|
1
|
Rybicka M, Woziwodzka A, Sznarkowska A, Romanowski T, Stalke P, Dręczewski M, Verrier ER, Baumert TF, Bielawski KP. Genetic variation in IL-10 influences the progression of hepatitis B infection. Int J Infect Dis 2020; 96:260-265. [PMID: 32387446 DOI: 10.1016/j.ijid.2020.04.079] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES The outcomes of hepatitis B virus (HBV) infection vary substantially among affected individuals, providing evidence of the role of host genetic background in the susceptibility to HBV persistence and the dynamics of liver injury progression to cirrhosis and hepatocellular carcinoma (HCC). METHODS Six single-nucleotide polymorphisms within the interleukin 10 gene (IL10) were genotyped by MALDI-TOF mass spectrometry in 857 patients with chronic HBV infection (CHB), 48 patients with resolved HBV infection, and 100 healthy volunteers. Associations of the selected polymorphisms with susceptibility to chronic HBV infection, liver injury progression, and outcomes were investigated. RESULTS IL10 -819T (rs1800871), -592A (rs1800872), and +504T (rs3024490) alleles were associated with treatment-induced hepatitis B surface antigen (HBsAg) seroclearance. Additionally, IL10 ATAC haplotype increased the chance of HBsAg loss and was significantly more frequent in patients with less liver injury. Moreover rs1800871TT, rs1518110TT, rs1800872AA, and rs3024490TT genotypes were identified as predictors of a lower FIB-4 score (<0.5). CONCLUSIONS This study indicates that polymorphisms within the promoter region and intronic sequences of IL10 are associated with chronicity of hepatitis B and with HBV-induced liver damage.
Collapse
Affiliation(s)
- Magda Rybicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
| | - Anna Woziwodzka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
| | - Alicja Sznarkowska
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland; International Centre for Cancer Vaccine Science, University of Gdansk, ul. Wita Stwosza 63, 80-308 Gdansk, Poland
| | - Tomasz Romanowski
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
| | - Piotr Stalke
- Department of Infectious Diseases, Medical University of Gdansk, ul. Powstania Styczniowego 9b, 81-519 Gdynia, Poland
| | - Marcin Dręczewski
- Department of Infectious Diseases, Medical University of Gdansk, ul. Powstania Styczniowego 9b, 81-519 Gdynia, Poland
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000 Strasbourg, France
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000 Strasbourg, France; Pôle Hépato-Digestif, Institut Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Krzysztof Piotr Bielawski
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
| |
Collapse
|
|
2
|
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.
Collapse
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.
| |
Collapse
|
|
3
|
Kahan SM, Zajac AJ. Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus. Viruses 2019; 11:E156. [PMID: 30781904 PMCID: PMC6410286 DOI: 10.3390/v11020156] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/08/2019] [Accepted: 02/09/2019] [Indexed: 12/16/2022] Open
Abstract
Lymphocytic choriomeningitis virus (LCMV) is a paradigm-forming experimental system with a remarkable track record of contributing to the discovery of many of the fundamental concepts of modern immunology. The ability of LCMV to establish a chronic infection in immunocompetent adult mice was instrumental for identifying T cell exhaustion and this system has been invaluable for uncovering the complexity, regulators, and consequences of this state. These findings have been directly relevant for understanding why ineffective T cell responses commonly arise during many chronic infections including HIV and HCV, as well as during tumor outgrowth. The principal feature of exhausted T cells is the inability to elaborate the array of effector functions necessary to contain the underlying infection or tumor. Using LCMV to determine how to prevent and reverse T cell exhaustion has highlighted the potential of checkpoint blockade therapies, most notably PD-1 inhibition strategies, for improving cellular immunity under conditions of antigen persistence. Here, we discuss the discovery, properties, and regulators of exhausted T cells and highlight how LCMV has been at the forefront of advancing our understanding of these ineffective responses.
Collapse
Affiliation(s)
- Shannon M Kahan
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Allan J Zajac
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| |
Collapse
|
|
4
|
Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
Collapse
MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
Collapse
Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| |
Collapse
|
|
5
|
Modulation of Hepatitis C Virus-Specific CD8 Effector T-Cell Function with Antiviral Effect in Infectious Hepatitis C Virus Coculture Model. J Virol 2017; 91:JVI.02129-16. [PMID: 28275182 DOI: 10.1128/jvi.02129-16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/14/2017] [Indexed: 01/03/2023] Open
Abstract
The antiviral effects of hepatitis C virus (HCV)-specific CD8 T cells have been shown in an HCV replicon system but not in an authentic infectious HCV cell culture (HCVcc) system. Here, we developed tools to examine the antigenicity of HCV-infected HLA-A2-positive Huh7.5 hepatoma cells (Huh7.5A2 cells) in activating HCV-specific CD8 T cells and the downstream antiviral effects. Infectious HCV epitope mutants encoding the well-defined genotype 1a-derived HLA-A2-restricted HCV NS3-1073 or NS5-2594 epitope were generated from a genotype 2a-derived HCV clone (Jc1Gluc2A) by site-directed mutagenesis. CD8 T-cell lines specific for NS3-1073 and NS5-2594 were expanded from HCV-seropositive persons by peptide stimulation in vitro or engineered from HCV-seronegative donor T cells by transduction of a lentiviral vector expressing HCV-specific T-cell receptors. HCV-specific CD8 T cells were cocultured with Huh7.5 cells that were pulsed with titrating doses of HCV epitope peptides or infected with HCV epitope mutants. HCV-specific CD8 T-cell activation (CD107a, gamma interferon, macrophage inflammatory protein 1β, tumor necrosis factor alpha) was dependent on the peptide concentrations and the relative percentages of HCV-infected Huh7.5A2 cells. HCV-infected Huh7.5A2 cells activated HCV-specific CD8 T cells at levels comparable to those achieved with 0.1 to 2 μM pulsed peptides, providing a novel estimate of the level at which endogenously processed HCV epitopes are presented on HCV-infected cells. While HCV-specific CD8 T-cell activation with cytolytic and antiviral effects was blunted by PD-L1 expression on HCV-infected Huh7.5A2 cells, resulting in the improved viability of Huh7.5A2 cells, PD-1 blockade reversed this effect, producing enhanced cytolytic elimination of HCV-infected Huh7.5A2 cells. Our findings, obtained using an infectious HCVcc system, show that the HCV-specific CD8 T-cell function is modulated by antigen expression levels, the percentage of HCV-infected cells, and the PD-1/PD-L1 pathways and has antiviral and cytotoxic effects.IMPORTANCE We developed several novel molecular and immunological tools to study the interactions among HCV, HCV-infected hepatocytes, and HCV-specific CD8 T cells. Using these tools, we show the level at which HCV-infected hepatoma cells present endogenously processed HCV epitopes to HCV-specific CD8 T cells with antiviral and cytotoxic effects. We also show the marked protective effect of PD-L1 expression on HCV-infected hepatoma cells against HCV-specific CD8 T cells.
