements were performed. Whole blood was analysed for immune subset changes by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced signal transducer and activator of transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production. Statistical analysis was performed using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T-cell activation/exhaustion, and constitutive STAT-1 phosphorylation compared to HCV. In contrast, CD4+ FoxP3+ CD25+ frequency, IFN-αR expression on NK cells, as well as constitutive and IFN-α-induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load and CD4+ T-cell count had an opposite effect between the two groups on NK cell activity and T-cell activation, respectively. HCV viral load in ART-treated HIV/HCV co-infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono-infection. The more pronounced immune modulation noted in ART-treated HIV-co-infected/untreated HCV viraemic subjects may impact HCV disease progression and/or response to immunotherapy.
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Affiliation(s)
| | - L. Azzoni
- The Wistar Institute, Philadelphia, PA, USA
| | - X. Yin
- The Wistar Institute, Philadelphia, PA, USA
| | - Q. Liu
- The Wistar Institute, Philadelphia, PA, USA
| | - J. Joseph
- The Wistar Institute, Philadelphia, PA, USA
| | | | - B. Ross
- The Wistar Institute, Philadelphia, PA, USA
| | - K. M. Lynn
- Presbyterian Hospital-University of Pennsylvania hospital, Philadelphia, PA, USA
| | - J. M. Jacobson
- Temple University, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - K. Mounzer
- Jonathan Lax Immune Disorders Treatment Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA, USA
| | - J. R. Kostman
- John Bell Health Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA, USA
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Fernández-Ponce C, Dominguez-Villar M, Muñoz-Miranda JP, Arbulo-Echevarria MM, Litrán R, Aguado E, García-Cozar F. Immune modulation by the hepatitis C virus core protein. J Viral Hepat 2017; 24:350-356. [PMID: 28092420 DOI: 10.1111/jvh.12675] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is currently the most important cause of chronic viral hepatitis in the world and one of the most frequent indications for liver transplantation. HCV uses different strategies to evade the innate and adaptive immune response, and this evasion plays a key role in determining viral persistence. Several HCV viral proteins have been described as immune modulators. In this review, we will focus on the effect of HCV nucleocapsid core protein in the function of immune cells and its correlation with the findings observed in HCV chronically infected patients. Effects on immune cell function related to both extracellular and intracellular HCV core localization will be considered. This review provides an updated perspective on the mechanisms involved in HCV evasion related to one single HCV protein, which could become a key tool in the development of new antiviral strategies able to control and/or eradicate HCV infection.
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Affiliation(s)
- C Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - M Dominguez-Villar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain.,Department of Neurology, Human Translational Immunology Program, Yale School of Medicine, 300 George St. 353D, New Haven, 06520, CT
| | - J P Muñoz-Miranda
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - M M Arbulo-Echevarria
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - R Litrán
- Department of Condensed Matter Physics, University of Cádiz, Puerto Real, Cádiz, Spain
| | - E Aguado
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - F García-Cozar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
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4
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Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. Sci Rep 2016; 6:39520. [PMID: 28000758 PMCID: PMC5175173 DOI: 10.1038/srep39520] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/24/2016] [Indexed: 01/23/2023] Open
Abstract
The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.
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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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Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE, Shata MTM. Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 2016; 65:703-712. [PMID: 27166142 DOI: 10.1099/jmm.0.000272] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.
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Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud I Nassar
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
| | - Mohamed Tarek M Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
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Kwak Y, Kim HE, Park SG. Insights into Myeloid-Derived Suppressor Cells in Inflammatory Diseases. Arch Immunol Ther Exp (Warsz) 2015; 63:269-85. [PMID: 25990434 DOI: 10.1007/s00005-015-0342-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 05/14/2015] [Indexed: 02/06/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells involved in immune regulation. This population subdivides into granulocytic MDSCs and monocytic MDSCs, which regulate immune responses via the production of various molecules including reactive oxygen species, nitric oxide, arginase-1, interleukin-10, and transforming growth factor-β. Most studies of MDSCs focused on their role in tumors. MDSCs protect tumor cells from immune responses, and thus the frequency of MDSCs associates with poor prognosis. Many recent studies reported an important role for MDSCs in inflammatory diseases via the regulation of immune cells. In addition, the utilization of MDSCs by infectious pathogens suggests an immune evasion mechanism. Thus, MDSCs are important immune regulators in inflammatory diseases, as well as in tumors. This review focuses on the role of MDSCs in the regulation of inflammation in non-tumor settings.
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Affiliation(s)
- Yewon Kwak
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 500-712, Republic of Korea
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Ashrafi Hafez A, Ahmadi Vasmehjani A, Baharlou R, Mousavi Nasab SD, Davami MH, Najafi A, Joharinia N, Rezanezhad H, Ahmadi NA, Imanzad M. Analytical assessment of interleukin - 23 and -27 cytokines in healthy people and patients with hepatitis C virus infection (genotypes 1 and 3a). HEPATITIS MONTHLY 2014; 14:e21000. [PMID: 25386199 PMCID: PMC4221962 DOI: 10.5812/hepatmon.21000] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Revised: 07/20/2014] [Accepted: 08/06/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The immune system plays important roles in determining the outcomes of hepatitis C virus (HCV) infection. Interleukin-23 and -27 (IL-23 and IL-27) are two novel IL-12 cytokine family members known to enhance the T-lymphocyte response, but their precise involvement in HCV infection is not well known. OBJECTIVES We investigated the serum IL-27 and IL-23 levels in patients with HCV infection and in healthy individuals. PATIENTS AND METHODS In this case-control study, we assessed IL-23 and IL-27 levels in serum of 37 healthy individuals and 64 patients with chronic HCV using Enzyme-linked immunosorbent assay (ELISA). The relationship of cytokines level with liver enzymes (ALT, AST, and ALP), HCV genotype and viral load were analyzed. The differences of these cytokine levels in the groups of treatment and no treatment was compared. HCV genotypes were classified by HCV-specific primers methods. HCV RNA loads were determined by fluorescence quantitative PCR. RESULTS Serum level of IL-23 was higher in HCV infected patients compared to control group (P = 0.005). However, no significant difference was seen in IL-27 serum level between patients compared to the control group (P = 0.65). There was no significant difference in IL-23 and IL-27 level between genotype 1 HCV-infected- and 3a HCV-infected- patients. Positive moderate correlation between IL-23 and IL-27 with viral load was found in type 3a and 1 HCV-infected patient. Positive relative correlation was seen between ALT and IL-23 in 1a HCV-infected patients, which was higher than 3a HCV-infected patients; but there were no significant difference between serums liver enzymes with IL-23 and IL-27 in respect to genotype 3a and 1a HCV-infected patients. CONCLUSIONS These findings may reflect a vigorous pro-inflammatory reaction orchestrated by the host immune system against chronic HCV. Also, a better understanding of the involvement mechanism considering the correlation between other genotypes with inflammatory cytokines in various stages of disease can be obtained.
