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Greene TT, Zuniga EI. Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings. Viruses 2021; 13:1839. [PMID: 34578420 PMCID: PMC8472174 DOI: 10.3390/v13091839] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/01/2021] [Accepted: 09/01/2021] [Indexed: 01/12/2023] Open
Abstract
Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.
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Affiliation(s)
| | - Elina I. Zuniga
- Division of Biological Sciences, University of California, San Diego, CA 92093, USA;
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2
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Greene TT, Jo YR, Zuniga EI. Infection and cancer suppress pDC derived IFN-I. Curr Opin Immunol 2020; 66:114-122. [PMID: 32947131 PMCID: PMC8526282 DOI: 10.1016/j.coi.2020.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/12/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) are specialized producers of Type I interferon (IFN-I) that promote anti-viral and anti-tumor immunity. However, chronic infections and cancer inhibit pDC-derived IFN-I. While the mechanisms of this inhibition are multifarious they can be classified broadly into two categories: i) reduction or ablation of pDC IFN-I-production capacity (functional exhaustion) and/or ii) decrease in pDC numbers (altered population dynamics). Recent work has identified many processes that contribute to suppression of pDC-derived IFN-I during chronic infections and cancer, including sustained stimulation through Toll Like Receptors (TLRs), inhibitory microenvironments, inhibitory receptor ligation, and reduced development from bone marrow progenitors and apoptosis. Emerging success leveraging pDCs in treatment of disease through TLR activation illustrates the therapeutic potential of targeting pDCs. Deeper understanding of the systems that limit pDC-derived IFN-I has the potential to improve these emerging therapies as well as help devising new approaches that harness the outstanding IFN-I-production capacity of pDCs.
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Affiliation(s)
- Trever T Greene
- University of California San Diego, Department of Biological Sciences, San Diego, United States
| | - Yea-Ra Jo
- University of California San Diego, Department of Biological Sciences, San Diego, United States
| | - Elina I Zuniga
- University of California San Diego, Department of Biological Sciences, San Diego, United States.
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3
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Doyle EH, Rahman A, Aloman C, Klepper AL, El-Shamy A, Eng F, Rocha C, Kim S, Haydel B, Florman SS, Fiel MI, Schiano T, Branch AD. Individual liver plasmacytoid dendritic cells are capable of producing IFNα and multiple additional cytokines during chronic HCV infection. PLoS Pathog 2019; 15:e1007935. [PMID: 31356648 PMCID: PMC6687199 DOI: 10.1371/journal.ppat.1007935] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 08/08/2019] [Accepted: 06/20/2019] [Indexed: 01/17/2023] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are "natural" interferon α (IFNα)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFNα mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFNα. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFNα in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFNα (~2 million molecules of IFNα/cell/hour) and produced more IFNα than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFNα than IFNλ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of "IFNα-response" pathway (R2 = 0.58, p = 0.007) and "monocyte surface" signature (R2 = 0.54, p = 0.01). Mass cytometry revealed that IFNα-producing pDCs were highly polyfunctional; >90% also made 2-4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFNα during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection.
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Affiliation(s)
- Erin Heather Doyle
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Adeeb Rahman
- Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Costica Aloman
- Rush University Medical Center, Chicago, Illinois, United States of America
| | - Arielle L. Klepper
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Ahmed El-Shamy
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Francis Eng
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Chiara Rocha
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Sang Kim
- Department of Anesthesiology, The Mount Sinai Hospital, New York, New York, United States of America
| | - Brandy Haydel
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Sander S. Florman
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - M. Isabel Fiel
- Department of Pathology, The Mount Sinai Hospital, New York, New York, United States of America
| | - Thomas Schiano
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Andrea D. Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail:
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4
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Chernykh ER, Oleynik EA, Leplina OY, Starostina NM, Ostanin AA. Dendritic cells in the pathogenesis of viral hepatitis C. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2019. [DOI: 10.15789/2220-7619-2019-2-239-252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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Yang Y, Tu ZK, Liu XK, Zhang P. Mononuclear phagocyte system in hepatitis C virus infection. World J Gastroenterol 2018; 24:4962-4973. [PMID: 30510371 PMCID: PMC6262249 DOI: 10.3748/wjg.v24.i44.4962] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/30/2018] [Accepted: 11/08/2018] [Indexed: 02/06/2023] Open
Abstract
The mononuclear phagocyte system (MPS), which consists of monocytes, dendritic cells (DCs), and macrophages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus (HCV) is efficient in evading the host immunity, thereby facilitating its development into chronic infection. Chronic HCV infection is the leading cause of end-stage liver diseases, liver cirrhosis, and hepatocellular carcinoma. Acquired immune response was regarded as the key factor to eradicate HCV. However, innate immunity can regulate the acquired immune response. Innate immunity-derived cytokines shape the adaptive immunity by regulating T-cell differentiation, which determines the outcome of acute HCV infection. Inhibition of HCV-specific T-cell responses is one of the most important strategies for immune system evasion. It is meaningful to illustrate the role of innate immune response in HCV infection. With the MPS being the important factor in innate immunity, therefore, understanding the role of the MPS in HCV infection will shed light on the pathophysiology of chronic HCV infection. In this review, we outline the impact of HCV infection on the MPS and cytokine production. We discuss how HCV is detected by the MPS and describe the function and impairment of MPS components in HCV infection.
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Affiliation(s)
- Yu Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng-Kun Tu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Xing-Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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7
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Sacchi A, Tumino N, Turchi F, Refolo G, Fimia G, Ciccosanti F, Montalbano M, Lionetti R, Taibi C, D'Offizi G, Casetti R, Bordoni V, Cimini E, Martini F, Agrati C. Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients. Clin Immunol 2017; 183:82-90. [PMID: 28736275 DOI: 10.1016/j.clim.2017.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 06/28/2017] [Accepted: 07/19/2017] [Indexed: 11/16/2022]
Abstract
First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-α and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome. HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested. In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-α production by plasmacytoid DC, able to inhibit in vitro HCV replication.
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Affiliation(s)
- Alessandra Sacchi
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy.
| | - Nicola Tumino
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Federica Turchi
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Giulia Refolo
- Cellular Biology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - GianMaria Fimia
- Cellular Biology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Fabiola Ciccosanti
- Cellular Biology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Marzia Montalbano
- Clinical Division, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Raffaella Lionetti
- Clinical Division, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Chiara Taibi
- Clinical Division, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Gianpiero D'Offizi
- Clinical Division, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Rita Casetti
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Veronica Bordoni
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Eleonora Cimini
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Federico Martini
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Chiara Agrati
- Cellular Immunology Laboratory, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
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Crosignani A, Riva A, Della Bella S. Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C. World J Gastroenterol 2016; 22:1393-1404. [PMID: 26819508 PMCID: PMC4721974 DOI: 10.3748/wjg.v22.i4.1393] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 09/11/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.