Collapse
|
|
6
|
Keoshkerian E, Hunter M, Cameron B, Nguyen N, Sugden P, Bull R, Zekry A, Maher L, Seddiki N, Zaunders J, Kelleher A, Lloyd AR. Hepatitis C-specific effector and regulatory CD4 T-cell responses are associated with the outcomes of primary infection. J Viral Hepat 2016; 23:985-993. [PMID: 27558465 DOI: 10.1111/jvh.12576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/29/2016] [Indexed: 12/31/2022]
Abstract
Clearance of primary hepatitis C virus (HCV) infection has been associated with strong and broadly targeted cellular immune responses. This study aimed to characterize HCV-specific CD4+ effector and regulatory T-cell numbers and cytokine production during primary infection. Antigen-specific CD4+ T-cell responses were investigated in a longitudinal cohort of subjects from pre-infection to postoutcome, including subjects who cleared [n=12] or became chronically infected [n=17]. A cross-sectional cohort with previously cleared, or chronic infection [n=15 for each], was also studied. Peripheral blood mononuclear cells were incubated with HCV antigens and surface stained for T-effector (CD4+CD25high CD134+CD39-) and T-regulatory (CD4+CD25high CD134+CD39+) markers, and culture supernatants assayed for cytokine production. Contrary to expectations, the breadth and magnitude of the HCV-specific CD4+ T-cell responses were higher in subjects who became chronically infected. Subjects who cleared the virus had HCV-specific CD4+ T-cell responses dominated by effector T cells and produced higher levels of IFN-γ, in contrast to HCV-specific CD4+ T-cell responses dominated by regulatory T cells and more IL-10 production in those who became chronically infected. Better understanding of the role of antigen-specific CD4+ T-cell responses in primary HCV will further define pathogenesis and help guide development of a preventative vaccine.
Collapse
Affiliation(s)
- E Keoshkerian
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
| | - M Hunter
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - B Cameron
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - N Nguyen
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - P Sugden
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - R Bull
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
| | - A Zekry
- UNSW Australia, St George and Sutherland Clinical School, Sydney, NSW, Australia
| | - L Maher
- UNSW Australia, Kirby Institute (Viral Hepatitis Epidemiology and Prevention Program VHEPP), Kensington, NSW, Australia
| | - N Seddiki
- The Vaccine Research Institute (VRI), INSERM, Créteil, France
| | - J Zaunders
- UNSW Australia, Kirby Institute (Immunovirology and Pathogenesis Program, IVPP), Kensington, NSW, Australia
| | - A Kelleher
- UNSW Australia, Kirby Institute (Immunovirology and Pathogenesis Program, IVPP), Kensington, NSW, Australia
| | - A R Lloyd
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
| | | |
Collapse
|
|
7
|
Park JJ, Wong DK, Wahed AS, Lee WM, Feld JJ, Terrault N, Khalili M, Sterling RK, Kowdley KV, Bzowej N, Lau DT, Kim WR, Smith C, Carithers RL, Torrey KW, Keith JW, Levine DL, Traum D, Ho S, Valiga ME, Johnson GS, Doo E, Lok ASF, Chang KM. Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B. Gastroenterology 2016; 150:684-695.e5. [PMID: 26684441 PMCID: PMC4766024 DOI: 10.1053/j.gastro.2015.11.050] [Citation(s) in RCA: 178] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 09/25/2015] [Accepted: 11/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
Collapse
Affiliation(s)
- Jang-June Park
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | | | - Abdus S Wahed
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | | | | | - Norah Terrault
- University of California, San Francisco, San Francisco, California
| | - Mandana Khalili
- University of California, San Francisco, San Francisco, California
| | | | | | - Natalie Bzowej
- California Pacific Medical Center, San Francisco, California
| | - Daryl T Lau
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | | | | | - Keith W Torrey
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - James W Keith
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Danielle L Levine
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Daniel Traum
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Suzanne Ho
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Mary E Valiga
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Geoffrey S Johnson
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Edward Doo
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - Kyong-Mi Chang
- Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
| |
Collapse
|
|
8
|
Lutz P, Krämer B, Kaczmarek DJ, Hübner MP, Langhans B, Appenrodt B, Lammert F, Nattermann J, Hoerauf A, Strassburg CP, Spengler U, Nischalke HD. A variant in the nuclear dot protein 52kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis. Dig Liver Dis 2016; 48:62-8. [PMID: 26493630 DOI: 10.1016/j.dld.2015.09.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 08/18/2015] [Accepted: 09/20/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Spontaneous bacterial peritonitis is frequently a fatal infection in patients with liver cirrhosis. We investigated if nuclear dot protein 52kDa (NDP52), a negative regulator of toll-like receptor (TLR) signalling and autophagy adaptor protein, might be involved. METHODS Two cohorts comprising 152 (derivation cohort) and 198 patients (validation cohort) with decompensated liver cirrhosis and 168 healthy controls were genotyped for the rs2303015 polymorphism in the NDP52 gene and prospectively followed-up for spontaneous bacterial peritonitis. RESULTS Overall, 57 (38%) patients in the derivation cohort and 77 (39%) in the validation cohort had spontaneous bacterial peritonitis. Cirrhosis was due to alcohol abuse in 57% of the derivation and 66% of the validation cohort. In patients with alcoholic cirrhosis, patients with spontaneous bacterial peritonitis had an increased frequency of the NDP52 rs2303015 minor variant in the derivation (p=0.04) and in the validation cohort (p=0.01). Multivariate analysis confirmed this minor variant (odds ratio 4.7, p=0.002) and the TLR2 -16934 TT variant (odds ratio 2.5, p=0.008) as risk factors for spontaneous bacterial peritonitis. In addition, presence of the NDP52 minor variant affected survival negatively. CONCLUSION Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis.
Collapse
Affiliation(s)
- Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany.
| | - Benjamin Krämer
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Dominik J Kaczmarek
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Marc P Hübner
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Beate Appenrodt
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Achim Hoerauf
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Hans Dieter Nischalke
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| |
Collapse
|
|
9
|
Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
Collapse
Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| |
Collapse
|
|
10
|
Barjon C, Dahlqvist G, Calmus Y, Conti F. Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence. Dig Liver Dis 2015. [PMID: 26216068 DOI: 10.1016/j.dld.2015.06.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.
Collapse
Affiliation(s)
- Clément Barjon
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France.
| | - Géraldine Dahlqvist
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France
| | - Yvon Calmus
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Filomena Conti
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| |
Collapse
|
|
11
|
Abstract
Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8(+) T cell functions, and specialization of CD4(+) T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.
Collapse
Affiliation(s)
- Elina I Zuniga
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - Monica Macal
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - Gavin M Lewis
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - James A Harker
- Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom
| |
Collapse
|
|
12
|
Abstract
BACKGROUND Acute hepatitis C (AHCV) provides a diagnostic challenge with diverse clinical presentations. GOALS This study was aimed to examine the clinical and demographic features as well as outcomes in AHCV patients identified from inpatient and outpatient hospital settings. STUDY Patients with suspected AHCV were recruited from Philadelphia VA Medical Center, Hospital of University of Pennsylvania and Brooklyn VA Medical Center between 2000 and 2010. AHCV was diagnosed by acute serum alanine aminotransferase elevation with anti-hepatitis C virus (HCV) seroconversion, HCV-RNA fluctuations above 1 log, and/or recent high-risk exposure without prior HCV infection, excluding those with human immunodeficiency virus infection. Clinical and therapeutic outcomes were monitored for at least 6 months. RESULTS A total of 40 AHCV patients were enrolled with a median follow-up of 129 weeks. They were mostly men (68%) and whites (73%) with median age of 43 years, diverse risk factors (33% injection drugs, 20% health care-associated, 3% sexual, and 45% unknown), and wide variations in peak alanine aminotransferase (143 to 3435 U/L) and total bilirubin levels (0.4 to 19.3 mg/dL). Viremia resolved spontaneously in 23% and persisted without therapy in 27%, whereas 50% received interferon α-based therapy with 90% cure (18/20). Distinct clinical scenarios included: (1) wide viremic fluctuations >1 log (65%) and intermittent HCV-RNA negativity; (2) autoantibodies (25% antinuclear antibodies, 69% antismooth muscle antibodies) or autoimmune features; (3) delayed spontaneous viral clearance in 2 patients; (4) rapid cirrhosis progression in 2 patients. CONCLUSIONS AHCV is a heterogenous disease that requires careful monitoring. The lack of apparent risk factor in high proportion of patients and its diverse presentations warrant diagnostic vigilance.