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Affiliation(s)
- Asghar Ashrafi Hafez
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Abbas Ahmadi Vasmehjani
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
| | - Rasoul Baharlou
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
| | | | - Mohammad Hasan Davami
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
- Corresponding Author: Mohammad Hasan Davami, Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran. Tel: +98-7913336086, Fax: +98-791341509,, E-mail:
| | - Ahmad Najafi
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
| | - Negar Joharinia
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
| | - Hasan Rezanezhad
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, IR Iran
| | - Nayeb Ali Ahmadi
- Department of Medical Lab Technology and Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Masoumeh Imanzad
- Department of Social Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, IR Iran
- Young Researchers Club, Shahr-e-Qods branch, Islamic Azad University, Tehran, IR Iran
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Goh C, Narayanan S, Hahn YS. Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 2014; 255:210-21. [PMID: 23947357 DOI: 10.1111/imr.12084] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.
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Affiliation(s)
- Celeste Goh
- Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA
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10
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Lim YP, Peng CY, Liao WL, Hung DZ, Tien N, Chen CY, Chang SY, Chang CY, Tsai FJ, Wan L. Genetic variation in NOS2A is associated with a sustained virological response to peginterferon plus ribavirin therapy for chronic hepatitis C in Taiwanese Chinese. J Med Virol 2014; 85:1206-14. [PMID: 23918539 DOI: 10.1002/jmv.23598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2013] [Indexed: 12/12/2022]
Abstract
This study aimed to evaluate whether genetic polymorphisms of the inducible nitric oxide synthase (iNOS) gene NOS2A could be associated with a sustained virological response (SVR) among patients infected with hepatitis C virus genotypes 1 and 2 (HCV-1 and HCV-2) who were treated with peginterferon plus ribavirin (PEG-IFNα-RBV). We analyzed the associations between SVR to PEG-IFNα-RBV therapy and two single nucleotide polymorphisms (SNPs) in NOS2A. This study included Taiwanese Chinese patients infected with either HCV-1 (n = 265) or HCV-2 (n = 195) with or without a SVR. Among the NOS2A SNPs examined, the combination of genotypes A/A and A/G of rs2248814 was inversely correlated with SVR in patients infected with HCV-1 (P = 0.0048), particularly in males (P = 0.0281). This effect was not observed in patients infected with HCV-2. The AC NOS2A haplotype comprising two SNPs (rs2248814 and rs2072324) was found to be associated with SVR, and its presence may decrease the chances for a successful outcome of treatment of patients infected with HCV-1 (P = 0.0053). HCV-1 infected patients who carried the A-C diplotype will have a lower success rate of achieving a SVR (P = 0.0117). In addition, a multivariate logistic regression model for predicting a SVR revealed that the presence of the A-C diplotype interactively affected the outcome of PEG-IFNα-RBV treatment. The presence of NOS2A SNPs and the association with SVR showed that NOS2A polymorphisms may influence the therapeutic outcomes of patients infected with HCV-1 under standard of care treatment.
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Affiliation(s)
- Yun-Ping Lim
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
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11
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Zhu W, Wu C, Deng W, Pei R, Wang Y, Cao L, Qin B, Lu M, Chen X. Inhibition of the HCV core protein on the immune response to HBV surface antigen and on HBV gene expression and replication in vivo. PLoS One 2012; 7:e45146. [PMID: 23024803 PMCID: PMC3443233 DOI: 10.1371/journal.pone.0045146] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 08/13/2012] [Indexed: 11/19/2022] Open
Abstract
The hepatitis C virus (HCV) core protein is a multifunctional protein that can interfere with the induction of an immune response. It has been reported that the HCV core protein inhibits HBV replication in vitro. In this study, we test the effect of the HCV core gene on the priming of the immune response to hepatitis B surface antigen (HBsAg) and on the replication of HBV in vivo. Our results showed that the full-length HCV core gene inhibits the induction of an immune response to the heterogeneous antigen, HBsAg, at the site of inoculation when HCV core (pC191) and HBsAg (pHBsAg) expression plasmids are co-administered as DNA vaccines into BALB/c mice. The observed interference effect of the HCV core occurs in the priming stage and is limited to the DNA form of the HBsAg antigen, but not to the protein form. The HCV core reduces the protective effect of the HBsAg when the HBsAg and the HCV core are co-administered as vaccines in an HBV hydrodynamic mouse model because the HCV core induces immune tolerance to the heterogeneous HBsAg DNA antigen. These results suggest that HCV core may play an important role in viral persistence by the attenuation of host immune responses to different antigens. We further tested whether the HCV core interfered with the priming of the immune response in hepatocytes via the hydrodynamic co-injection of an HBV replication-competent plasmid and an HCV core plasmid. The HCV core inhibited HBV replication and antigen expression in both BALB/c (H-2d) and C57BL/6 (H-2b) mice, the mouse models of acute and chronic hepatitis B virus infections. Thus, the HCV core inhibits the induction of a specific immune response to an HBsAg DNA vaccine. However, HCV C also interferes with HBV gene expression and replication in vivo, as observed in patients with coinfection.
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Affiliation(s)
- Wenbo Zhu
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Chunchen Wu
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- * E-mail: (XC)
| | - Wanyu Deng
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Rongjun Pei
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yun Wang
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Liang Cao
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Bo Qin
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Mengji Lu
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- Institute of Virology, University Hospital of Essen, Essen, Germany
| | - Xinwen Chen
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
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Lages ELE, Belo AV, Andrade SP, Rocha MÂ, Ferreira de Freitas G, Lamaita RM, Traiman P, Silva-Filho AL. Analysis of systemic inflammatory response in the carcinogenic process of uterine cervical neoplasia. Biomed Pharmacother 2011; 65:496-9. [DOI: 10.1016/j.biopha.2011.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Accepted: 06/05/2011] [Indexed: 10/17/2022] Open
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13
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Attenuation of nitric oxide bioavailability in porcine aortic endothelial cells by classical swine fever virus. Arch Virol 2011; 156:1151-60. [DOI: 10.1007/s00705-011-0972-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Accepted: 03/07/2011] [Indexed: 10/18/2022]
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14
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The wild-type hepatitis C virus core inhibits initiation of antigen-specific T- and B-cell immune responses in BALB/c mice. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2010; 17:1139-47. [PMID: 20519445 DOI: 10.1128/cvi.00490-09] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In this study, the effects of wild-type and deletion mutant hepatitis C virus (HCV) core proteins on the induction of immune responses in BALB/c mice were assessed. p2HA-C145-S23, encoding a core protein with the C-terminal 46 amino acids truncated, significantly produced stronger antibody and cellular responses than p2HA-C191-S23. The induction of immune responses by p2HA-C145-S23 was dose dependent. However, increasing the doses or repeated administration did not enhance immune responses by the wild-type core protein. In addition, p2HA-C191-S23 was apparently able to interfere with the priming of specific immune responses by p2HA-C145-S23 when the two were coadministered. These results demonstrated that the wild-type HCV core protein itself could inhibit the priming of immune responses in the course of a DNA vaccination, whereas the truncated HCV core protein could provide potential applications for the development of DNA- and peptide-based HCV vaccines.