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9
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Sachdeva M, Chawla YK, Arora SK. Dendritic cells: The warriors upfront-turned defunct in chronic hepatitis C infection. World J Hepatol 2015; 7:2202-2208. [PMID: 26380045 PMCID: PMC4561774 DOI: 10.4254/wjh.v7.i19.2202] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/14/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection causes tremendous morbidity and mortality with over 170 million people infected worldwide. HCV gives rise to a sustained, chronic disease in the majority of infected individuals owing to a failure of the host immune system to clear the virus. In general, an adequate immune response is elicited by an efficient antigen presentation by dendritic cells (DCs), the cells that connect innate and adaptive immune system to generate a specific immune response against a pathogen. However, HCV seems to dysregulate the activity of DCs, making them less proficient antigen presenting cells for the optimal stimulation of virus-specific T cells, hence interfering with an optimal anti-viral immune response. There are discordant reports on the functional status of DCs in chronic HCV infection (CHC), from no phenotypic or functional defects to abnormal functions of DCs. Furthermore, the molecular mechanisms behind the impairment of DC function are even so not completely elucidated during CHC. Understanding the mechanisms of immune dysfunction would help in devising strategies for better management of the disease at the immunological level and help to predict the prognosis of the disease in the patients receiving antiviral therapy. In this review, we have discussed the outcomes of the interaction of DCs with HCV and the mechanisms of DC impairment during HCV infection with its adverse effects on the immune response in the infected host.
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Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. J Virol 2014; 89:3200-8. [PMID: 25552725 DOI: 10.1128/jvi.03229-14] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
UNLABELLED Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV. IMPORTANCE Although pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses.
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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12
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Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. THE JOURNAL OF IMMUNOLOGY 2014; 193:5723-32. [PMID: 25355916 DOI: 10.4049/jimmunol.1400725] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Several tumor-derived factors have been implicated in dendritic cell (DC) dysfunction in cancer patients. α-fetoprotein (AFP) is an oncofetal Ag that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we observed a lower ratio of myeloid/plasmacytoid circulating DCs compared with patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function were assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DCs expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular mass (LMM) species that copurify with tAFP and function equivalently to the LMM fractions of both tumor and nontumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMM molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Jian Shi
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Lisa H Butterfield
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
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13
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Leone P, Di Tacchio M, Berardi S, Santantonio T, Fasano M, Ferrone S, Vacca A, Dammacco F, Racanelli V. Dendritic cell maturation in HCV infection: altered regulation of MHC class I antigen processing-presenting machinery. J Hepatol 2014; 61:242-51. [PMID: 24732300 PMCID: PMC8759579 DOI: 10.1016/j.jhep.2014.04.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 03/04/2014] [Accepted: 04/06/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Modulation of dendritic cell (DC) function has been theorized as one of the mechanisms used by hepatitis C virus (HCV) to evade the host immune response and cause persistent infection. METHODS We used a range of cell and molecular biology techniques to study DC subsets from uninfected and HCV-infected individuals. RESULTS We found that patients with persistent HCV infection have lower numbers of circulating myeloid DC and plasmacytoid DC than healthy controls or patients who spontaneously recovered from HCV infection. Nonetheless, DC from patients with persistent HCV infection display normal phagocytic activity, typical expression of the class I and II HLA and co-stimulatory molecules, and conventional cytokine production when stimulated to mature in vitro. In contrast, they do not display the strong switch from immunoproteasome to standard proteasome subunit expression and the upregulation of the transporter-associated proteins following stimulation, which were instead observed in DC from uninfected individuals. This different modulation of components of the HLA class I antigen processing-presenting machinery results in a differential ability to present a CD8(+) T cell epitope whose generation is dependent on the LMP7 immunoproteasome subunit. CONCLUSIONS Overall, these findings establish that under conditions of persistent HCV antigenemia, HLA class I antigen processing and presentation are distinctively regulated during DC maturation.
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Affiliation(s)
- Patrizia Leone
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Mariangela Di Tacchio
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Simona Berardi
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | | | - Massimo Fasano
- Department of Infectious Diseases, University of Foggia, Foggia, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Franco Dammacco
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
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14
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Abstract
Persistent viral infection, such as HCV infection, is the result of the inability of the host immune system to mount a successful antiviral response, as well as the escape strategies devised by the virus. Although each individual component of the host immune system plays important roles in antiviral immunity, the interactive network of immune cells as a whole acts against the virus. The innate immune system forms the first line of host defense against viral infection, and thus, virus elimination or chronic HCV infection is linked to the direct outcome of the interactions between the various innate immune cells and HCV. By understanding how the distinct components of the innate immune system function both individually and collectively during HCV infection, potential therapeutic targets can be identified to overcome immune dysfunction and control chronic viral infection.
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Affiliation(s)
- Banishree Saha
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
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15
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Abdel-Hakeem MS, Shoukry NH. Protective immunity against hepatitis C: many shades of gray. Front Immunol 2014; 5:274. [PMID: 24982656 PMCID: PMC4058636 DOI: 10.3389/fimmu.2014.00274] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/27/2014] [Indexed: 12/11/2022] Open
Abstract
The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada ; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University , Cairo , Egypt
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Médecine, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada
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16
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Stone AEL, Mitchell A, Brownell J, Miklin DJ, Golden-Mason L, Polyak SJ, Gale MJ, Rosen HR. Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One 2014; 9:e95627. [PMID: 24788809 PMCID: PMC4006833 DOI: 10.1371/journal.pone.0095627] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/28/2014] [Indexed: 12/11/2022] Open
Abstract
Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV.
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Affiliation(s)
- Amy E. L. Stone
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Angela Mitchell
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Jessica Brownell
- Department of Global Health, University of Washington, Seattle, Washington, United States of America
| | - Daniel J. Miklin
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Lucy Golden-Mason
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Stephen J. Polyak
- Department of Global Health, University of Washington, Seattle, Washington, United States of America
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
| | - Michael J. Gale
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Hugo R. Rosen
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
- Denver Veteran’s Affairs Medical Center, Denver, Colorado, United States of America
- * E-mail:
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17
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Taraldsrud E, Fevang B, Aukrust P, Beiske KH, Fløisand Y, Frøland S, Rollag H, Olweus J. Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol 2014; 175:439-48. [PMID: 24237110 DOI: 10.1111/cei.12239] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2013] [Indexed: 01/21/2023] Open
Abstract
Patients with common variable immunodeficiency (CVID) have reduced numbers and frequencies of dendritic cells (DCs) in blood, and there is also evidence for defective activation through Toll-like receptors (TLRs). Collectively, these observations may point to a primary defect in the generation of functional DCs. Here, we measured frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) in peripheral blood of 26 CVID patients and 16 healthy controls. The results show that the patients have reduced absolute counts of both subsets. However, the decreased numbers in peripheral blood were not reflected in reduced frequencies of CD34(+) pDC progenitors in the bone marrow. Moreover, studies at the single cell level showed that DCs from CVID patients and healthy controls produced similar amounts of interferon-α or interleukin-12 and expressed similar levels of activation markers in response to human cytomegalovirus and ligands for TLR-7 and TLR-9. The study represents the most thorough functional characterization to date, and the first to assess bone marrow progenitor output, of naturally occurring DCs in CVID. In conclusion, it seems unlikely that CVID is secondary to insufficient production of naturally occurring DCs or a defect in their signalling through TLR-7 or TLR-9.