Collapse
|
|
13
|
Spaan M, Claassen MAA, Hou J, Janssen HLA, de Knegt RJ, Boonstra A. The Intrahepatic T Cell Compartment Does Not Normalize Years After Therapy-Induced Hepatitis C Virus Eradication. J Infect Dis 2015; 212:386-90. [PMID: 25637348 DOI: 10.1093/infdis/jiv059] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/16/2015] [Indexed: 01/27/2023] Open
Abstract
Little is known about the immune status in liver and blood of patients with chronic hepatitis C virus (HCV) infection long after therapy-induced viral clearance. In this study, we demonstrate that, 4 years after clearance, regulation of HCV-specific immunity in blood by regulatory T cells (Tregs) and the immunosuppressive cytokines interleukin 10 and transforming growth factor β is still ongoing. Importantly, analysis of liver specimens collected 4 years after HCV clearance shows that intrahepatic Tregs are still present in all patients, suggesting that liver T cells remain regulated. Identifying mechanisms that regulate HCV-specific memory T-cell responses after clearance is highly relevant for the development of protective vaccines, especially in patients at high risk of reinfection.
Collapse
Affiliation(s)
| | - Mark A A Claassen
- Department of Gastroenterology and Hepatology Department of Internal Medicine, Infectious Diseases Section, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Jun Hou
- Department of Gastroenterology and Hepatology
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology Liver Clinic University Health Network, Division of Gastroenterology, University of Toronto, Canada
| | | | | |
Collapse
|
|
14
|
T cell exhaustion during persistent viral infections. Virology 2015; 479-480:180-93. [PMID: 25620767 DOI: 10.1016/j.virol.2014.12.033] [Citation(s) in RCA: 236] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 12/17/2014] [Accepted: 12/19/2014] [Indexed: 02/08/2023]
Abstract
Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control.
Collapse
|
|
15
|
Chen WN, Liu LL, Jiao BY, Lin WS, Lin XJ, Lin X. Hepatitis B virus X protein increases the IL-1β-induced NF-κB activation via interaction with evolutionarily conserved signaling intermediate in Toll pathways (ECSIT). Virus Res 2014; 195:236-45. [PMID: 25449573 DOI: 10.1016/j.virusres.2014.10.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 10/28/2014] [Accepted: 10/28/2014] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus X protein (HBx) transactivates multiple transcription factors including nuclear factor-kappa B (NF-κB) that regulates inflammatory-related genes. However, the regulatory mechanism of HBx in NF-κB activation remains largely unknown. This study reports that HBx augments the interleukin-1β (IL-1β)-induced NF-κB activation via interaction with a Toll-like receptor (TLR) adapter protein, ECSIT (evolutionarily conserved signaling intermediate in Toll pathways). GST pull-down and co-immunoprecipitation analyses showed that HBx interacted with ECSIT. Deletion analysis of HBx in a CytoTrap two-hybrid system revealed that the interaction region of HBx for ECSIT was attributed to aa 51-80. Co-transfection of HBx and ECSIT in IL-1β-stimulated cells appeared to activate IKK and IκB signaling pathway as phosphorylation of both IKK α/β and IκBα was increased whereas knockdown of ECSIT or HBxΔ51-80 mutant attenuated the phosphorylation. As a consequence of IκBα degradation, NF-κB was activated as evidenced by increases in NF-κB transcriptional activity and the nuclear translocation of p65 and p50 that resulted in the induction of IL-10. In contrast, knockdown of ECSIT by siRNA or treatment with an NF-κB selective inhibitor (helenalin) abolished the NF-κB activation and IL-10 expression. We conclude that ECSIT appears to be a novel HBx-interacting signal molecule and their interaction is mechanistically important in IL-1β induction of NF-κB activation.
Collapse
Affiliation(s)
- Wan-nan Chen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Ling-ling Liu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Bo-yan Jiao
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Wan-song Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Xin-jian Lin
- Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, CA, USA.
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
| |
Collapse
|
|
16
|
Niesen E, Schmidt J, Flecken T, Thimme R. Suppressive effect of interleukin 10 on priming of naive hepatitis C virus-specific CD8+ T cells. J Infect Dis 2014; 211:821-6. [PMID: 25355941 DOI: 10.1093/infdis/jiu541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Growing evidence suggests a role for the immunomodulatory cytokine interleukin-10 (IL-10) in hepatitis C virus (HCV)-specific CD8(+) T-cell failure. To address the possible role of IL-10 during priming, we performed in vitro priming experiments with naive HCV-specific CD8(+) T cells and autologous monocyte-derived dendritic cells in the absence or presence of IL-10. Our results showed that IL-10, when present during priming, significantly reduced the frequency of HCV-specific CD8(+) T cells after coculture; It was directly targeting CD8(+) T cells and led to impaired effector cell differentiation. These results may provide a possible mechanistic basis for the association between early IL-10 elevation, T-cell failure, and viral persistence.
Collapse
Affiliation(s)
| | - Julia Schmidt
- Department of Medicine II, University Hospital Freiburg
| | - Tobias Flecken
- Department of Medicine II, University Hospital Freiburg Spemann Graduate School of Biology and Medicine Faculty of Biology, Albert-Ludwigs University Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg
| |
Collapse
|
|
17
|
Ondondo BO. Fallen angels or risen apes? A tale of the intricate complexities of imbalanced immune responses in the pathogenesis and progression of immune-mediated and viral cancers. Front Immunol 2014; 5:90. [PMID: 24639678 PMCID: PMC3944202 DOI: 10.3389/fimmu.2014.00090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 02/20/2014] [Indexed: 12/13/2022] Open
Abstract
Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes.
Collapse
|
|
18
|
Fernandez-Ponce C, Dominguez-Villar M, Aguado E, Garcia-Cozar F. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. PLoS One 2014; 9:e85191. [PMID: 24465502 PMCID: PMC3896374 DOI: 10.1371/journal.pone.0085191] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 11/30/2013] [Indexed: 12/11/2022] Open
Abstract
Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127(low)PD-1(high)TIM-3(high) regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.
Collapse
Affiliation(s)
- Cecilia Fernandez-Ponce
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Margarita Dominguez-Villar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Enrique Aguado
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Francisco Garcia-Cozar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| |
Collapse
|
|
19
|
Amador-Cañizares Y, Martínez-Donato G, Álvarez-Lajonchere L, Vasallo C, Dausá M, Aguilar-Noriega D, Valenzuela C, Raíces I, Dubuisson J, Wychowski C, Cinza-Estévez Z, Castellanos M, Núñez M, Armas A, González Y, Revé I, Guerra I, Pérez Aguiar &A, Dueñas-Carrera S. HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin. World J Gastroenterol 2014; 20:148-162. [PMID: 24415868 PMCID: PMC3886004 DOI: 10.3748/wjg.v20.i1.148] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 06/14/2013] [Accepted: 07/13/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze hepatitis C virus (HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α (IFN-α) plus ribavirin and CIGB-230.
METHODS: CIGB-230 was administered in different schedules with respect to IFN-α plus ribavirin therapy. Paired serum and peripheral blood mononuclear cells (PBMC) samples from baseline and end of treatment were analyzed. The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay, neutralizing antibodies were evaluated by cell culture HCV neutralization assays, PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γ secretion was assessed by enzyme-linked immunospot. Data on virological and histological response and their association with immune variables are also provided.
RESULTS: From week 12 to week 48, all groups of patients showed a significant reduction in mean leukocyte counts. Statistically significant reductions in antibody titers were frequent, but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response, and the neutralizing antibody response was enhanced only in patients receiving CIGB-230. Cell-mediated immune responses also tended to decline, but significant reductions in IFN-γ secretion and total absence of core-specific lymphoproliferation were exclusive of the control group. Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens. Importantly, it was demonstrated that the quality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy. Specifically, the administration of 6 doses of CIGB-230 as late add-on to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γ secretion, both of which were associated with the sustained virological response.