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15
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Guzzo C, Hopman WM, Che Mat NF, Wobeser W, Gee K. Impact of HIV infection, highly active antiretroviral therapy, and hepatitis C coinfection on serum interleukin-27. AIDS 2010; 24:1371-1374. [PMID: 20375875 DOI: 10.1097/qad.0b013e3283391d2b] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A newly described cytokine, interleukin-27 (IL-27), that activates naive CD4 T cells, has recently been shown to be an anti-HIV cytokine. However, the effect of HIV infection on IL-27 expression has not been characterized. We found that clinical characteristics, including HIV viral load, hepatitis C virus coinfection, and CD4 T cell counts, were associated with changes in serum IL-27. Overall, our results suggest circulating HIV may suppress IL-27, a critical concept in treatment development with this cytokine.
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Affiliation(s)
- Christina Guzzo
- Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada
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16
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Zaki MES, Saudy N, El Diasty A. Study of nitric oxide in patients with chronic hepatitis C genotype 4: relationship to viremia and response to antiviral therapy. Immunol Invest 2010; 39:598-610. [PMID: 20653427 DOI: 10.3109/08820131003720710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a global medical problem. The role of Nitric oxide (NO) in chronic viral hepatitis is still unknown. It may play a prominent role as an antiviral agent that reduces its replication or as a mediator that causes accumulation of oxidative DNA damage and oncogenesis. The present study was carried out to study effect of combined peginterferon and ribavirin therapy for hepatitis C on NO in both responders and in non responder patients. The study included seventy three patients with positive serological markers for HCV. They were classified according to presence or absence of HCV viremia and the response to therapy. In addition sixteen control subjects were included. NO levels were determined as the stable end product nitrate and nitrite. Serum nitrite and nitrate concentrations in the patients with viral hepatitis were significantly higher than normal subjects and patients with serological evidence of hepatitis C infection in absence of viral load. The levels of nitrite >or= 31 microM, nitrate >or= 15 microM and NO(2)/NO(3) ratio < 1.5 microM were associated with increased risk of resistance to therapy. The multivariate logistic regression analysis showed that NO(2)/NO(3) ratio at levels < 1.5 microM was associated with HCV eradication independently. This study provides new insight into the pathogenesis of hepatitis C and highlights the effect of combined peginterferon and ribavirin on nitrite and nitrate as markers of endogenous NO system. There is a limitation level of NO that if it is increased above it may lead to non response to antiviral therapy. Therefore, it may be an important factor for chronic hepatitis C, which suggests an additional therapeutic pathway of anti-oxidants in combination with the standard regimen for further study.
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Affiliation(s)
- Maysaa El Sayed Zaki
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Egypt.
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17
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Affiliation(s)
- Mathis Heydtmann
- Liver Research Laboratories, Institute for Biomedical Research, Birmingham University, Birmingham B15 2TT, United Kingdom.
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18
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HCV and innate immunity. Uirusu 2009; 58:19-26. [PMID: 19122385 DOI: 10.2222/jsv.58.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Hepatitis C virus (HCV) is a single-strand, positive sense RNA virus belonging to the flaviviridae family. HCV develops persistent infection in >70% of infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Once chronic infection is established in patients with HCV, spontaneous viral clearance fails, although how HCV remains persistently infecting the liver is largely unknown. Insufficient immune response, involving antiviral innate immune response including dendritic cells (DCs), has been focused. A number of controversial studies have been reported as to HCV genome replication and HCV-mediated immune responses in human DCs. A tantalizing point of these earlier studies is the lack of the system for viral propagation in HCV. Recently, an in vitro system was exploited to propagate HCV particles using the JFH1 strain. In this review, we review the previous reports about the subversion of innate immunity by HCV and show the innate response of monocyte-derived dendritic cells (MoDCs) against the JFH1 strain. We could not observe HCV direct interaction with MoDC maturation. MoDCs maturated by phagocytosing HCV-infected apoptotic cells containing virus-derived dsRNA, which interacted with TLR3 in the phagosomes. All of these data suggests the importance of TLR3 signal for the induction of anti-HCV innate immunity.
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19
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Abstract
The complement system is a family of serum and cell surface proteins that recognize pathogen-associated molecular patterns, altered-self ligands, and immune complexes. Activation of the complement cascade triggers several antiviral functions including pathogen opsonization and/or lysis, and priming of adaptive immune responses. In this review, we will examine the role of complement activation in protection and/or pathogenesis against infection by Flaviviruses, with an emphasis on experiments with West Nile and Dengue viruses.
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Affiliation(s)
- Panisadee Avirutnan
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
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20
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Amador-Cañizares Y, Alvarez-Lajonchere L, Guerra I, Rodríguez-Alonso I, Martínez-Donato G, Triana J, González-Horta EE, Pérez A, Dueñas-Carrera S. Induction of IgA and sustained deficiency of cell proliferative response in chronic hepatitis C. World J Gastroenterol 2008; 14:6844-52. [PMID: 19058312 PMCID: PMC2773881 DOI: 10.3748/wjg.14.6844] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: In the present study, antibody and peripheral blood mononuclear cells (PBMC) proliferative responses against hepatitis C virus (HCV) antigens were evaluated in HCV chronically infected patients.
METHODS: Paired serum and PBMC samples were taken six months apart from 34 individuals, either treated or not, and tested by enzyme-linked immunosorbent assay (ELISA) and carboxyfluorescein succinimidyl ester staining.
RESULTS: Over 70% of the patients showed specific IgG and IgM against capsid, E1 and NS3, while HVR-1 was recognized by half of the patients. An increase in the levels of the anti-capsid IgM (P = 0.027) and IgG (P = 0.0006) was observed in six-month samples, compared to baseline. Similarly, a significantly higher percent of patients had detectable IgA reactivity to capsid (P = 0.017) and NS3 (P = 0.005) after six months, compared to baseline. Particularly, IgA against structural antigens positively correlated with hepatic damage (P = 0.036). IgG subclasses evaluation against capsid and NS3 revealed a positive recognition mediated by IgG1 in more than 80% of the individuals. On the contrary, less than 30% of the patients showed a positive proliferative response either of CD4+ or CD8+ T cells, being the capsid poorly recognized.
CONCLUSION: These results confirm that while the cellular immune response is narrow and weak, a broad and vigorous humoral response occurs in HCV chronic infection. The observed correlation between IgA and hepatic damage may have diagnostic significance, although it warrants further confirmation.