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Affiliation(s)
- E Taraldsrud
- Department of Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy and K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
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18
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Miles B, Abdel-Ghaffar KA, Gamal AY, Baban B, Cutler CW. Blood dendritic cells: "canary in the coal mine" to predict chronic inflammatory disease? Front Microbiol 2014; 5:6. [PMID: 24478766 PMCID: PMC3902297 DOI: 10.3389/fmicb.2014.00006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 01/07/2014] [Indexed: 12/19/2022] Open
Abstract
The majority of risk factors for chronic inflammatory diseases are unknown. This makes personalized medicine for assessment, prognosis, and choice of therapy very difficult. It is becoming increasingly clear, however, that low-grade subclinical infections may be an underlying cause of many chronic inflammatory diseases and thus may contribute to secondary outcomes (e.g., cancer). Many diseases are now categorized as inflammatory-mediated diseases that stem from a dysregulation in host immunity. There is a growing need to study the links between low-grade infections, the immune responses they elicit, and how this impacts overall health. One such link explored in detail here is the extreme sensitivity of myeloid dendritic cells (mDCs) in peripheral blood to chronic low-grade infections and the role that these mDCs play in arbitrating the resulting immune responses. We find that emerging evidence supports a role for pathogen-induced mDCs in chronic inflammation leading to increased risk of secondary clinical disease. The mDCs that are elevated in the blood as a result of low-grade bacteremia often do not trigger a productive immune response, but can disseminate the pathogen throughout the host. This aberrant trafficking of mDCs can accelerate systemic inflammatory disease progression. Conversely, restoration of dendritic cell homeostasis may aid in pathogen elimination and minimize dissemination. Thus it would seem prudent when assessing chronic inflammatory disease risk to consider blood mDC numbers, and the microbial content (microbiome) and activation state of these mDCs. These may provide important clues (“the canary in the coal mine”) of high inflammatory disease risk. This will facilitate development of novel immunotherapies to eliminate such smoldering infections in atherosclerosis, cancer, rheumatoid arthritis, and pre-eclampsia.
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Affiliation(s)
- Brodie Miles
- Department of Periodontics, College of Dental Medicine, Georgia Regents University Augusta, GA, USA
| | | | | | - Babak Baban
- Department of Oral Biology, Georgia Regents University Augusta, GA, USA
| | - Christopher W Cutler
- Department of Periodontics, College of Dental Medicine, Georgia Regents University Augusta, GA, USA
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19
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Sehgal M, Zeremski M, Talal AH, Khan ZK, Capocasale R, Philip R, Jain P. Host Genetic Factors and Dendritic Cell Responses Associated with the Outcome of Interferon/Ribavirin Treatment in HIV-1/HCV Co-Infected Individuals. ACTA ACUST UNITED AC 2014; 5. [PMID: 25705565 PMCID: PMC4332701 DOI: 10.4172/2155-9899.1000271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HIV-1/HCV co-infection is a significant health problem. Highly active antiretroviral treatment (HAART) against HIV-1 has proved to be fairly successful. On the other hand, direct acting antiviral drugs against HCV have improved cure rates but high cost and development of drug resistance are important concerns. Therefore PEGylated interferon (PEG-IFN) and ribavirin (RBV) still remain essential components of HCV treatment, and identification of host factors that predict IFN/RBV treatment response is necessary for effective clinical management of HCV infection. Impaired dendritic cell (DC) and T cell responses are associated with HCV persistence. It has been shown that IFN/RBV treatment enhances HCV-specific T cell functions and it is likely that functional restoration of DCs is the underlying cause. To test this hypothesis, we utilized an antibody cocktail (consisting of DC maturation, adhesion and other surface markers) to perform comprehensive phenotypic characterization of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment. Our results show that pre-treatment frequencies of mDCs are lower in non-responders (NRs) compared to responders (SVRs) and healthy controls. Although, the treatment was able to restore the frequency of mDCs in NRs, it downregulated the frequency of CCR7+, CD54+ and CD62L+ mDCs. Pre-treatment frequencies of pDCs were lower in NRs and decreased further upon treatment. Compared to SVRs, NRs exhibited higher ratio of PD-L1+/CD86+ pDCs prior to treatment; and this ratio remained high even after treatment. These findings demonstrate that enumeration and phenotypic assessment of DCs before/during therapy can help predict the treatment outcome. We also show that before treatment, PBMCs from SVRs secrete higher amounts of IFN-γ compared to controls and NRs. Upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Collectively, our study led to identification of important correlates of IFN/RBV treatment response in HIV-1/HCV co-infected individuals.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Marija Zeremski
- School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Andrew H Talal
- School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Renold Capocasale
- Flowmetric, Inc., Pennsylvania Biotechnology Center, Doylestown, PA, USA
| | - Ramila Philip
- Immunotope, Inc., Pennsylvania Biotechnology Center, Doylestown, PA, USA
| | - Pooja Jain
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
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20
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Abstract
Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.
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21
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Zhang S, Kodys K, Babcock GJ, Szabo G. CD81/CD9 tetraspanins aid plasmacytoid dendritic cells in recognition of hepatitis C virus-infected cells and induction of interferon-alpha. Hepatology 2013; 58:940-9. [PMID: 22577054 PMCID: PMC4511847 DOI: 10.1002/hep.25827] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/01/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Recognition of hepatitis C virus (HCV)-infected hepatocyes and interferon (IFN) induction are critical in antiviral immune response. We hypothesized that cell-cell contact between plasmacytoid dendritic cells (pDCs) and HCV-infected cells was required for IFN-α induction through the involvement of cell-surface molecules. Coculture of human peripheral blood mononuclear cells (PBMCs) with genotype 1a full-length (FL) HCV genomic replicon cells or genotype 2a Japanese fulminant hepatitis type 1 (JFH-1) virus-infected hepatoma cells (JFH-1), and not with uninfected hepatoma cells (Huh7.5), induced IFN-α production. Depletion of pDCs from PBMCs attenuated IFN-α release, and purified pDCs produced high levels of IFN-α after coculture with FL replicons or JFH-1-infected cells. IFN-α induction by HCV-containing hepatoma cells required viral replication, direct cell-cell contact with pDCs, and receptor-mediated endocytosis. We determined that the tetraspanin proteins, CD81 and CD9, and not other HCV entry receptors, were required for IFN-α induction in pDCs by HCV-infected hepatoma cells. Disruption of cholesterol-rich membrane microdomains, the localization site of CD81, or inhibition of the CD81 downstream molecule, Rac GTPase, inhibited IFN-α production. IFN-α induction involved HCV RNA and Toll-like receptor (TLR) 7. IFN-α production by HCV-infected hepatoma cells was decreased in pDCs from HCV-infected patients, compared to healthy controls. We found that preexposure of healthy PBMCs to HCV viral particles attenuated IFN-α induction by HCV-infected hepatoma cells or TLR ligands, and this inhibitory effect could be prevented by an anti-HCV envelope glycoprotein 2-blocking antibody. CONCLUSION Our novel data show that recognition of HCV-infected hepatoma cells by pDCs involves CD81- and CD9-associated membrane microdomains and induces potent IFN-α production.