CONCLUSION: CIGB-230, combined with IFN-α-based therapy, modifies the immune response in chronic patients. The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.
Collapse
MESH Headings
- Adult
- Antiviral Agents/administration & dosage
- Antiviral Agents/adverse effects
- Biomarkers/blood
- Cells, Cultured
- Cuba
- Double-Blind Method
- Drug Administration Schedule
- Drug Therapy, Combination
- Female
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepatitis C Antibodies/blood
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Humans
- Immunity, Cellular/drug effects
- Immunity, Humoral/drug effects
- Immunization Schedule
- Interferon alpha-2
- Interferon-alpha/administration & dosage
- Interferon-alpha/adverse effects
- Interferon-gamma/metabolism
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/virology
- Male
- Middle Aged
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/adverse effects
- Ribavirin/administration & dosage
- Ribavirin/adverse effects
- Time Factors
- Treatment Outcome
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/adverse effects
- Viral Hepatitis Vaccines/administration & dosage
- Viral Hepatitis Vaccines/adverse effects
Collapse
|
|
20
|
Eberhardt MK, Barry PA. Pathogen manipulation of cIL-10 signaling pathways: opportunities for vaccine development? Curr Top Microbiol Immunol 2014; 380:93-128. [PMID: 25004815 DOI: 10.1007/978-3-662-43492-5_5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Interleukin-10 (IL-10) is a tightly regulated, pleiotropic cytokine that has profound effects on all facets of the immune system, eliciting cell-type-specific responses within cells expressing the IL-10 receptor (IL-10R). It is considered a master immune regulator, and imbalances in IL-10 expression, resulting from either inherent or infectious etiologies, have far reaching clinical ramifications. Regarding infectious diseases, there has been accumulating recognition that many pathogens, particularly those that establish lifelong persistence, share a commonality of their natural histories: manipulation of IL-10-mediated signaling pathways. Multiple viral, bacterial, protozoal, and fungal pathogens appear to have evolved mechanisms to co-opt normal immune functions, including those involving IL-10R-mediated signaling, and immune effector pathways away from immune-mediated protection toward environments of immune evasion, suppression, and tolerance. As a result, pathogens can persist for the life of the infected host, many of whom possess otherwise competent immune systems. Because of pathogenic avoidance of immune clearance, persistent infections can exact incalculable physical and financial costs, and represent some of the most vexing challenges for improvements in human health. Enormous benefits could be gained by the development of efficient prevention and/or therapeutic strategies that block primary infection, or clear the infection. There are now precedents that indicate that modalities focusing on pathogen-mediated manipulation of IL-10 signaling may have clinical benefit.
Collapse
Affiliation(s)
- Meghan K Eberhardt
- Center for Comparative Medicine, University of California, Davis, CA, 95616, USA
| | | |
Collapse
|
|
21
|
Ng CT, Snell LM, Brooks DG, Oldstone MBA. Networking at the level of host immunity: immune cell interactions during persistent viral infections. Cell Host Microbe 2013; 13:652-64. [PMID: 23768490 DOI: 10.1016/j.chom.2013.05.014] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Persistent viral infections are the result of a series of connected events that culminate in diminished immunity and the inability to eliminate infection. By building our understanding of how distinct components of the immune system function both individually and collectively in productive versus abortive responses, new potential therapeutic targets can be developed to overcome immune dysfunction and thus fight persistent infections. Using lymphocytic choriomeningitis virus (LCMV) as a model of a persistent virus infection and drawing parallels to persistent human viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), we describe the cellular relationships and interactions that determine the outcome of initial infection and highlight immune targets for therapeutic intervention to prevent or treat persistent infections. Ultimately, these findings will further our understanding of the immunologic basis of persistent viral infection and likely lead to strategies to treat human viral infections.
Collapse
Affiliation(s)
- Cherie T Ng
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | | | | | | |
Collapse
|
|
22
|
Flynn JK, Dore GJ, Hellard M, Yeung B, Rawlinson WD, White PA, Kaldor JM, Lloyd AR, Ffrench RA. Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment. J Gastroenterol Hepatol 2013; 28:1770-81. [PMID: 23663030 PMCID: PMC3808486 DOI: 10.1111/jgh.12265] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance. METHODS HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays. RESULTS Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non-responders (higher interferon [IFN]-γ and interleukin (IL)-2 magnitude at week 24, broader IFN-γ responses at weeks 24 and 48, P < 0.05) and significantly increased IFN-γ responses between screening and week 48 (magnitude P = 0.026, breadth P = 0.009). Treatment-induced viral clearance was also associated with a trend toward decreased IL-10 responses (screening to week 48, P = 0.070), higher expression of CD45RO (P = 0.042) and CD38 (P = 0.088) on CD4+ T cells, and higher IFN-γR expression (CD56+ IFN-γR+ P = 0.033) compared to treatment non-responders. Untreated subjects with viral clearance also displayed high magnitude and broad HCV-specific IFN-γ and IL-2 responses early in infection; however, IFN-γ responses were not as well maintained compared to treated subjects with a SVR (week 48 magnitude, breadth P = 0.064). CONCLUSION Treatment-induced viral clearance of recent HCV infection is associated with maintenance of HCV-specific Th1 responses.
Collapse
Affiliation(s)
- Jacqueline K Flynn
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia,Department of Immunology, Monash University, Melbourne, Australia
| | - Gregory J Dore
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | - Barbara Yeung
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - William D Rawlinson
- Virology Division, Southern Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia
| | - Peter A White
- School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia
| | - John M Kaldor
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Rosemary A Ffrench
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia,Department of Immunology, Monash University, Melbourne, Australia
| | | |
Collapse
|
|
23
|
Adeyemo O, Doi H, Reddy KR, Kaplan DE. Impact of oral silymarin on virus- and non-virus-specific T-cell responses in chronic hepatitis C infection. J Viral Hepat 2013; 20:453-62. [PMID: 23730838 PMCID: PMC3675799 DOI: 10.1111/jvh.12050] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 11/01/2012] [Indexed: 01/26/2023]
Abstract
Silymarin displays anti-inflammatory effects on T lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T cells while increasing anti-inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon nonresponders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in (3) H-thymidine proliferation assays, IFNγ ELISPOT and IL-10 ELISPOT. The frequency of CD4(+) CD25(hi) and CD4(+) foxp3(+) regulatory T cells, serum cytokine levels, serum IP-10 and lymphocyte interferon-stimulated gene expression were also quantified at baseline and week 20. Thirty-two patients were recruited (10; placebo, 11; 420 mg three times a day, 11; 700 mg three times a day). Serum ALT and HCV RNA titres did not change in any group. HCV-specific CD4(+) T-cell proliferation and the frequency of IFNγ- and IL-10-producing T cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNγ and phytohaemagglutinin-induced T-cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T cells was identified, these data confirm that high-dose oral silymarin exerts modest nonspecific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation.
Collapse
Affiliation(s)
- Oluwasayo Adeyemo
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - Hiroyoshi Doi
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - K. Rajender Reddy
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| |
Collapse
|
|
24
|
Claassen MAA, Janssen HLA, Boonstra A. Role of T cell immunity in hepatitis C virus infections. Curr Opin Virol 2013; 3:461-7. [PMID: 23735335 DOI: 10.1016/j.coviro.2013.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 04/17/2013] [Accepted: 05/10/2013] [Indexed: 12/16/2022]
Abstract
Chronic infections with the hepatitis C virus (HCV) are a major global health issue. Viral replication is restricted to hepatocytes, and occurs for decades at high replication rates. Over the last decade, it became accepted that HCV-specific CD4(+) and CD8(+) T cells are crucial for protective immunity to HCV. However, a characteristic feature of persistent HCV infection is the dysfunctional T cell response, and over recent years enormous progress has been made in understanding the mechanisms that dampen the antiviral T cell responses in blood and liver of chronic HCV patients and also impact disease progression.