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21
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Thimme R, Neumann-Haefelin C, Boettler T, Blum HE. Adaptive immune responses to hepatitis C virus: from viral immunobiology to a vaccine. Biol Chem 2008; 389:457-67. [PMID: 18953713 DOI: 10.1515/bc.2008.061] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) causes chronic infection in approximately two-thirds of cases, leading to chronic hepatitis, liver cirrhosis, liver disease, liver failure, and hepatocellular carcinoma in a substantial proportion of the 170 million HCV-infected individuals worldwide. It is generally accepted that the cellular immune response plays the most important role in determining the outcome of HCV infection. First, vigorous, multispecific and sustained CD4+ and CD8+ T-cell responses are associated with viral clearance. Second, depletion studies in chimpanzees, the only other host of HCV besides humans, have shown that both CD4+ and CD8+ T-cells are required for virus elimination. Third, the host's human leukocyte antigen alleles, which restrict the repertoire of CD4+ and CD8+ T-cell responses, influence the outcome of infection. Of note, protective immunity has been demonstrated in population-based studies, as well as in experimentally infected chimpanzees. Thus, a detailed understanding of the mechanisms contributing to the failure of the antiviral immune response should allow successful development of prophylactic and therapeutic vaccination strategies.
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Affiliation(s)
- Robert Thimme
- Department of Medicine II, University Hospital Freiburg, D-79106 Freiburg, Germany
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22
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Cummings KL, Waggoner SN, Tacke R, Hahn YS. Role of complement in immune regulation and its exploitation by virus. Viral Immunol 2008; 20:505-24. [PMID: 18158725 DOI: 10.1089/vim.2007.0061] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Complement is activated during the early phase of viral infection and promotes destruction of virus particles as well as the initiation of inflammatory responses. Recently, complement and complement receptors have been reported to play an important role in the regulation of innate as well as adaptive immune responses during infection. The regulation of host immune responses by complement involves modulation of dendritic cell activity in addition to direct effects on T-cell function. Intriguingly, many viruses encode homologs of complement regulatory molecules or proteins that interact with complement receptors on antigen-presenting cells and lymphocytes. The evolution of viral mechanisms to alter complement function may augment pathogen persistence and limit immune-mediated tissue destruction. These observations suggest that complement may play an important role in both innate and adaptive immune responses to infection as well as virus-mediated modulation of host immunity.
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Affiliation(s)
- Kara L Cummings
- Beirne Carter Center for Immunology Research and Department of Microbiology, University of Virginia, Charlottesville, Virginia
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23
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Effect of hepatitis C virus core protein on interferon-induced antiviral genes expression and its mechanisms. Virol Sin 2008. [DOI: 10.1007/s12250-007-0035-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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24
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Quer J, Martell M, Rodriguez F, Bosch A, Jardi R, Buti M, Esteban J. The Impact of Rapid Evolution of Hepatitis Viruses. ORIGIN AND EVOLUTION OF VIRUSES 2008:303-349. [DOI: 10.1016/b978-0-12-374153-0.00015-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Zaffuto KM, Piccone ME, Burrage TG, Balinsky CA, Risatti GR, Borca MV, Holinka LG, Rock DL, Afonso CL. Classical swine fever virus inhibits nitric oxide production in infected macrophages. J Gen Virol 2007; 88:3007-3012. [PMID: 17947523 DOI: 10.1099/vir.0.83042-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Classical swine fever virus (CSFV)-macrophage interactions during infection were analysed by examining macrophage transcriptional responses via microarray. Eleven genes had increased mRNA levels (>2.5-fold, P<0.05) in infected cell cultures, including arginase-1, an inhibitor of nitric oxide production, phosphoinositide 3-kinase, chemokine receptor 4 and interleukin-1beta. Lower levels of nitric oxide and increased arginase activity were found in CSFV-infected macrophages. These changes in gene expression in macrophages suggest viral modulation of host expression to suppress nitric oxide production.
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Affiliation(s)
- K M Zaffuto
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - M E Piccone
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - T G Burrage
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - C A Balinsky
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - G R Risatti
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - M V Borca
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - L G Holinka
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - D L Rock
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
| | - C L Afonso
- Plum Island Animal Disease Center, USDA-ARS, PO Box 848, Greenport, NY 11944, USA
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26
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Neumann-Haefelin C, Spangenberg HC, Blum HE, Thimme R. Host and viral factors contributing to CD8+ T cell failure in hepatitis C virus infection. World J Gastroenterol 2007; 13:4839-47. [PMID: 17828815 PMCID: PMC4611762 DOI: 10.3748/wjg.v13.i36.4839] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV-specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.
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Affiliation(s)
- Christoph Neumann-Haefelin
- Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, Freiburg D-79106, Germany.
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27
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Ciccaglione AR, Stellacci E, Marcantonio C, Muto V, Equestre M, Marsili G, Rapicetta M, Battistini A. Repression of interferon regulatory factor 1 by hepatitis C virus core protein results in inhibition of antiviral and immunomodulatory genes. J Virol 2006; 81:202-14. [PMID: 17050603 PMCID: PMC1797261 DOI: 10.1128/jvi.01011-06] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferon-stimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.
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Affiliation(s)
- Anna R Ciccaglione
- Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 Rome 00161, Italy.
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28
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Abstract
Hepatocellular carcinoma (HCC) is a frequent malignancy worldwide with a high rate of metastasis. The hepatitis B and C viruses are considered major etiological factors associated with the development of HCC, particularly as a result of their induction of chronic inflammation. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including HCC. Specifically, this review aims to cover evidence for the potential roles of cytokines, an important component of the immune system, in promoting HCC carcinogenesis and progression. A global summary of cytokine levels, functions, polymorphisms, and therapies with regard to HCC is presented. In particular, the role of proinflammatory Th1 and anti-inflammatory Th2 cytokine imbalances in the microenvironment of HCC patients with metastasis and the possible clinical significance of these findings are addressed. Overall, multiple studies, spanning many decades, have begun to elucidate the important role of cytokines in HCC.
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Affiliation(s)
- Anuradha Budhu
- National Cancer Institute, 37 Convent Dr., Bldg. 37, Rm. 3044A, Bethesda, MD 20892, USA
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29
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Jin YH, Crispe IN, Park S. Expression of hepatitis C virus core protein in hepatocytes does not modulate proliferation or apoptosis of CD8+ T cells. Yonsei Med J 2005; 46:827-34. [PMID: 16385660 PMCID: PMC2810598 DOI: 10.3349/ymj.2005.46.6.827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocytes are the primary targets of the hepatitis C virus (HCV). While immunosuppressive roles of HCV core protein have been found in several studies, it remains uncertain whether core protein expressed in hepatocytes rather than in immune cells affects the CD8+ T cell response. In order to transduce genes selectively into hepatocytes, we developed a baculoviral vector system that enabled primary hepatocytes to express a target epitope for CD8+ T cells, derived from ovalbumin (OVA), with or without HCV core protein. Culture of OVA-specific CD8+ T cells with hepatocytes infected with these baculoviral vectors revealed that core protein has no effect on proliferation or apoptosis of CD8+ T cells. Our results suggest that HCV core protein does not exert its suppressive role on the CD8+ T cell immune response through expression in hepatocytes.