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22
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Cross-linking of CD81 by HCV-E2 protein inhibits human intrahepatic plasmacytoid dendritic cells response to CpG-ODN. Cell Immunol 2013; 284:98-103. [PMID: 23954883 DOI: 10.1016/j.cellimm.2013.07.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 07/18/2013] [Accepted: 07/23/2013] [Indexed: 12/17/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) are reported to be defective in HCV-infected patients, the mechanisms of which remain poorly understood. We isolated liver derived mononuclear cells (LMNCs) and pDCs from normal liver tissues of benign tumor dissections and liver transplant donors. Isolated pDCs and LMNCs were cultured with precoated HCV envelop protein E2 (HCV-E2) or anti-CD81 mAb in the presence of CpG-ODN. Our results show that cross-linking of CD81 by either HCV-E2 or anti-CD81 mAb inhibits IFN-α secretion in CpG-induced pDCs; down-regulates HLA-DR, CD80 and CD86 expression in pDCs; and suppresses CpG-ODN induced proliferation and survival of pDCs. The blockade of CD81 by soluble anti-CD81 antibody restores pDCs response to CpG-ODN. These results suggest that HCV E2 protein interacts with CD81 to inhibit pDC maturation, activation, and IFN-α production, and may thereby contribute to the impaired innate anti-viral immune response in HCV infection.
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23
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Pelletier S, Bédard N, Said E, Ancuta P, Bruneau J, Shoukry NH. Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C. J Virol 2013; 87:6769-81. [PMID: 23576504 PMCID: PMC3676083 DOI: 10.1128/jvi.02445-12] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 03/25/2013] [Indexed: 12/11/2022] Open
Abstract
Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, a group with acute HCV infection with spontaneous resolution, and a group with acute infection with chronic evolution. We examined the frequency, maturation status, and cytokine production capacity of DCs in response to the Toll-like receptor 4 (TLR4) and TLR7/8 ligands lipopolysaccharide (LPS) and single-stranded RNA (ssRNA), respectively. Several observations could distinguish HCV-negative IDUs and acute HCV resolvers from patients with acute infection with chronic evolution. First, we observed a decrease in the frequency of mature CD86(+), programmed death-1 receptor ligand-positive (PDL1(+)), and PDL2(+) pDCs. This phenotype was associated with the increased sensitivity of pDCs from resolvers and HCV-negative IDUs versus the group with acute infection with chronic evolution to ssRNA stimulation in vitro. Second, LPS-stimulated mDCs from resolvers and HCV-negative IDUs produced higher levels of cytokines than mDCs from the group with acute infection with chronic evolution. Third, mDCs from all patients with acute HCV infection, irrespective of their outcomes, produced higher levels of cytokines during the early acute phase in response to ssRNA than mDCs from healthy controls. However, this hyperresponsiveness was sustained only in spontaneous resolvers. Altogether, our results suggest that the immature pDC phenotype and sustained pDC and mDC hyperresponsiveness are associated with spontaneous resolution of acute HCV infection.
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Affiliation(s)
- Sandy Pelletier
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
| | - Elias Said
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Petronela Ancuta
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Médecine Familiale,
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Médecine, Université de Montréal, Montréal, Quebec, Canada
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24
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Self AA, Losikoff PT, Gregory SH. Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C. Hum Vaccin Immunother 2013; 9:1569-76. [PMID: 23732899 DOI: 10.4161/hv.24726] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus-infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed.
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Affiliation(s)
- Ayssa A Self
- Department of Medicine; Rhode Island Hospital and the Warren Alpert Medical School of Brown University; Providence, RI USA
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25
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Stone AEL, Giugliano S, Schnell G, Cheng L, Leahy KF, Golden-Mason L, Gale M, Rosen HR. Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. PLoS Pathog 2013; 9:e1003316. [PMID: 23637605 PMCID: PMC3630164 DOI: 10.1371/journal.ppat.1003316] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 03/05/2013] [Indexed: 01/23/2023] Open
Abstract
Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell in the defense against viruses. Through pattern recognition receptors (PRRs), these cells detect viral pathogen associated molecular patterns (PAMPs) and initiate an Interferon (IFN) response. pDCs produce the antiviral IFNs including the well-studied Type I and the more recently described Type III. Recent genome wide association studies (GWAS) have implicated Type III IFNs in HCV clearance. We examined the IFN response induced in a pDC cell line and ex vivo human pDCs by a region of the HCV genome referred to as the HCV PAMP. This RNA has been shown previously to be immunogenic in hepatocytes, whereas the conserved X-region RNA is not. We show that in response to the HCV PAMP, pDC-GEN2.2 cells upregulate and secrete Type III (in addition to Type I) IFNs and upregulate PRR genes and proteins. We also demonstrate that the recognition of this RNA is dependent on RIG-I-like Receptors (RLRs) and Toll-like Receptors (TLRs), challenging the dogma that RLRs are dispensable in pDCs. The IFNs produced by these cells in response to the HCV PAMP also control HCV replication in vitro. These data are recapitulated in ex vivo pDCs isolated from healthy donors. Together, our data shows that pDCs respond robustly to HCV RNA to make Type III Interferons that control viral replication. This may represent a novel therapeutic strategy for the treatment of HCV.
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Affiliation(s)
- Amy E. L. Stone
- Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Silvia Giugliano
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Gretja Schnell
- Department of Immunology, University of Washington, School of Medicine, Seattle, Washington, United States of America
| | - Linling Cheng
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Katelyn F. Leahy
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Lucy Golden-Mason
- Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Michael Gale
- Department of Immunology, University of Washington, School of Medicine, Seattle, Washington, United States of America
| | - Hugo R. Rosen
- Integrated Department in Immunology: University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
- Denver Veteran's Affairs Medical Center, Denver, Colorado, United States of America
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26
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Sehgal M, Khan ZK, Talal AH, Jain P. Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 2013; 4:1-25. [PMID: 25512691 PMCID: PMC4222345 DOI: 10.4137/vrt.s11046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew H Talal
- Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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27
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Levitsky J, Mathew JM, Abecassis M, Tambur A, Leventhal J, Chandrasekaran D, Herrera N, Al-Saden P, Gallon L, Abdul-Nabi A, Yang GY, Kurian SM, Salomon DR, Miller J. Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 2013; 57:239-48. [PMID: 22234876 PMCID: PMC3334454 DOI: 10.1002/hep.25579] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 12/21/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ≈ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. CONCLUSIONS TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal.