Collapse
Affiliation(s)
- Mark A A Claassen
- Liver Unit, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | | | | |
Collapse
|
|
25
|
Cameron B, Galbraith S, Li H, Lloyd A. Correlates and characteristics of hepatitis C virus-specific T-cell immunity in exposed uninfected high-risk prison inmates. J Viral Hepat 2013; 20:e96-106. [PMID: 23490396 DOI: 10.1111/jvh.12016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 08/01/2012] [Indexed: 01/04/2023]
Abstract
Some hepatitis C (HCV)-uninfected, high-risk individuals have HCV-specific cellular immunity without viraemia or seroconversion. The characteristics of these responses and the risk behavioural associations were studied in 94 subjects in a prospective cohort of recently seronegative prisoners reporting injecting drug use (IDU). Detailed behavioural data were collected. HCV antibody and PCR testing were performed. ELISpot assays for HCV-induced interferon (IFN)-γ and interleukin (IL)-2 production by T lymphocytes, as well as multiplex in vitro cytokine production assays, were performed. Seventy-eight subjects remained antibody and PCR negative and 16 seroconverted. Of the seronegative group, 22 (28%) had IFN-γ ELISpot responses in comparison with 13 of the 16 seroconverters (82%). This seronegative immune status was associated positively with injecting anabolic steroids and negatively with a recent break from IDU. The IFN-γ ELISpot responses involved both CD4 and CD8 T lymphocytes and were comparable in magnitude, but narrower in specificity, in uninfected subjects than in seroconverters. A subset of seronegative subjects had HCV-induced cytokine production patterns comparable with the seroconverters with increased production of IFN-γ, IL-2 and tumour necrosis factor (TNF)-α and reduced IL-10 in response to nonstructural peptides. In conclusion, comparable patterns of HCV-specific cellular immunity are found in recently infected subjects and in a minority of high-risk, uninfected subjects. Further characterization of these responses and their protective efficacy will inform HCV vaccine development.
Collapse
Affiliation(s)
- B Cameron
- Inflammation and Infection Research Centre, School of Medical Sciences, Sydney, NSW, Australia.
| | | | | | | | | |
Collapse
|
|
26
|
Cox MA, Kahan SM, Zajac AJ. Anti-viral CD8 T cells and the cytokines that they love. Virology 2013; 435:157-69. [PMID: 23217625 DOI: 10.1016/j.virol.2012.09.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 09/10/2012] [Indexed: 12/01/2022]
Abstract
Viral infections cause an immunological disequilibrium that provokes CD8 T cell responses. These cells play critical roles in purging acute infections, limiting persistent infections, and conferring life-long protective immunity. At every stage of the response anti-viral CD8 T cells are sensitive to signals from cytokines. Initially cytokines operate as immunological warning signs that inform of the presence of an infection, and also influence the developmental choices of the responding cells. Later during the course of the response other sets of cytokines support the survival and maintenance of the differentiated anti-viral CD8 T cells. Although many cytokines promote virus-specific CD8 T cells, other cytokines can suppress their activities and thus favor viral persistence. In this review we discuss how select cytokines act to regulate anti-viral CD8 T cells throughout the response and influence the outcome of viral infections.
Collapse
Affiliation(s)
- Maureen A Cox
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | | |
Collapse
|
|
27
|
Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy. PLoS One 2012; 7:e49389. [PMID: 23145169 PMCID: PMC3493527 DOI: 10.1371/journal.pone.0049389] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 10/09/2012] [Indexed: 12/24/2022] Open
Abstract
Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-α/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-γ production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-α/ribavirin therapy, negative regulation of especially HCV-specific IFN-γ production by TGF-β and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies.
Collapse
|
|
28
|
Three polymorphisms in the IL-10 gene and the risk of HCV infection: a meta-analysis plus a Chinese Association Study involving 1140 subjects. Epidemiol Infect 2012; 141:893-904. [DOI: 10.1017/s0950268812002154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
SUMMARYThe influence of an immunosuppressive cytokine, interleukin-10 (IL-10), on the outcome of hepatitis C virus (HCV) infection has been increasingly reported recently. A number of polymorphisms appear to control the level of IL-10 production. Among them, −592C/A, −819C/T and −1082G/A in the IL-10 gene are three most studied single nucleotide polymorphisms. To provide a more definitive conclusion about their association with the risk of HCV infection, a meta-analysis was performed by combining and summarizing a total of 17 studies. A biological justification for the choice of genetic model was provided. The results indicated no significant association between these IL-10 polymorphisms and the susceptibility to HCV infection [–592C/A: odds ratio (OR) 0·99, 95% confidence interval (CI) 0·78–1·25; –819C/T: OR 0·90, 95% CI 0·69–1·18; –1082G/A: OR 1·34, 95% CI 0·90–2·00]. However, this analysis did not account for the possible risk modifications by other factors, such as ethnicity and virus persistence. Therefore, the effects of ethnicity and virus persistence were investigated using Bayesian meta-regression and subgroup analysis. Finally, an extended case-control association study was conducted in a Chinese population involving 1140 subjects. Both serum level and genotype data of IL-10 −1082G/A were determined. As a result, a low prevalence of G allele was observed. Significantly higher IL-10 production was observed in HCV patients, especially patients with the GG genotype.
Collapse
|
|
29
|
Restoration of innate and adaptive immune responses by HCV viral inhibition with an induction approach using natural interferon-beta in chronic hepatitis C. Clin Dev Immunol 2012; 2012:582716. [PMID: 22966239 PMCID: PMC3433154 DOI: 10.1155/2012/582716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 06/03/2012] [Accepted: 06/03/2012] [Indexed: 12/30/2022]
Abstract
Chronic hepatitis C (CHC) is a serious medical problem necessitating more effective treatment. This study investigated the hypothesis that an induction approach with nIFN-beta for 24 weeks followed by PEG-IFN-alpha+ribavirin (standard of care: SOC) for 48 weeks (novel combination treatment: NCT) would increase the initial virologic response rate and restore innate and adaptive immune responses in CHC. Seven CHC patients with a high viral load and genotype 1b were treated with NCT. Serum cytokine and chemokine levels were evaluated during NCT. NCT prevented viral escape and breakthrough resulting in persistent viral clearance of HCVRNA. IL-15 was increased at the end of induction therapy in both early virologic responders (EAVRs) and late virologic responders (LAVRs); CXCL-8, CXCL-10, and CCL-4 levels were significantly decreased (P < 0.05) in EAVR but not in LAVR during NCT, and IL-12 increased significantly (P < 0.05) and CXCL-8 decreased significantly (P < 0.05) after the end of NCT in EAVR but not in LAVR. NCT prevented viral breakthrough with viral clearance leading to improvement of innate and adaptive immunity resulting in a sustained virologic response (SVR). NCT (n = 8) achieved a higher SVR rate than SOC (n = 8) in difficult-to-treat CHC patients with genotype 1 and high viral loads.
Collapse
|
|
30
|
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.
Collapse
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.
| | | |
Collapse
|
|
31
|
Abstract
The immune response in patients chronically infected with HCV plays a unique role during the infection because of its potential to contribute not only to viral clearance and, in some cases, protective immunity, but also to liver injury. A detailed understanding of the immunological mechanisms involved in persistence to HCV is essential to fully appreciate the complexity of the disease. In recent years, enormous progress has been made to characterize the dysfunctional natural killer cells and T cells during the chronic phase of infection. This information is important to further optimize treatment strategies based on the strengthening antiviral and immunomodulatory activities in patients chronically infected with HCV.