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Affiliation(s)
- Young-Hee Jin
- The David H Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA
| | - I. Nicholas Crispe
- The David H Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA
| | - Sun Park
- The David H Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York 14642, USA
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30
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Youn JW, Park SH, Lavillette D, Cosset FL, Yang SH, Lee CG, Jin HT, Kim CM, Shata MTM, Lee DH, Pfahler W, Prince AM, Sung YC. Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee. Hepatology 2005; 42:1429-36. [PMID: 16317673 DOI: 10.1002/hep.20934] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Immune correlates of protection against hepatitis C virus (HCV) infection are not well understood. Here we investigated 2 naive and 6 immunized chimpanzees before and after intravenous challenge, 12 weeks after the last immunization, with 100 50% chimpanzee infectious doses (CID(50)) of heterologous genotype 1b HCV. Vaccination with recombinant DNA and adenovirus vaccines expressing HCV core, E1E2, and NS3-5 genes induced long-term HCV-specific antibody and T-cell responses and reduced peak viral load about 100 times compared with controls (5.91 +/- 0.38 vs. 3.81 +/- 0.71 logs, respectively). There was a statistically significant inverse correlation between peak viral loads and envelope glycoprotein 2 (E2)-specific antibody responses at the time of challenge. Interestingly, one vaccinee that had sterilizing immunity against slightly heterologous virus generated the highest level of E2-specific total and neutralizing antibody responses as well as strong NS3/NS5-specific T-cell proliferative responses. The other four vaccinees with low levels of E2-specific antibody had about 44-fold reduced peak viral loads but eventually developed persistent infections. In conclusion, vaccine-induced E2-specific antibody plays an important role in prevention from nonhomologous virus infection and may provide new insight into the development of an effective HCV vaccine.
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Affiliation(s)
- Jin-Won Youn
- National Research Laboratory of DNA Medicine, Division of Molecular and Life Science, POSTECH Biotech Center, Pohang University of Science and Technology, Republic of Korea
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31
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Waggoner SN, Cruise MW, Kassel R, Hahn YS. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway. THE JOURNAL OF IMMUNOLOGY 2005; 175:4706-14. [PMID: 16177118 DOI: 10.4049/jimmunol.175.7.4706] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
gC1qR, a complement receptor for C1q, plays a pivotal role in the regulation of inflammatory and antiviral T cell responses. Several pathogens, including hepatitis C virus, exploit gC1qR-dependent regulatory pathways to manipulate host immunity. However, the molecular mechanism(s) of gC1qR signaling involved in regulating inflammatory responses remains unknown. We report the selective inhibition of TLR4-induced IL-12 production after cross-linking of gC1qR on the surface of macrophages and dendritic cells. Suppression of IL-12 did not result from increased IL-10 or TGF-beta, but was dependent on PI3K activation. Activation of PI3K and subsequent phosphorylation of Akt define an intracellular pathway mediating gC1qR signaling and cross-talk with TLR4 signaling. This is the first report to identify signaling pathways used by gC1qR-mediated immune suppression, and it establishes a means of complement-mediated immune suppression to inhibit Th1 immunity crucial for clearing pathogenic infection.
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Affiliation(s)
- Stephen N Waggoner
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville 22908, USA
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32
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Abstract
Chronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC), has been a major cause of mortality in Korea. The prevalence rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in the general population of Korea are approximately 1 and 5%, respectively. The most common genotypes of HCV in Korea are 1b and 2a. The sustained virological response rates after antiviral therapies, including combined interferon-alpha and ribavirin, have been reported to be 38-59%. The annual incidence of HCC among HCV-related liver cirrhosis has been estimated at 5%, and approximately 12% of HCC is attributable to HCV and 68% to HBV in Korea. The mean age of patients with HCV-related HCC at the time of diagnosis was consistently 10 years older than that of patients with HBV-related HCC. Moreover, HCV-related HCC was accompanied by more advanced liver cirrhosis than HBV-related HCC. Coinfection with HBV seemed to increase the risk of developing HCC in chronic HCV infection. After the successful program of hepatitis B vaccination, HCV infection is now emerging as an important etiology of chronic liver disease in Korea, which warrants more detailed and large-scale studies.
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Affiliation(s)
- Dong Jin Suh
- Division of Gastroenterology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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33
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Hokari A, Zeniya M, Esumi H, Ishikawa T, Kurasima Y, Toda G. Role of nitric oxide (NO) in interferon-alpha therapy for hepatitis C. J Infect 2005; 51:47-53. [PMID: 15979491 DOI: 10.1016/j.jinf.2004.08.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2004] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM The role of nitric oxide in infectious disease is gaining increased attention because antiviral effects of nitric oxide. In addition, there is evidence that nitric oxide synthase-2 expression was noted in chronic hepatitis C found within mononuclear cells. METHODS We studied serum levels of nitrite and nitrate before and during interferon alpha therapy in 66 patients with chronic hepatitis C. RESULTS There was no significant difference of their levels between the healthy control subjects and the patients before the treatment with interferon (55.9+/-21.8 microM vs. 60.9+/-30.0 microM). Their levels were determined at 2 weeks after the initiation of treatment with interferon and compared with those before the treatment in the patients with chronic hepatitis C. In the total patients treated, there was no significant difference between their levels before and at 2 weeks after the treatment (60.9+/-30.0 microM vs. 65.5+/-30.0 microM, P=0.14). However, when the levels were compared between sustained responders, in whom hepatitis C virus was eradicated, and non-responders, in whom the virus was not eradicated, the former had significantly higher levels of nitrite and nitrate than the latter at 2 weeks after the initiation of treatment (83.7+/-40.9 microM vs. 57.6+/-19.5 microM, P<0.01). The multivariate logistic regression analysis showed that the rise of nitrite and nitrate was an independent predictive factor for efficacy of interferon treatment. CONCLUSIONS Nitric oxide may be an important factor for antiviral therapy by interferon treatment for chronic hepatitis C, which suggests an additional therapeutic pathway for further study.
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Affiliation(s)
- Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato, Tokyo 105-0003, Japan.
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34
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Falcón V, Acosta-Rivero N, Shibayama M, Chinea G, Gavilondo JV, de la Rosa MC, Menéndez I, Gra B, Dueñas-Carrera S, Viña A, García W, González-Bravo M, Luna-Munoz J, Miranda-Sanchez M, Morales-Grillo J, Kouri J, Tsutsumi V. HCV core protein localizes in the nuclei of nonparenchymal liver cells from chronically HCV-infected patients. Biochem Biophys Res Commun 2005; 329:1320-8. [PMID: 15766571 DOI: 10.1016/j.bbrc.2005.02.107] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2005] [Indexed: 12/28/2022]
Abstract
Understanding the mechanism of hepatitis C virus (HCV) pathogenesis is an important part of HCV research. Recent experimental evidence suggests that the HCV core protein (HCcAg) has numerous functional activities. These properties suggest that HCcAg, in concert with cellular factors, may contribute to pathogenesis during persistent HCV infection. HCV is capable of infecting cells other than hepatocytes. Although the extrahepatic cellular tropism of HCV may play a role in the pathophysiology of this infection, the precise biological significance of the presence of HCV components in different liver cell types presently remains to be established. In this study, HCcAg was detected in nonparenchymal liver cells of six patients out of eight positive for serum HCV RNA. Immunostaining with anti-HCcAg mAbs revealed the presence of this protein in different liver cell types such as lymphocytes, Kupffer, polymorphonuclear, pit, endothelial, stellate, and fibroblast-like cells. Interestingly, HCcAg was immunolabeled not only in the cytoplasm but also in the nucleus of these cells. Remarkably, HCcAg co-localized with large lipid droplets present in stellate cells and with collagen fibers in the extracellular matrix. Moreover, HCcAg was immunolabeled in bile canaliculus suggesting the involvement of the biliary system in the pathobiology of HCV. Data suggest that nonparenchymal liver cells may constitute a reservoir for HCV replication. Besides, HCcAg may contribute to modulate immune function and fibrosis in the liver as well as steatosis.