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Affiliation(s)
- Josh Levitsky
- Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - James M. Mathew
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Michael Abecassis
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anat Tambur
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Joseph Leventhal
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Dhivya Chandrasekaran
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Nancy Herrera
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Patrice Al-Saden
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lorenzo Gallon
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anmaar Abdul-Nabi
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Sunil M. Kurian
- The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
| | - Daniel R. Salomon
- The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
| | - Joshua Miller
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Jesse Brown VA Medical Center, Chicago, Illinois
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28
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Velazquez VM, Hon H, Ibegbu C, Knechtle SJ, Kirk AD, Grakoui A. Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection. Hepatology 2012; 56:2071-81. [PMID: 22711645 PMCID: PMC3747821 DOI: 10.1002/hep.25904] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 06/04/2012] [Indexed: 02/06/2023]
Abstract
UNLABELLED Chronic hepatitis C virus (HCV) infection is a serious disease that can result in numerous long-term complications leading to liver failure or death. Approximately 80% of people fail to clear their infection, largely as the result of weak, narrowly targeting or waning antiviral T-cell responses. Although professional antigen presenting cells (APCs) like dendritic cells (DCs) might serve as targets for modulation of T-cell immunity, the particular role of DCs in immunity to HCV is not known. Moreover the identity, phenotype, and functional characteristics of such populations in the liver, the site of HCV replication, have proven difficult to elucidate. Using a multicolor flow-based approach, we identified six distinct populations of professional APCs among liver interstitial leukocytes isolated from uninfected and HCV-infected patients. Although a generalized enrichment of DCs in the liver compared to blood was observed for all patients, HCV infection was characterized by a significant increase in the frequency of intrahepatic myeloid DCs (both CD1c+ and CD141+). Phenotypic analyses of liver plasmacytoid (pDC) and myeloid DCs (mDC) further revealed the HCV-induced expression of maturation molecules CD80, CD83, CD40, and programmed death ligand-1. Importantly, pDC and mDCs from HCV-infected liver were capable of secreting effector cytokines, interferon-alpha and interleukin-12, respectively, in response to Toll-like receptor stimulation in vitro. CONCLUSION Chronic HCV infection facilitates the "customized" recruitment of liver DC subsets with established functional roles in antigen presentation. These DCs are characterized by a mature, activated phenotype and are functionally responsive to antigenic stimulation in vitro. Such findings highlight an important paradox surrounding liver DC recruitment during HCV infection, where despite their activation these cells do not provide adequate protection from the virus.
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Affiliation(s)
| | - Huiming Hon
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, 30322
| | - Chris Ibegbu
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, 30322
- Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, 30322
| | - Stuart J. Knechtle
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, 30322
| | - Allan D. Kirk
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, 30322
| | - Arash Grakoui
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, 30322
- Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, 30322
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, 30322
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29
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Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 2012; 3:610-20. [PMID: 23076334 PMCID: PMC3545943 DOI: 10.4161/viru.21823] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is a small, enveloped RNA virus and a major cause of chronic liver disease. Resolution of primary HCV infections depends upon the vigorous responses of CD4+ and CD8+ T cells to multiple viral epitopes. Although such broad-based responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Ostensibly, a variety of factors contribute to the diminished T cell responses observed in chronic, HCV-infected patients including impaired dendritic cell function and the induction of CD4+FoxP3+ regulatory T cells. Overwhelming evidence suggests that the complex interaction of dendritic cells and regulatory T cells plays a critical role in the pathogenesis of chronic hepatitis C.
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Affiliation(s)
- Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, RI, USA
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30
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Alvarez-Lajonchere L, Dueñas-Carrera S. Complete definition of immunological correlates of protection and clearance of hepatitis C virus infection: a relevant pending task for vaccine development. Int Rev Immunol 2012; 31:223-42. [PMID: 22587022 DOI: 10.3109/08830185.2012.680552] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infects approximately 3% of global population. This pathogen is one of the main causes of chronic viral hepatitis, cirrhosis, and liver cancer, as well as the principal reason for liver transplant in Western countries. Therapy against HCV infection is effective in only half of treated patients. There is no vaccine available against HCV. Some vaccine candidates have reached the clinical trials but several factors, including the incomplete definition of immunological correlates of protection and treatment-related clearance have slowed down vaccine development. Precisely, the present review discusses the state of the art in the establishment of parameters related with immunity against HCV. Validity and limitations of the information accumulated from chimpanzees and other animal models, analysis of studies in humans infected with HCV, and relevance of aspects like type, strength, duration, and specificity of immune response related to successful outcome are evaluated in detail. Moreover, the immune responses induced in some clinical trials with vaccine candidates resemble the theoretical immunological correlates, raising questions about the validity of those correlates. When all facts are taken together, complete definition of immunological correlates for protection or treatment-related clearance is an urgent priority. A limited or wrong criterion with respect to this relevant matter might cause incorrect vaccine design and selection of immunization strategies or erroneous clinical evaluation.
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31
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Zhou Y, Zhang Y, Yao Z, Moorman JP, Jia Z. Dendritic cell-based immunity and vaccination against hepatitis C virus infection. Immunology 2012; 136:385-96. [PMID: 22486354 DOI: 10.1111/j.1365-2567.2012.03590.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) has chronically infected an estimated 170 million people worldwide. There are many impediments to the development of an effective vaccine for HCV infection. Dendritic cells (DC) remain the most important antigen-presenting cells for host immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self and non-self antigens. Researchers have recently explored the mechanisms by which DC function is regulated during HCV infection, leading to impaired antiviral T-cell responses and so to persistent viral infection. Recently, DC-based vaccines against HCV have been developed. This review summarizes the current understanding of DC function during HCV infection and explores the prospects of DC-based HCV vaccine. In particular, it describes the biology of DC, the phenotype of DC in HCV-infected patients, the effect of HCV on DC development and function, the studies on new DC-based vaccines against HCV infection, and strategies to improve the efficacy of DC-based vaccines.
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Affiliation(s)
- Yun Zhou
- Centre of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
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32
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Brenndörfer ED, Sällberg M. Hepatitis C virus-mediated modulation of cellular immunity. Arch Immunol Ther Exp (Warsz) 2012; 60:315-29. [PMID: 22911132 DOI: 10.1007/s00005-012-0184-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 03/09/2012] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic liver disease globally. A chronic infection can result in liver fibrosis, liver cirrhosis, hepatocellular carcinoma and liver failure in a significant ratio of the patients. About 170 million people are currently infected with HCV. Since 80 % of the infected patients develop a chronic infection, HCV has evolved sophisticated escape strategies to evade both the innate and the adaptive immune system. Thus, chronic hepatitis C is characterized by perturbations in the number, subset composition and/or functionality of natural killer cells, natural killer T cells, dendritic cells, macrophages and T cells. The balance between HCV-induced immune evasion and the antiviral immune response results in chronic liver inflammation and consequent immune-mediated liver injury. This review summarizes our current understanding of the HCV-mediated interference with cellular immunity and of the factors resulting in HCV persistence. A profound knowledge about the intrinsic properties of HCV and its effects on intrahepatic immunity is essential to be able to design effective immunotherapies against HCV such as therapeutic HCV vaccines.
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Affiliation(s)
- Erwin Daniel Brenndörfer
- Division of Clinical Microbiology F68, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
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33
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Zwolak A, Jastrzebska I, Surdacka A, Kasztelan-Szczerbińska B, Łozowski CT, Roliński J, Skrzydło-Radomańska B, Radwan P, Daniluk J. Peripheral blood dendritic cells in alcoholic and autoimmune liver disorders. Hum Exp Toxicol 2012; 31:438-446. [PMID: 22076495 DOI: 10.1177/0960327111426582] [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: 01/12/2023]
Abstract
Little is known about effects of alcohol consumption on dendritic cell (DC) function and resultant immune response. However, quantitative and qualitative disturbances of DCs are speculated to be involved in alcohol-related as well as in other liver pathology. The present study aimed to evaluate changes in circulating DC subsets in alcoholic liver disease (N = 43), autoimmune hepatitis (N = 26) and primary biliary cirrhosis (N = 20). DCs isolated from the peripheral blood of recruited participants were stained with monoclonal antibodies against blood dendritic cell antigens (BDCAs) and estimated using the flow cytometry. Myeloid DCs were defined as BDCA-1(+)/CD19(-) cells, and lymphoid DCs as BDCA-2(+)/CD123(+) cells. Total numbers of circulating DCs in subjects with some liver diseases were markedly lower than in the healthy participants (p = 0.03). There was a significantly lower percentage of circulating BDCA-2(+)/CD123(+) (p = 0.02), and a tendency for the percentage of circulating BDCA-1(+)/CD19(-) cells to decrease in patients with liver diseases compared to the controls (p = 0.09). These results may suggest that decreased numbers of DCs may be responsible for reduced adaptive immune responses and increased susceptibility to infections and cancer development observed in patients exposed to alcohol. Moreover, numerical abnormalities of DCs may contribute to the breakdown of self-tolerance, a feature of autoimmune diseases.