Collapse
Affiliation(s)
- Michelle Spaan
- Liver Unit, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | | |
Collapse
|
|
32
|
Harfouch S, Guiguet M, Valantin MA, Samri A, Ouazene Z, Slama L, Dominguez S, Simon A, Theodorou I, Thibault V, Autran B. Lack of TGF-β production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection. J Hepatol 2012; 56:1259-68. [PMID: 22326469 DOI: 10.1016/j.jhep.2012.01.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 01/05/2012] [Accepted: 01/05/2012] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-β) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism. METHODS Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-β-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors' samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15 months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures). RESULTS During the acute pretreatment phase, core/NS2-specific TGF-β-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-β+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-β+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-β production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0). CONCLUSIONS During acute hepatitis C, pre-therapeutic HCV-specific TGF-β-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.
Collapse
Affiliation(s)
- Sawsan Harfouch
- INSERM, UMRS-945, Laboratoire Immunité et Infection, Hôpital Pitié-Salpêtrière, F-75013 Paris, France
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Host immune responses to a viral immune modulating protein: immunogenicity of viral interleukin-10 in rhesus cytomegalovirus-infected rhesus macaques. PLoS One 2012; 7:e37931. [PMID: 22655082 PMCID: PMC3360012 DOI: 10.1371/journal.pone.0037931] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 04/30/2012] [Indexed: 12/23/2022] Open
Abstract
Background Considerable evidence has accumulated that multiple viruses, bacteria, and protozoa manipulate interleukin-10 (IL-10)-mediated signaling through the IL-10 receptor (IL-10R) in ways that could enable establishment of a persistent microbial infection. This suggests that inhibition of pathogen targeting of IL-10/IL-10R signaling could prevent microbial persistence. Human cytomegalovirus (HCMV) and rhesus cytomegalovirus (RhCMV) express a viral interleukin-10 (cmvIL-10 and rhcmvIL-10, respectively) with comparable immune modulating properties in vitro to that of their host's cellular IL-10 (cIL-10). A prior study noted that rhcmvIL-10 alters innate and adaptive immunity to RhCMV in vivo, consistent with a central role for rhcmvIL-10 during acute virus-host interactions. Since cmvIL-10 and rhcmvIL-10 are extremely divergent from the cIL-10 of their respective hosts, vaccine-mediated neutralization of their function could inhibit establishment of viral persistence without inhibition of cIL-10. Methods and Findings As a prelude to evaluating cmvIL-10-based vaccines in humans, the rhesus macaque model of HCMV was used to interrogate peripheral and mucosal immune responses to rhcmvIL-10 in RhCMV-infected animals. ELISA were used to detect rhcmvIL-10-binding antibodies in plasma and saliva, and an IL-12-based bioassay was used to quantify plasma antibodies that neutralized rhcmvIL-10 function. rhcmvIL-10 is highly immunogenic during RhCMV infection, stimulating high avidity rhcmvIL-10-binding antibodies in the plasma of all infected animals. Most infected animals also exhibited plasma antibodies that partially neutralized rhcmvIL-10 function but did not cross-neutralize the function of rhesus cIL-10. Notably, minimally detectable rhcmvIL-10-binding antibodies were detected in saliva. Conclusion This study demonstrates that rhcmvIL-10, as a surrogate for cmvIL-10, is a viable vaccine candidate because (1) it is highly immunogenic during natural RhCMV infection, and (2) neutralizing antibodies to rhcmvIL-10 do not cross-react with rhesus cIL-10. Exceedingly low rhcmvIL-10 antibodies in saliva further suggest that the oral mucosa, which is critical in RhCMV natural history, is associated with suboptimal anti-rhcmvIL-10 antibody responses.
Collapse
|
|
34
|
Different aspects of CD4 T cells that lead to viral clearance or persistence of HCV infection. Hepatol Int 2012. [PMID: 26201340 DOI: 10.1007/s12072-011-9321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
More than 170 million people worldwide are infected with hepatitis C virus (HCV). A characteristic of this virus is a high tendency toward chronic infection. Several factors affect the viral outcome after infection. Among them, HCV-specific CD4 T cells are thought to play a crucial role in controlling viremia. Cumulative data showed that spontaneously resolved individuals have vigorous CD4 T-cell responses to a broad spectrum of HCV antigens and maintain these responses over a long period of time, whereas chronically infected patients lose their CD4 T-cell responses in the acute phase of infection. Although several possibilities of why CD4 T cells lose their function have been proposed, the mechanisms are not completely understood. Moreover, there is another subset of CD4 T cells called regulatory T cells (Tregs). These cells suppress immune reaction of T cells, B cells, and antigen-presenting cells, and are thought to protect organs from immune overreaction and autoimmunity. An increasing amount of data supports the possibility that Tregs participate in the mechanism of HCV persistence. It is obvious that CD4 T cells are the main effectors controlling HCV outcome. To achieve a better prognosis, we need to understand the mechanism of how HCV earns its chronicity by escaping from host cellular immune attacks. In this review, we will focus on the role of HCV-specific T cells in controlling viremia, particularly the aspects of these cells being either inhibitors or propellers of chronic infection.
Collapse
|
|
35
|
Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. PLoS One 2011; 6:e28127. [PMID: 22132227 PMCID: PMC3221699 DOI: 10.1371/journal.pone.0028127] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 11/01/2011] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Human cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ∼26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties. METHODS AND FINDINGS Structural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10. CONCLUSION This study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection.
Collapse
|
|
36
|
Windsor MA, Carr BV, Bankowski B, Gibson D, Reid E, Hamblin P, Gubbins S, Juleff N, Charleston B. Cattle remain immunocompetent during the acute phase of foot-and-mouth disease virus infection. Vet Res 2011; 42:108. [PMID: 22014145 PMCID: PMC3207891 DOI: 10.1186/1297-9716-42-108] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 10/20/2011] [Indexed: 11/21/2022] Open
Abstract
Infection of cattle with foot-and-mouth disease virus (FMDV) results in the development of long-term protective antibody responses. In contrast, inactivated antigen vaccines fail to induce long-term protective immunity. Differences between susceptible species have also been observed during infection with FMDV, with cattle often developing persistent infections whilst pigs develop more severe symptoms and excrete higher levels of virus. This study examined the early immune response to FMDV in naïve cattle after in-contact challenge. Cattle exposed to FMDV were found to be viraemic and produced neutralising antibody, consistent with previous reports. In contrast to previous studies in pigs these cattle did not develop leucopenia, and the proliferative responses of peripheral blood mononuclear cells to either mitogen or third party antigen were not suppressed. Low levels of type 1 interferon and IL-10 were detected in the circulation. Taken together, these results suggest that there was no generalised immunosuppression during the acute phase of FMDV infection in cattle.
Collapse
Affiliation(s)
- Miriam A Windsor
- Pirbright Laboratory, Institute for Animal Health, Ash Road, Woking, Surrey, GU24 0NF, UK.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Protective effect of Thymic Humoral Factor on porcine serum-induced hepatic fibrosis and liver damage in Wistar rats. Ann Hepatol 2011. [DOI: 10.1016/s1665-2681(19)31523-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
|
|
38
|
Abstract
T cell exhaustion develops under conditions of antigen-persistence caused by infection with various chronic pathogens, such as human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB), or by the development of cancer. T cell exhaustion is characterized by stepwise and progressive loss of T cell function, which is probably the main reason for the failed immunological control of chronic pathogens and cancers. Recent observations have detailed some of the intrinsic and extrinsic factors that influence the severity of T cell exhaustion. Duration and magnitude of antigenic activation of T cells might be associated with up-regulation of inhibitory receptors, which is a major intrinsic factor of T cell exhaustion. Extrinsic factors might include the production of suppressive cytokines, T cell priming by either non-professional antigen-presenting cells (APCs) or tolerogenic dendritic cells (DCs), and alteration of regulatory T (Treg) cells. Further investigation of the cellular and molecular processes behind the development of T cell exhaustion can reveal therapeutic targets and strategies for the treatment of chronic infections and cancers. Here, we report the properties and the mechanisms of T cell exhaustion in a chronic environment.