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Affiliation(s)
- Viviana Falcón
- Biomedicine Division, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, C.P. 10600, Havana, Cuba.
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35
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Neumann-Haefelin C, Blum HE, Chisari FV, Thimme R. T cell response in hepatitis C virus infection. J Clin Virol 2005; 32:75-85. [PMID: 15653409 DOI: 10.1016/j.jcv.2004.05.008] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Accepted: 05/24/2004] [Indexed: 12/25/2022]
Abstract
Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It is widely accepted that cellular immune responses play an important role in viral clearance and disease pathogenesis. However, HCV often evades effective immune recognition and has a propensity to persist in the majority of acutely infected individuals (ca. 80%). The immunological and virological basis for the inefficiency of the cellular immune response to clear or control the virus is not known. Recent studies, however, have provided new insights into the mechanisms of viral clearance and persistence that will be discussed in detail.
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Affiliation(s)
- C Neumann-Haefelin
- Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany
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36
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Missale G, Cariani E, Ferrari C. Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies? Dig Liver Dis 2004; 36:703-11. [PMID: 15570998 DOI: 10.1016/j.dld.2004.07.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection.
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Affiliation(s)
- G Missale
- Division of Infectious Diseases and Hepatology, University of Parma, via Gramsci 14, 43100 Parma, Italy
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37
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Eisen-Vandervelde AL, Waggoner SN, Yao ZQ, Cale EM, Hahn CS, Hahn YS. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem 2004; 279:43479-86. [PMID: 15292184 DOI: 10.1074/jbc.m407640200] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon-gamma production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon-gamma synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1beta, and tumor necrosis factor alpha. In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening TH1 responses.
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38
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Ruggieri A, Murdolo M, Rapicetta M. Induction of FAS ligand expression in a human hepatoblastoma cell line by HCV core protein. Virus Res 2004; 97:103-10. [PMID: 14602201 DOI: 10.1016/j.virusres.2003.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Tumour cells and virus infected cells expressing Fas ligand (FasL) can evade immune surveillance by inducing apoptosis in T cells expressing Fas. In order to characterise a possible role of hepatitis C virus (HCV) core protein in similar mechanisms during HCV infection, we investigated Fas ligand expression and activity in a human hepatoblastoma cell line (HepG2) constitutively expressing this protein. Strong FasL induction was detected by immunoblotting and flow cytometry analysis in the core expressing cell lines Hep39. In contrast, vector transfected cells or cell lines expressing HCV E1-E2 proteins did not show FasL expression. Co-cultivation experiments of Hep39 cells with a Fas-sensitive T cell line indicated that FasL induced by the core protein had apoptotic activity toward target cells. Effect of the core protein on induction of FasL promoter was further examined by co-transfection of HepG2 cells with core-bearing plasmid and a vector in which luciferase gene expression is driven by human FasL promoter. Results of the luciferase assay indicated a positive regulation of FasL promoter by the core protein. In conclusion, HCV core protein plays a role in the induction of functional FasL in hepatoblastoma cell line and apoptosis in a target T cell line expressing Fas. Similar mechanisms may contribute, in vivo, to establishment of chronic infection and development of hepatocellular carcinoma (HCC).
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Affiliation(s)
- A Ruggieri
- Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy
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39
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Youn JW, Park SH, Cho JH, Sung YC. Optimal induction of T-cell responses against hepatitis C virus E2 by antigen engineering in DNA immunization. J Virol 2003; 77:11596-602. [PMID: 14557645 PMCID: PMC229347 DOI: 10.1128/jvi.77.21.11596-11602.2003] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Although DNA immunization is a safe and efficient method for inducing cellular immune responses, it generates relatively weak and slow immune responses. Here, we investigated the effect of hepatitis C virus (HCV) antigen modifications on the induction of T-cell responses in DNA immunization. It is likely that the strength of T-cell responses has an inverse relationship with the length of the insert DNA. Interestingly, a mixture of several plasmids carrying each gene induced a higher level of T-cell responses than a single plasmid expressing a long polyprotein. Moreover, the presence of a transmembrane domain in HCV E2 resulted in stronger T-cell responses against E2 protein than its absence. Taken together, our results indicate that the tailored modifications of DNA-encoded antigens are capable of optimizing the induction of T-cell responses which is required for eliminating the cells chronically infected with highly variable viruses such as HCV and human immunodeficiency virus.
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Affiliation(s)
- Jin-Won Youn
- Laboratory of Cellular Immunology, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Hyoja Dong, Pohang, Kyungbuk 790-784, Republic of Korea
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40
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Roayaie S, Schiano TD, Thung SN, Emre SH, Fishbein TM, Miller CM, Schwartz ME. Results of retransplantation for recurrent hepatitis C. Hepatology 2003; 38:1428-36. [PMID: 14647054 DOI: 10.1016/j.hep.2003.09.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Retransplantation for recurrent hepatitis C virus (HCV) has been evaluated in small series. In this study, patients undergoing transplantation for HCV-related cirrhosis with subsequent retransplantation more than 90 days for recurrent HCV (proven by pathologic examination of the explant and exclusion of other factors) were prospectively followed. This group was compared with a simultaneous cohort without HCV infection undergoing retransplantation more than 90 days after primary transplantation. Forty-two patients underwent retransplantation for recurrent HCV with a median survival of 12.9 +/- 6.7 months after retransplantation. Twenty patients (48%) were dead at 6 months, and 13 (65%) of these deaths were due to sepsis. On univariate analysis, creatinine level greater than or equal to 3 mg/dL, platelet count less than 100000/microL, prothrombin time (PT) greater than or equal to 16 seconds, alkaline phosphatase level less than or equal to 240 U/L, gamma-glutamyltransferase level less than or equal to 130 U/L, and donor age of 60 years or greater all correlated significantly with shorter survival after retransplantation. PT and donor age were predictors of survival on multivariate analysis. Patients undergoing retransplantation for recurrent HCV had a significantly shorter median survival than the 55 patients undergoing retransplantation for other chronic reasons of graft loss (75.6 +/- 17.7 months). In conclusion, median survival after liver retransplantation for recurrent HCV is significantly shorter than after retransplantation for other causes of late graft loss. Most deaths occur in the first 6 months and are due to sepsis. Candidates for retransplantation with a preoperative PT less than 16 seconds and those receiving grafts from donors younger than 60 years can expect a significantly longer median survival after retransplantation.