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Affiliation(s)
- A Zwolak
- Department of Internal Medicine and Internal Medicine in Nursing, Medical University of Lublin, Poland.
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34
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Buonaguro L, Petrizzo A, Tornesello ML, Buonaguro FM. Innate immunity and hepatitis C virus infection: a microarray's view. Infect Agent Cancer 2012; 7:7. [PMID: 22448617 PMCID: PMC3511806 DOI: 10.1186/1750-9378-7-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 02/24/2012] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) induces a chronic infection in more than two-thirds of HCV infected subjects. The inefficient innate and adaptive immune responses have been shown to play a major pathogenetic role in the development and persistence of HCV chronic infection. Several aspects of the interactions between the virus and the host immune system have been clarified and, in particular, mechanisms have been identified which underlie the ability of HCV to seize and subvert innate as well as adaptive immune responses. The present review summarizes recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence.
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Affiliation(s)
- Luigi Buonaguro
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori “Fond. G. Pascale”, 80131, Naples, Italy
| | - Annacarmen Petrizzo
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori “Fond. G. Pascale”, 80131, Naples, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori “Fond. G. Pascale”, 80131, Naples, Italy
| | - Franco M Buonaguro
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori “Fond. G. Pascale”, 80131, Naples, Italy
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35
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Liang CC, Liu CH, Lin YL, Liu CJ, Chiang BL, Kao JH. Functional impairment of dendritic cells in patients infected with hepatitis C virus genotype 1 who failed peginterferon plus ribavirin therapy. J Med Virol 2011; 83:1212-1220. [PMID: 21567425 DOI: 10.1002/jmv.22096] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Although chronic hepatitis C patients have a lower frequency and functions of dendritic cells (DCs) than healthy subjects, little is known about the serial changes in frequency and functions of DCs following anti-viral treatment and the relationship with treatment outcomes. Twenty patients with hepatitis C virus genotype 1 receiving peginterferon (PEG-IFN) and ribavirin for 24 weeks were enrolled. The frequency and functions of DCs were assayed at baseline and 24 weeks post-treatment. Ten sex and age-matched healthy adults served as controls. Nineteen of the 20 chronic hepatitis C patients completed 24 weeks of combination therapy. Fifteen patients achieved rapid virologic response and 12 achieved sustained virologic response (SVR). The baseline frequency of peripheral blood myeloid DCs and plasmacytoid DCs was significantly lower in chronic hepatitis C patients than in healthy controls. In patients who achieved SVR, the frequency of DCs subsets at the end of follow-up increased to a level comparable to healthy controls. Although no functional defects of DCs was found in chronic hepatitis C patients in comparison with healthy controls, in patients without SVR had a lower CD83 expression and higher interleukin-10 production of DCs than SVR patients. The results suggest that low CD83 expression and high IL-10 production of DCs at the baseline may predict a poor virologic response to 24-week PEG-IFN plus ribavirin therapy in HCV genotype 1 patients.
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Affiliation(s)
- Cheng-Chao Liang
- Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan
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36
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Onomoto K, Morimoto S, Kawaguchi T, Toyoda H, Tanaka M, Kuroda M, Uno K, Kumada T, Matsuda F, Shimotohno K, Fujita T, Murakami Y. Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C. PLoS One 2011; 6:e19799. [PMID: 21603632 PMCID: PMC3094385 DOI: 10.1371/journal.pone.0019799] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Accepted: 04/11/2011] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome. METHODOLOGY Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917). PRINCIPAL FINDINGS Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA). CONCLUSION IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.
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Affiliation(s)
- Koji Onomoto
- Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan
- Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
| | - Shiho Morimoto
- Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan
| | - Takahisa Kawaguchi
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Masami Tanaka
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Kazuko Uno
- Louis Pasteur Center for Medical Research, Kyoto, Kyoto, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Takashi Fujita
- Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan
| | - Yoshiki Murakami
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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37
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Dolganiuc A, Szabo G. Dendritic cells in hepatitis C infection: can they (help) win the battle? J Gastroenterol 2011; 46:432-47. [PMID: 21327958 DOI: 10.1007/s00535-011-0377-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 12/13/2010] [Indexed: 02/04/2023]
Abstract
Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of unraveling an HCV-specific DC signature or DC-dependent mechanisms of antiviral immunity which would lead to a successful HCV elimination strategy. This review incorporates the latest update in the current status of knowledge on the role of DCs in anti-HCV immunity as it relates to several challenging questions: (a) the phenotype and function of diverse DC subsets in HCV-infected patients; (b) the characteristics of non-human HCV infection models from the DCs' point of view; (c) how can in vitro systems, ranging from HCV protein- or peptide-exposed DC to HCV protein-expressing DCs, and in vivo systems, ranging from HCV protein-expressing transgenic mice to HCV-infected non-human primates, be employed to dissect the role of DCs in triggering/maintaining a robust antiviral response; and (d) the prospect of DC-based strategy for managing and finding a cure for HCV infection.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB-270-H, Worcester, MA 01605, USA.
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38
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Akbar SMF, Horiike N, Chen S, Michitaka K, Abe M, Hiasa Y, Matsuura B, Onji M. Mechanism of restoration of immune responses of patients with chronic hepatitis B during lamivudine therapy: increased antigen processing and presentation by dendritic cells. J Viral Hepat 2011; 18:200-5. [PMID: 20367796 DOI: 10.1111/j.1365-2893.2010.01300.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Restoration of host immunity has been reported in patients with chronic hepatitis B (CHB) after treatment with lamivudine; however, the underlying mechanisms of this treatment have not been determined. This study examined the role of antigen-presenting dendritic cells (DC) in restoration of host immunity. Circulating DC were isolated from peripheral blood of 23 patients with CHB before and 1, 3, and 12 months after starting lamivudine therapy. The non-antigen-specific proliferation of DC was assessed in allogenic mixed leucocyte reaction. Dendritic cells were cultured with hepatitis B surface antigen (HBsAg) to prepare HBsAg-pulsed DC. Proliferative capacity and production of interleukin (IL)-12 and interferon (IFN)-γ of HBsAg-pulsed DC were evaluated. Circulating unpulsed DC and HBsAg-pulsed DC showed significantly higher levels of T-cell proliferation capacities 1 month after lamivudine therapy compared to proliferation levels before therapy (P<0.05). HBsAg-pulsed DC also produced significantly higher levels of IL-12 and IFN-γ with lamivudine therapy compared to levels before therapy (P<0.05). HBsAg-pulsed DC from lamivudine-treated patients induced proliferation of T cells of patients with CHB in an antigen-specific manner (P<0.05). However, T-cell stimulatory capacity of DC did not increase significantly 3 and 12 months after lamivudine therapy compared to 1 month after lamivudine therapy. Immune restoration as a result of lamivudine therapy is regulated at least in part by activation of DC. However, progressive activation of DC was not seen as treatment duration progressed, indicating the limitations of this mechanism of viral clearance.