Collapse
Affiliation(s)
- Hyun-Tak Jin
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | | | | | | |
Collapse
|
|
39
|
Flynn JK, Dore GJ, Hellard M, Yeung B, Rawlinson WD, White PA, Kaldor JM, Lloyd AR, Ffrench RA. Early IL-10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users. J Viral Hepat 2011; 18:549-61. [PMID: 20626625 PMCID: PMC4277610 DOI: 10.1111/j.1365-2893.2010.01335.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin-10 (IL-10) production (P = 0.048), in the relative absence of interferon-gamma (IFN-γ) and IL-2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN-γ (magnitude P < 0.001, breadth P = 0.004) and IL-2 responses, in the relative absence of IL-10. Early IL-10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN-γ and IL-2 production was inversely correlated with HCV RNA level at baseline (IFN-γ P = 0.020, IL-2 P = 0.050) and week 48 (IFN-γ P = 0.045, IL-2 P = 0.026). Intracellular staining (ICS) indicated the HCV-specific IFN-γ response was primarily from CD8(+) T cells and NK cells, whereas IL-10 production was predominantly from monocytes, with a subset of IL-10 producing CD8(+) T cells present only in those who progressed to chronic infection. IL-10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.
Collapse
Affiliation(s)
| | - Gregory J Dore
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | - Barbara Yeung
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - William D Rawlinson
- Virology Division, Southern Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia
| | - Peter A White
- School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia
| | - John M Kaldor
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | | | | |
Collapse
|
|
40
|
Bruno CM, Valenti M, Bertino G, Ardiri A, Amoroso A, Consolo M, Mazzarino CM, Neri S. Relationship between circulating interleukin-10 and histological features in patients with chronic C hepatitis. Ann Saudi Med 2011; 31:360-4. [PMID: 21808111 PMCID: PMC3156511 DOI: 10.4103/0256-4947.83215] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND OBJECTIVES An imbalance in cytokine production may be involved in the pathogenesis of chronic C hepatitis. The aim of the study was to investigate circulating levels of interleukin-10 (IL-10) in a selected cohort of patients affected by chronic C hepatitis. DESIGN AND SETTING Retrospective study based on consecutive hepatitis C virus patients, affected by chronic active hepatitis, attending the general hospital of hepatology unit from June to September 2009 PATIENTS AND METHODS A total of 49 patients with chronic C hepatitis and 20 healthy control subjects similar in gender and age were examined. Circulating IL-10 was assessed by ELISA commercial kit (R and D Systems) in all investigated subjects. RESULTS There was no significant difference in IL-10 values between controls and overall patients (P>.05). Nevertheless, among patients, subjects with more severe necroinflammation had higher values than others (P<.001). Moreover, a close relationship was found between IL-10 values and serum aspartate aminotransferase (r=0.61; P<.001). CONCLUSIONS These findings suggest that IL-10 may be a useful additional marker to assess necroinflammation and to monitor the evolution of liver damage. They also argue for a potential pathophysiological role for IL-10 in the persistence and progression of hepatitis.
Collapse
Affiliation(s)
- Cosimo Marcello Bruno
- Department of Internal Medicine and Systemic Diseases, University of Catania, Catania, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Virally expressed interleukin-10 ameliorates acute encephalomyelitis and chronic demyelination in coronavirus-infected mice. J Virol 2011; 85:6822-31. [PMID: 21593179 DOI: 10.1128/jvi.00510-11] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The absence of interleukin-10 (IL-10), a potent anti-inflammatory cytokine results in increased immune-mediated demyelination in mice infected with a neurotropic coronavirus (recombinant J2.2-V-1 [rJ2.2]). Here, we examined the therapeutic effects of increased levels of IL-10 at early times after infection by engineering a recombinant J2.2 virus to produce IL-10. We demonstrate that viral expression of IL-10, which occurs during the peak of virus replication and at the site of disease, enhanced survival and diminished morbidity in rJ2.2-infected wild-type B6 and IL-10(-/-) mice. The protective effects of increased IL-10 levels were associated with reductions in microglial activation, inflammatory cell infiltration into the brain, and proinflammatory cytokine and chemokine production. Additionally, IL-10 increased both the frequency and number of Foxp3(+) regulatory CD4 T cells in the infected central nervous system. Most strikingly, the ameliorating effects of IL-10 produced during the first 5 days after infection were long acting, resulting in decreased demyelination during the resolution phase of the infection. Collectively, these results suggest that the pathogenic processes that result in demyelination are initiated early during infection and that they can be diminished by exogenous IL-10 delivered soon after disease onset. IL-10 functions by dampening the innate or very early T cell immune response. Further, they suggest that early treatment with IL-10 may be useful adjunct therapy in some types of viral encephalitis.
Collapse
|
|
42
|
Xu Y, Li H, Gao RL, Adeyemo O, Itkin M, Kaplan DE. Expansion of interferon-gamma-producing multifunctional CD4+ T-cells and dysfunctional CD8+ T-cells by glypican-3 peptide library in hepatocellular carcinoma patients. Clin Immunol 2011; 139:302-13. [PMID: 21419713 DOI: 10.1016/j.clim.2011.02.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 02/01/2011] [Accepted: 02/17/2011] [Indexed: 12/24/2022]
Abstract
Glypican-3 is a promising target for immunotherapy for hepatocellular carcinoma, but limited data exist regarding its immunogenicity in patients with diverse HLA types, immunogenicity for CD4(+) T-cells, and the impact of inhibitory co-stimulation on glypican-3-specific T-cells. Using a 15mer overlapping peptide library for glypican-3, PBMC from patients with HCC were assessed ex vivo and after short-term in vitro expansion for tumor antigen-specific T-cell responses with and without blockade of PD-1/PD-L1 and CTLA-4 signaling. Glypican-3-specific T-cells were undetectable ex vivo, but primarily IFNγ(+)TNFα(+) CD4(+) T-cells expanded with short-term in vitro stimulation in 10/19 (52%) patients. Glypican-3-specific CD8(+) T-cells predominantly produced TNFα, but did not secrete IFNγ nor degranulate. CTLA-4 and PD-1 blockade minimally impacted the cytokine secretion and proliferation of glypican-3-specific T-cells. These data suggest that CD8(+) T-cell-directed tumor vaccines in HCC may have limited potential for efficacy unless optimal co-stimulation conditions can be identified but CD4(+)-directed vaccines merit consideration.
Collapse
Affiliation(s)
- Yanhui Xu
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, USA
| | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.