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Affiliation(s)
- Sasan Roayaie
- Recanati-Miller Transplantation Institute, Mount Sinai Hospital of Mount Sinai-NYU Health, New York, NY 10029, USA.
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41
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Park SH, Yang SH, Lee CG, Youn JW, Chang J, Sung YC. Efficient induction of T helper 1 CD4+ T-cell responses to hepatitis C virus core and E2 by a DNA prime-adenovirus boost. Vaccine 2003; 21:4555-64. [PMID: 14575768 DOI: 10.1016/s0264-410x(03)00499-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) is an important causative agent of liver disease, but currently there is no available prophylactic vaccine against HCV infection. Here, we investigated the HCV E2- and core-specific T-cell responses induced by DNA (D) and/or recombinant adenovirus (A) vaccines. In single (D versus A) or double immunizations (D-D versus A-A), the recombinant adenovirus vaccines induced higher levels of IFN-gamma secreting T-cell response and cytotoxic T lymphocytes (CTL) response than the DNA vaccines. However, a heterologous (D-A) regimen elicited the highest level of T helper 1 (Th1) CD4(+) T-cell responses. Furthermore, three E2-specific CTL epitopes were mapped using a peptide pool spanning the E2 protein sequence (a.a. 384-713) in BALB/c mice, and one of these (E2 405-414: SGPSQKIQLV) was shown to be immunodominant. Interestingly, no significant differences were found in the repertoire of E2-specific T-cell responses or in the immunodominance hierarchy of the three epitopes induced by D-D, D-A, A-A, and A-D, indicating that the breadth and hierarchy of T-cell responses is independent of these different vaccination regimens. In conclusion, the heterologous DNA prime-recombinant adenovirus boost regimen described offers an efficient promising strategy for the development of an effective T-cell-based HCV vaccine.
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Affiliation(s)
- Su-Hyung Park
- National Research Laboratory of DNA Medicine, Division of Molecular and Life Science, Pohang University of Science and Technology, San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, South Korea
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42
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Yao ZQ, Eisen-Vandervelde A, Ray S, Hahn YS. HCV core/gC1qR interaction arrests T cell cycle progression through stabilization of the cell cycle inhibitor p27Kip1. Virology 2003; 314:271-82. [PMID: 14517080 DOI: 10.1016/s0042-6822(03)00419-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Hepatitis C virus (HCV) is efficient in the establishment of persistent infection. We have previously shown that HCV core protein inhibits T cell proliferation through its interaction with the complement receptor, gC1qR. Here we show that HCV core-induced inhibition of T cell proliferation involves a G(0)/G(1) cell cycle arrest, which is reversible upon addition of anti-gC1qR antibody. Correspondingly, the expression of cyclin-dependent kinases (Cdk) 2/4 and cyclin E/D, as well as subsequent phosphorylation of retinoblastoma (pRb), is reduced in core-treated T cells in response to mitogenic stimulation. Remarkably, degradation of p27(Kip1), a negative regulator of both Cdk4/cyclin D and Cdk2/cyclin E complexes, is significantly diminished in T cells treated with HCV core upon mitogenic stimulation. These data indicate that the stability of p27(Kip1) by HCV core is associated with blocking activated T cells for the G(1) to S phase transition and inhibiting T cell proliferation.
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Affiliation(s)
- Zhi Qiang Yao
- Department of Pathology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA
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43
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Hahn YS. Subversion of immune responses by hepatitis C virus: immunomodulatory strategies beyond evasion? Curr Opin Immunol 2003; 15:443-9. [PMID: 12900277 DOI: 10.1016/s0952-7915(03)00076-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) is an important human pathogen that causes mild to severe liver disease worldwide. This positive-strand RNA virus is remarkably efficient at establishing persistent infection. In order for a non-cytopathic virus such as HCV to persist, the virus must escape immune recognition or inhibit the host immune responses. Immune escape via mutations in antigenic sites may occur under selective pressure during B-cell or T-cell responses to HCV infection, and may serve as a mechanism for the establishment HCV persistence. In addition to antigenic variation, HCV is able to subvert the host immune response by encoding specific viral gene product(s). An understanding of the mechanisms behind HCV persistence will provide a basis for the rational design of vaccines and novel therapeutic agents targeting human HCV infection.
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Affiliation(s)
- Young S Hahn
- Department of Microbiology and Beirne B. Carter Center for Immunology Research, University of Virginia, Health Sciences Center, Charlottesville 22908, USA.
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44
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Giannini C, Bréchot C. Hepatitis C virus biology. Cell Death Differ 2003; 10 Suppl 1:S27-38. [PMID: 12655344 DOI: 10.1038/sj.cdd.4401121] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2002] [Revised: 06/11/2002] [Accepted: 06/13/2002] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus infection represents a major problem of public health with around 350 millions of chronically infected individuals worldwide. The frequent evolution towards severe liver disease and cancer are the main features of HCV chronic infection. Antiviral therapies, mainly based on the combination of IFN and ribavirin can only assure a long term eradication of the virus in less than half of treated patients. The mechanisms underlying HCV pathogenesis and persistence in the host are still largely unknown and the efforts made by researchers in the understanding the viral biology have been hampered by the absence of a reliable in vitro and in vivo system reproducing HCV infection. The present review will mainly focus on viral pathogenetic mechanisms based on the interaction of HCV proteins (especially core, NS3 and NS5A) with host cellular signaling transduction pathways regulating cell growth and viability and on the strategies developed by the virus to persist in the host and escape to antiviral therapy. Past and recent data obtained in this field with different experimental approaches will be discussed.
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Affiliation(s)
- C Giannini
- Liver Cancer and Molecular Virology, Pasteur-INSERM Unit 370, 156, Rue de Vaugirard 75015 Paris, France
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45
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Chen YC, Wang SY. Activation of terminally differentiated human monocytes/macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol 2002; 76:9877-87. [PMID: 12208965 PMCID: PMC136495 DOI: 10.1128/jvi.76.19.9877-9887.2002] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Dengue virus (DV) primarily infects blood monocytes (MO) and tissue macrophages (M phi). We have shown in the present study that DV can productively infect primary human MO/M phi regardless of the stage of cell differentiation. After DV infection, the in vitro-differentiated MO/M phi secreted multiple innate cytokines and chemokines, including tumor necrosis factor alpha, alpha interferon (IFN-alpha), interleukin-1 beta (IL-1 beta), IL-8, IL-12, MIP-1 alpha, and RANTES but not IL-6, IL-15, or nitric oxide. Secretion of these mediators was highlighted by distinct magnitude, onset, kinetics, duration, and induction potential. A chemokine-to-cytokine hierarchy was noted in the magnitude and induction potential of secretion, and a chemokine-to-cytokine-to-chemokine/Th1 cytokine cascade could be seen in the production kinetics. Furthermore, we found that terminally differentiated MO/M phi cultured for more than 45 days could support productive DV infection and produce innate cytokines and chemokines, indicating that these mature cells were functionally competent in the context of a viral infection. In addition, DV replication in primary differentiated human MO/M phi was enhanced and prolonged in the presence of lipopolysaccharide (LPS), and LPS-mediated synergistic production of IFN-alpha could be seen in DV-infected MO/M phi. The secretion of innate cytokines and chemokines by differentiated MO/M phi suggests that regional accumulation of these mediators may occur in various tissues to which DV has disseminated and may thus result in local inflammation. The LPS-mediated enhancement of virus replication and synergistic IFN-alpha production suggests that concurrent bacterial infection may modulate cytokine-mediated disease progression during DV infection.