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Affiliation(s)
- S M F Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan.
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39
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Zhang Y, Ma CJ, Ni L, Zhang CL, Wu XY, Kumaraguru U, Li CF, Moorman JP, Yao ZQ. Cross-talk between programmed death-1 and suppressor of cytokine signaling-1 in inhibition of IL-12 production by monocytes/macrophages in hepatitis C virus infection. THE JOURNAL OF IMMUNOLOGY 2011; 186:3093-103. [PMID: 21263070 DOI: 10.4049/jimmunol.1002006] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) dysregulates innate immune responses and induces persistent viral infection. We previously demonstrated that HCV core protein impairs IL-12 expression by monocytes/macrophages (M/M(Φ)s) through interaction with a complement receptor gC1qR. Because HCV core-mediated lymphocyte dysregulation occurs through the negative immunomodulators programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1), the aim of this study was to examine their role in HCV core-mediated IL-12 suppression in M/M(Φ)s. We analyzed TLR-stimulated, primary CD14(+) M/M(Φ)s from chronically HCV-infected and healthy subjects or the THP-1 cell line for PD-1, SOCS-1, and IL-12 expression following HCV core treatment. M/M(Φ)s from HCV-infected subjects at baseline exhibited comparatively increased PD-1 expression that significantly correlated with the degree of IL-12 inhibition. M/M(Φ)s isolated from healthy and HCV-infected individuals and treated with HCV core protein displayed increased PD-1 and SOCS-1 expression and decreased IL-12 expression, an effect that was also observed in cells treated with gC1qR's ligand, C1q. Blocking gC1qR rescued HCV core-induced PD-1 upregulation and IL-12 suppression, whereas blocking PD-1 signaling enhanced IL-12 production and decreased the expression of SOCS-1 induced by HCV core. Conversely, silencing SOCS-1 expression using small interfering RNAs increased IL-12 expression and inhibited PD-1 upregulation. PD-1 and SOCS-1 were found to associate by coimmunoprecipitation studies, and blocking PD-1 or silencing SOCS-1 in M/M(Φ) led to activation of STAT-1 during TLR-stimulated IL-12 production. These data suggested that HCV core/gC1qR engagement on M/M(Φ)s triggers the expression of PD-1 and SOCS-1, which can associate to deliver negative signaling to TLR-mediated pathways controlling expression of IL-12, a key cytokine linking innate and adaptive immunity.
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Affiliation(s)
- Ying Zhang
- Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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Jo J, Lohmann V, Bartenschlager R, Thimme R. Experimental models to study the immunobiology of hepatitis C virus. J Gen Virol 2010; 92:477-93. [PMID: 21148278 DOI: 10.1099/vir.0.027987-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Effective host immune responses are essential for the control of hepatitis C virus (HCV) infection and persistence of HCV has indeed been attributed to their failure. In recent years, several in vitro and in vivo experimental models have allowed studies of host immune responses against HCV. Numerous observations derived from these models have improved our understanding of the mechanisms responsible for the host's ability to clear the virus as well as of the mechanisms responsible for the host's failure to control HCV replication. Importantly, several findings obtained with these model systems have been confirmed in studies of acutely or chronically HCV-infected individuals. Collectively, several mechanisms are used by HCV to escape host immune responses, such as poor induction of the innate immune response and escaping/impairing adaptive immunity. In this review, we summarize current findings from experimental models available for studies of the immune response targeting HCV and discuss the relevance of these findings for the in vivo situation in HCV-infected humans.
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Affiliation(s)
- Juandy Jo
- Department of Medicine II, University Medical Center Freiburg, Germany
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41
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Eksioglu EA, Bess JR, Zhu H, Xu Y, Dong HJ, Elyar J, Nelson DR, Liu C. Hepatitis C virus modulates human monocyte-derived dendritic cells. J Viral Hepat 2010; 17:757-69. [PMID: 20051006 PMCID: PMC3731759 DOI: 10.1111/j.1365-2893.2009.01231.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study is to examine the monocyte-derived dendritic cell (DC) response to hepatitis C virus (HCV) in a cell culture system. Adherence-derived DCs were incubated with various titres of JFH-1 (HCV genotype 2a), generated from transfected Huh 7.5 cells or co-incubated with Newcastle disease virus (NDV). Infection and the type 1 interferon (IFN) response were assessed by real-time reverse transcriptase-polymerase chain reaction, morphology by light microscopy and immunophenotype by flow cytometry. Our data demonstrated no viral replication or particle release from DC after HCV infection. Morphologically, monocytes showed a tendency to shift to immature DCs when cultured with HCV, when compared with control monocytes. This shift was confirmed by flow cytometry and appeared to be related to viral titres. There was also an increase in immature DC numbers. HCV infection induced IFNβ expression in DCs, and the amount seemed to be inversely correlated with viral titres indicating that HCV has the capacity to negatively regulate such cells. However, IFNα does not appear to be affected by direct contact with the virus. A strong IFNβ signal induced by NDV in DC was substantially diminished by HCV. HCV negatively affects the maturation of DCs and suppresses the type 1 IFN response of DC. Our results suggest a mechanism of viral evasion of host immunity.
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Affiliation(s)
- Erika A. Eksioglu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Jennifer R. Bess
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Haizhen Zhu
- Biomedical Engineering Center of Hunan University, Changsha, Hunan province, China
| | - Yiling Xu
- Department of Medicine, division of Hepatobiliary Diseases, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Hui-jia Dong
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - John Elyar
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - David R. Nelson
- Department of Medicine, division of Hepatobiliary Diseases, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Chen Liu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA,Corresponding author: Chen Liu, MD., PhD., Department of Pathology, Immunology and Laboratory Medicine, Room M646 MSB, University of Florida, College of Medicine, PO. Box 100275, Gainesville, FL 32610-0275, , Phone: (352)273-5413, Fax: (352) 392-6249
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Murakami Y, Tanaka M, Toyoda H, Hayashi K, Kuroda M, Tajima A, Shimotohno K. Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C. BMC Med Genomics 2010; 3:48. [PMID: 20969775 PMCID: PMC2984584 DOI: 10.1186/1755-8794-3-48] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 10/22/2010] [Indexed: 02/06/2023] Open
Abstract
Background HCV infection frequently induces chronic liver diseases. The current standard treatment for chronic hepatitis (CH) C combines pegylated interferon (IFN) and ribavirin, and is less than ideal due to undesirable effects. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that control gene expression by degrading or suppressing the translation of target mRNAs. In this study we administered the standard combination treatment to CHC patients. We then examined their miRNA expression profiles in order to identify the miRNAs that were associated with each patient's drug response. Methods 99 CHC patients with no anti-viral therapy history were enrolled. The expression level of 470 mature miRNAs found their biopsy specimen, obtained prior to the combination therapy, were quantified using microarray analysis. The miRNA expression pattern was classified based on the final virological response to the combination therapy. Monte Carlo Cross Validation (MCCV) was used to validate the outcome of the prediction based on the miRNA expression profile. Results We found that the expression level of 9 miRNAs were significantly different in the sustained virological response (SVR) and non-responder (NR) groups. MCCV revealed an accuracy, sensitivity, and specificity of 70.5%, 76.5% and 63.3% in SVR and non-SVR and 70.0%, 67.5%, and 73.7% in relapse (R) and NR, respectively. Conclusions The hepatic miRNA expression pattern that exists in CHC patients before combination therapy is associated with their therapeutic outcome. This information can be utilized as a novel biomarker to predict drug response and can also be applied to developing novel anti-viral therapy for CHC patients.