Collapse
|
|
44
|
Díaz-Valdés N, Manterola L, Belsúe V, Riezu-Boj JI, Larrea E, Echeverria I, Llópiz D, López-Sagaseta J, Lerat H, Pawlotsky JM, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P. Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10. Hepatology 2011; 53:23-31. [PMID: 21154952 DOI: 10.1002/hep.23980] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 09/04/2010] [Indexed: 01/17/2023]
Abstract
UNLABELLED The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro. In cultures of human leukocytes where HCV core protein induces the production of IL-10, p13 restored the ability of plasmacytoid DC to produce interferon alpha (IFN-α) after Toll-like receptor 9 (TLR9) stimulation. Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV core, p9 enhanced IL-12 production by inhibiting HCV core-induced as well as CD40L-induced IL-10. Moreover, in vitro, p13 potentiated the effect of maturation stimuli on human and murine DC, increasing their IL-12 production and stimulatory activity, which resulted in enhanced proliferation and IFN-γ production by responding T-cells. Finally, immunization with p13-treated murine DC induced stronger anti-HCV T-cell responses not only in wildtype mice but also in HCV transgenic mice and in mice transiently expressing HCV core in the liver. CONCLUSION These results suggest that IL-10 inhibiting peptides may have important applications to enhance anti-HCV immune responses by restoring the immunostimulatory capabilities of DC.
Collapse
Affiliation(s)
- Nancy Díaz-Valdés
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity. Proc Natl Acad Sci U S A 2010; 107:22647-52. [PMID: 21149711 DOI: 10.1073/pnas.1013794108] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Human cytomegalovirus (HCMV) and many other pathogens exploit the IL-10 pathway, as part of their infectious cycle, either through their own encoded IL-10 (hcmvIL-10 for HCMV) or manipulation of the cellular IL-10 signaling cascade. Based on the in vitro demonstrations of its pleiotropic and cell type-dependent modulatory nature, hcmvIL-10 could profoundly attenuate host immunity, facilitating the establishment and maintenance of a persistent infection in an immune-competent host. To investigate the impact of extrinsic IL-10 on the induction and maintenance of antiviral immune responses in vivo, rhesus macaques were inoculated with variants of rhesus cytomegalovirus (RhCMV) either expressing or lacking the RhCMV ortholog of hcmvIL-10 (rhcmvIL-10). The results show that rhcmvIL-10 alters the earliest host responses to viral antigens by dampening the magnitude and specificity of innate effector cells to primary RhCMV infection. In addition, there is a commensurate reduction in the quality and quantity of early and long-term, RhCMV-specific adaptive immune responses. These findings provide a mechanistic basis of how early interactions between a newly infected host and HCMV could shape the long-term virus-host balance, which may facilitate the development of new prevention and intervention strategies for HCMV.
Collapse
|
|
46
|
Barnaba V. Hepatitis C virus infection: a "liaison a trois" amongst the virus, the host, and chronic low-level inflammation for human survival. J Hepatol 2010; 53:752-61. [PMID: 20673595 DOI: 10.1016/j.jhep.2010.06.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2010] [Revised: 05/20/2010] [Accepted: 06/09/2010] [Indexed: 01/26/2023]
Abstract
This review covers the various aspects of the immune system that allows the relationship between the hepatitis-C virus, the host and chronic low-level inflammation, to be highly flexible and able to defend the host from persistent infections. This ambiguity mainly stems from the property of the immune system that can be both protective and harmful. Immunity cannot be fully protective without producing a certain degree of damage (acute hepatitis resulting in resolving HCV infection). In addition, the balance between protection and tissue damage is critical for the development of chronic HCV infection. The establishment of a state of chronic low-level inflammation is instrumental to limit liver immunopathology, to limit viral spread, and ultimately to ensure a long-lasting survival of the host. It is dictated by a fine equilibrium maintained by multiple immunologic mechanisms, including: sensory perception of innate immunity, virus-specific T and B cell functions, control of immune responses, and finally the balance between immunity and immunopathology that has principally evolved to favor the survival of the species.
Collapse
Affiliation(s)
- Vincenzo Barnaba
- Departimento of Medicina Interna, Sapienza Università di Roma, Fondazione Andrea Cesalpino, Fondazione Cenci Bolognetti, Italy.
| |
Collapse
|
|
47
|
Watanabe T, Bertoletti A, Tanoto TA. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat 2010; 17:453-8. [PMID: 20487259 DOI: 10.1111/j.1365-2893.2010.01313.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Dysfunctional virus-specific T cells are a hallmark of many chronic viral infections. Recent studies have implicated the inhibitory PD-1/PD-L1 pathway with the functional impairment of T cells. In this respect, we will review the latest research on PD-1/PD-L1 pathway and T-cell exhaustion in the context of human chronic hepatitis B and C virus infections. We will also discuss the therapeutic potential of PD-1 blockade and how it may be enhanced through the modulation of other co-stimulatory/inhibitory pathways.
Collapse
Affiliation(s)
- T Watanabe
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore, Singapore
| | | | | |
Collapse
|
|
48
|
Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology 2010; 129:474-81. [PMID: 20201977 PMCID: PMC2842494 DOI: 10.1111/j.1365-2567.2010.03255.x] [Citation(s) in RCA: 468] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 01/23/2010] [Accepted: 01/25/2010] [Indexed: 12/11/2022] Open
Abstract
T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.
Collapse
Affiliation(s)
- John S Yi
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | | |
Collapse
|
|
49
|
Dunn C, Peppa D, Khanna P, Nebbia G, Jones M, Brendish N, Lascar RM, Brown D, Gilson RJ, Tedder RJ, Dusheiko GM, Jacobs M, Klenerman P, Maini MK. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 2009; 137:1289-300. [PMID: 19591831 DOI: 10.1053/j.gastro.2009.06.054] [Citation(s) in RCA: 279] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 05/20/2009] [Accepted: 06/18/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) causes more than 1 million deaths annually from immune-mediated liver damage. The long incubation period has been difficult to study; by the time most patients present, massive viremia and the majority of viral clearance have already occurred. The aim of this study was to investigate the contribution of innate and adaptive immune mechanisms in early acute HBV through access to an unusual cohort of patients sampled in the preclinical phase and followed up to resolution of their infection. METHODS Twenty-one patients with acute HBV were studied, 8 of them from before the peak of viremia. Circulating innate cytokines were quantitated by enzyme-linked immunosorbent assay and natural killer (NK) and T-cell effector function by flow cytometry. Results were correlated with temporal changes in viral load, serology, and liver inflammation and compared with healthy controls. RESULTS Type I interferon (IFN) remained barely detectable throughout, with concentrations no higher than those found in healthy controls. Similarly, interleukin-15 and IFN-lambda1 were not induced during peak viremia. NK cell activation and capacity for IFN-gamma production were reduced at peak viremia. Early functional HBV-specific CD4 and CD8 T-cell responses were attenuated as viral load increased and recovered again as infection resolved. The transient inhibition of NK and T-cell responses coincided with a surge in the immunosuppressive cytokine interleukin-10 accompanying HBV viremia. CONCLUSIONS The early stages of acute HBV are characterized by induction of interleukin-10 rather than type I IFN, accompanied by a temporary attenuation of NK and T-cell responses.
Collapse
Affiliation(s)
- Claire Dunn
- Division of Infection and Immunity, University College London, London, England
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Kim AY, Chung RT. Coinfection with HIV-1 and HCV--a one-two punch. Gastroenterology 2009; 137:795-814. [PMID: 19549523 PMCID: PMC3146750 DOI: 10.1053/j.gastro.2009.06.040] [Citation(s) in RCA: 133] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 05/22/2009] [Accepted: 06/13/2009] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis, and death; it is estimated that 180 million persons are infected with HCV worldwide. The consequences of HCV are worse in those who are coinfected with human immunodeficiency virus 1 (HIV-1), which is unfortunately a common scenario because of shared risk factors of the viruses. More studies into effects of HCV/HIV-1 coinfection are needed, but efforts have been hampered by limitations in our understanding of the combined pathogenesis of the 2 viruses. Gaining insight into the mechanisms that underlie the immunopathogenesis of these persistent viral infections could lead to new therapeutic strategies for patients with HCV/HIV-1 coinfection.
Collapse
Affiliation(s)
- Arthur Y Kim
- Division of Infectious Diseases and the Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
| | | |
Collapse
|