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Affiliation(s)
- Yun-Chi Chen
- Laboratory of Hematology, Department of Medical Research and Education, Veterans General Hospital-Taipei, Taipei, Taiwan, Republic of China.
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46
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Amaraa R, Mareckova H, Urbanek P, Fucikova T. Production of interleukins 10 and 12 by activated peripheral blood monocytes/macrophages in patients suffering from chronic hepatitis C virus infection with respect to the response to interferon and ribavirin treatment. Immunol Lett 2002; 83:209-14. [PMID: 12095711 DOI: 10.1016/s0165-2478(02)00102-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Circulating monocytes/macrophages are important for the initiation of immune responses to hepatitis C virus (HCV). Their presentation capacities and production of immunoregulatory cytokines enable them to activate cellular immune responses which is critical in determining the outcome of infection. We used flow cytometry to examine the expression of a CD80 costimulatory molecule on the surface of peripheral blood CD14+ monocytes/macrophages and to analyse the production of IL10 and IL12 by these cells. Forty-three individuals (6 asymptomatic HCV carriers, 37 patients with chronic hepatitis C (CHC)) were enrolled in this study. Thirty-seven patients with CHC (23 responders and 14 non-responders, NR) received combination (interferon+ribavirin) treatment for 52 weeks. The baseline percentage of CD14+CD80+ peripheral blood monocytes/macrophages was high in patients with CHC (P<0.001) and returned to normal after the treatment. All patients with CHC showed significantly high production of IL10 (P<0.001). In asymptomatic HCV carriers production level of this cytokine tended to be higher than in patients with CHC (P<0.001). A baseline production of IL12 was higher in asymptomatic HCV carriers and patients with CHC compared to healthy controls (P<0.001). The level of IL12 production was increased in treatment responders whereas in NR returned to normal value. Our data argue against functional impairment of circulating monocytes/macrophages during HCV infection. Furthermore, the positive therapeutic outcome following combination treatment might associate with increased production of IL12 by these cells.
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Affiliation(s)
- Ravdan Amaraa
- Institute of Microbiology and Clinical Immunology, 1st Medical Faculty, Charles University, Karlovo nam 32, Prague 2 Cz 12111, Czech Republic.
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47
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Kim HS, Lee JK, Yang IH, Ahn JK, Oh YI, Kim CJ, Kim YS, Lee CK. Identification of hepatitis C virus core domain inducing suppression of allostimulatory capacity of dendritic cells. Arch Pharm Res 2002; 25:364-9. [PMID: 12135111 DOI: 10.1007/bf02976640] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Hepatitis C virus (HCV) is remarkably efficient at establishing chronic infection. One of the reasons for this appears to be the suppression of the accessory cell function of professional antigen presenting cells. In the present study, the immunosuppressive activity of HCV protein was examined on dendritic cells (DCs) generated from mouse bone marrow progenitor cells in vitro. We found that the DCs forced to express HCV protein have defective allostimulatory ability. DCs expressing HCV protein were phenotypically indistinguishable from normal DCs. However, they were unable to produce IL-12 effectively when stimulated with lipopolysaccharide. The functional domain of the HCV protein essential for immunosuppression was determined using a series of NH2-and C-terminal deletion mutants of HCV core protein. We found that amino acid residues residing between the 21st and the 40th residues from the NH2-terminus of HCV core protein are required for immunosuppression. These findings suggest that HCV core protein suppresses the elicitation of protective Th1 responses by the inhibition of IL-12 production by DCs.
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Affiliation(s)
- Ho Sang Kim
- Department of Pharmacy, and Research Center for Bioresource and Health, Chungbuk National University, Cheongju, Korea
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48
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Sarobe P, Lasarte JJ, Casares N, López-Díaz de Cerio A, Baixeras E, Labarga P, García N, Borrás-Cuesta F, Prieto J. Abnormal priming of CD4(+) T cells by dendritic cells expressing hepatitis C virus core and E1 proteins. J Virol 2002; 76:5062-70. [PMID: 11967322 PMCID: PMC136154 DOI: 10.1128/jvi.76.10.5062-5070.2002] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4(+) T cells responding to HCV core in patients with chronic HCV infection. However, CD4(+) response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4(+) response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.
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Affiliation(s)
- Pablo Sarobe
- Department of Internal Medicine, Medical School and University Clinic, University of Navarra, 31008 Pamplona, Spain
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49
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Abstract
The liver has emerged as an organ with distinct immunological properties. In this review, we summarize evidence that shows that the liver can remove apoptotic, or non-apoptotic but activated, CD8+ T cells from the circulation and induce apoptosis in these activated T cells by either active or passive mechanisms. Hepatitis viruses, particularly hepatitis C virus, often establish persistent infection. We review evidence that suggests that these viruses exploit intrahepatic tolerance mechanisms to protect themselves from immune attack.
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Affiliation(s)
- Sun Park
- The David H Smith Center for VaccineBiology and Immunology, The University of Rochester, Rochester, New York 14642, USA
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50
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Cho JH, Youn JW, Sung YC. Cross-priming as a predominant mechanism for inducing CD8(+) T cell responses in gene gun DNA immunization. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 167:5549-57. [PMID: 11698425 DOI: 10.4049/jimmunol.167.10.5549] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
DNA immunization induces CD8(+) CTL responses by bone marrow-derived APCs, which are directly transfected with a plasmid DNA and/or acquire Ags from DNA-transfected non-APCs. To investigate the relative contribution of DNA-transfected APCs vs non-APCs to the initiation of CD8(+) T cell responses, we used tissue-specific promoter-directed gene expression and adoptive transfer systems in gene gun DNA immunization. In this study, we demonstrated that non-APC-specific gene expressions induced significant CD8(+) CTL and IFN-gamma-producing cells and Ab responses, whereas APC-specific gene expressions led to moderate CTL and IFN-gamma-producers, but no Ab responses. Interestingly, mice immunized with a non-APC-specific plasmid induced more rapid, vigorous, and prolonged proliferation of adoptively transferred Ag-specific CD8(+) T cells than APC-specific plasmid-immunized mice. In addition, the in vivo proliferative responses elicited by a non-APC-specific plasmid administration were dependent on TAP, but were independent of CD4(+) T cell help. Collectively, our results suggest that cross-priming, in which Ags expressed in non-APCs are taken up, processed, and presented by APCs, plays an important role in the initiation, magnitude, and maintenance of CD8(+) T cell responses in gene gun DNA immunization.
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Affiliation(s)
- J H Cho
- National Research Laboratory of DNA Medicine, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Hyojadong, Pohang, Kyungbuk, Korea
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