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Affiliation(s)
- Yoshiki Murakami
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
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Canaday DH, Burant CJ, Jones L, Aung H, Woc-Colburn L, Anthony DD. Preserved MHC-II antigen processing and presentation function in chronic HCV infection. Cell Immunol 2010; 266:187-91. [PMID: 21055734 DOI: 10.1016/j.cellimm.2010.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Revised: 10/04/2010] [Accepted: 10/12/2010] [Indexed: 01/07/2023]
Abstract
Individuals with chronic HCV infection have impaired response to vaccine, though the etiology remains to be elucidated. Dendritic cells (DC) and monocytes (MN) provide antigen uptake, processing, presentation, and costimulatory functions necessary to achieve optimal immune responses. The integrity of antigen processing and presentation function within these antigen presenting cells (APC) in the setting of HCV infection has been unclear. We used a novel T cell hybridoma system that specifically measures MHC-II antigen processing and presentation function of human APC. Results demonstrate MHC-II antigen processing and presentation function is preserved in both myeloid DC (mDC) and MN in the peripheral blood of chronically HCV-infected individuals, and indicates that an alteration in this function does not likely underlie the defective HCV-infected host response to vaccination.
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Affiliation(s)
- D H Canaday
- GRECC, Louis Stokes Cleveland VA Hospital, United States.
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Tomescu C, Duh FM, Lanier MA, Kapalko A, Mounzer KC, Martin MP, Carrington M, Metzger DS, Montaner LJ. Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users. AIDS 2010; 24:2151-60. [PMID: 20647906 PMCID: PMC3253656 DOI: 10.1097/qad.0b013e32833dfc20] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated. OBJECTIVE We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia. DESIGN We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals. RESULTS As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion. CONCLUSION Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.
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Affiliation(s)
- Costin Tomescu
- The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, PA 19104
| | - Fuh-Mei Duh
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702 and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02114
| | - Michael A. Lanier
- The University of Pennsylvania, Department of Psychiatry, HIV Prevention Division, Philadelphia, PA, 19104
| | - Angela Kapalko
- Philadelphia FIGHT, The Jonathan Lax Treatment Center, Philadelphia, PA, 19017
| | - Karam C. Mounzer
- Philadelphia FIGHT, The Jonathan Lax Treatment Center, Philadelphia, PA, 19017
| | - Maureen P. Martin
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702 and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02114
| | - Mary Carrington
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702 and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02114
| | - David S. Metzger
- The University of Pennsylvania, Department of Psychiatry, HIV Prevention Division, Philadelphia, PA, 19104
| | - Luis J. Montaner
- The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, PA 19104
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A look behind closed doors: interaction of persistent viruses with dendritic cells. Nat Rev Microbiol 2010; 8:350-60. [PMID: 20372157 DOI: 10.1038/nrmicro2332] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Persistent infections with HIV, hepatitis B virus and hepatitis C virus are major causes of morbidity and mortality worldwide. As sentinels of the immune system, dendritic cells (DCs) are crucial for the generation of protective antiviral immunity. Recent advances in our understanding of the role of DCs during infection with these viruses provide insights into the mechanisms used by these viruses to exploit DC function and evade innate and adaptive immunity. In this Review we highlight the current knowledge about the interaction between DCs and these viruses and the underlying mechanisms that might influence the outcome of viral infections.
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Gonzalez VD, Landay AL, Sandberg JK. Innate immunity and chronic immune activation in HCV/HIV-1 co-infection. Clin Immunol 2010; 135:12-25. [PMID: 20100670 DOI: 10.1016/j.clim.2009.12.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Revised: 12/09/2009] [Accepted: 12/16/2009] [Indexed: 02/07/2023]
Abstract
Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host.
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Affiliation(s)
- Veronica D Gonzalez
- Center for Infection Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden
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Ferrari C, Mondelli M. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2009:835-857. [DOI: 10.1002/9780470747919.ch51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function. J Virol 2009; 83:11175-87. [PMID: 19692459 DOI: 10.1128/jvi.00753-09] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.
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49
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Kishida Y, Haruna Y, Naitoh M, Katayama K, Kashiwagi T. Multiple Cytokine Profiling of the Therapeutic Responses to Ribavirin and Pegylated Interferon-α2b Using an “Induction” Approach With Natural Interferon-β in Difficult-to-Treat Chronic Hepatitis C. J Interferon Cytokine Res 2009; 29:353-68. [PMID: 19441887 DOI: 10.1089/jir.2008.0110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Affiliation(s)
- Yutaka Kishida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Kaisei Hospital, Osaka, Japan
| | - Yoshimichi Haruna
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Prefectural General Medical Center, Osaka, Japan
| | - Masahumi Naitoh
- Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan
| | - Kazuhiro Katayama
- Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan
| | - Toru Kashiwagi
- Department of Nuclear Medicine and PET Center, Hyogo College of Medicine, Hyogo, Japan
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Differential effects of hepatitis C virus JFH1 on human myeloid and plasmacytoid dendritic cells. J Virol 2009; 83:5693-707. [PMID: 19297478 DOI: 10.1128/jvi.02671-08] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dendritic cells (DCs) are reported to be functionally deficient during chronic hepatitis C virus (HCV) infection. Differing results have been reported on direct effects of intact replicative-form HCV on DC function. To better understand the effect of HCV on DC function, we treated freshly purified human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) with HCV JFH1. We found that HCV upregulated mDC maturation marker (CD83, CD86, and CD40) expression and did not inhibit Toll-like receptor 3 (TLR3) ligand [poly(I:C)]-induced mDC maturation, a finding consistent with the phenotype of DCs from HCV-infected subjects. At the same time, HCV JFH1 inhibited the ability of poly(I:C)-treated mDCs to activate naive CD4 T cells. In contrast, although there was no direct effect of virus on pDC maturation, HCV JFH1 inhibited TLR7 ligand (R848)-induced pDC CD40 expression, and this was associated with impaired ability to activate naive CD4 T cells. Parallel experiments with recombinant HCV proteins indicated HCV core protein may be responsible for a portion of the activity. Furthermore, HCV-mediated mDC maturation was dependent upon CD81-E2 interaction and, in part, TLR2. Using UV-treated HCV, we show that HCV-mediated mDC and pDC maturation is virus replication independent and, using strand specific PCR, we found no evidence for HCV replication within DCs. Because these effects of HCV on DC subset maturation and function in part recapitulate direct ex vivo analysis of DCs in chronic HCV infection, the mechanisms described here likely account for a portion of the DC subset defects observed in vivo.
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