|
1
|
Maretti-Mira AC, Salomon MP, Hsu AM, Matsuba C, Golden-Mason L. Chronic HCV infection promotes cytotoxicity in antigen-specific CD8 + T cells regardless of virus specificity. FRONTIERS IN VIROLOGY (LAUSANNE, SWITZERLAND) 2023; 3:1198361. [PMID: 37886042 PMCID: PMC10601542 DOI: 10.3389/fviro.2023.1198361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Introduction Despite advancements in hepatitis C virus (HCV) infection treatment, HCV still represents a significant public health burden. Besides progressive hepatic damage, viral persistence has lasting effects on innate and adaptive immune responses. Lack of a complete understanding of the factors driving an effective HCV response contributes to the failure to develop a vaccine for prevention. This study advances the existing knowledge on HCV-specific CD8+ T cells and describes the impact of current or past HCV infection on CD8+ T cells specific for other viruses. Methods We used barcoded-dextramers to identify and sort CD8+ T cells specific for HCV, cytomegalovirus, and influenza, and characterized them using single-cell RNA sequencing technology. Our cohort included chronic (cHCV), spontaneously resolved (rHCV), and subjects undergoing direct-acting antiviral (DAA) therapy. Results We show that HCV-specific CD8+ T cells have cytotoxic features in patients with cHCV, which is progressively reduced with DAA therapy and persists 12 weeks after treatment completion. We also observe a shift in the CD8+ T cell phenotype on DAA treatment, with decreased effector memory and exhausted cell signatures. In rHCV, we also detected a smaller proportion of effector memory cells compared to cHCV. The proportion of CD8+ exhausted T cells in cHCV and rHCV subjects was comparable. Moreover, we also observed that non-HCV virus-specific CD8+ T cells exhibit robust cytotoxic traits during cHCV infection. Discussion Altogether, our findings suggest that cHCV infection promotes cytotoxicity in CD8+ T cells regardless of virus specificity. The immunological changes caused by cHCV infection in CD8+ T cells may contribute to worsening the ongoing hepatic damage caused by HCV infection or exacerbate the immune response to possible co-infections. Our data provide a resource to groups exploring the underlying mechanisms of HCV-specific T cell spontaneous and treatment-induced resolution to inform the development of effective vaccines against HCV infection.
Collapse
Affiliation(s)
- Ana C. Maretti-Mira
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Matthew P. Salomon
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Angela M. Hsu
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Chikako Matsuba
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Lucy Golden-Mason
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| |
Collapse
|
|
2
|
Bokelmann M, Vogel U, Debeljak F, Düx A, Riesle-Sbarbaro S, Lander A, Wahlbrink A, Kromarek N, Neil S, Couacy-Hymann E, Prescott J, Kurth A. Tolerance and Persistence of Ebola Virus in Primary Cells from Mops condylurus, a Potential Ebola Virus Reservoir. Viruses 2021; 13:v13112186. [PMID: 34834992 PMCID: PMC8622823 DOI: 10.3390/v13112186] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Although there have been documented Ebola virus disease outbreaks for more than 40 years, the natural reservoir host has not been identified. Recent studies provide evidence that the Angolan free-tailed bat (Mops condylurus), an insectivorous microbat, is a possible ebolavirus reservoir. To investigate the potential role of this bat species in the ecology of ebolaviruses, replication, tolerance, and persistence of Ebola virus (EBOV) were investigated in 10 different primary bat cell isolates from M. condylurus. Varying EBOV replication kinetics corresponded to the expression levels of the integral membrane protein NPC1. All primary cells were highly tolerant to EBOV infection without cytopathic effects. The observed persistent EBOV infection for 150 days in lung primary cells, without resultant selective pressure leading to virus mutation, indicate the intrinsic ability of EBOV to persist in this bat species. These results provide further evidence for this bat species to be a likely reservoir of ebolaviruses.
Collapse
Affiliation(s)
- Marcel Bokelmann
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Uwe Vogel
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Franka Debeljak
- Department of Infectious Diseases, King’s College London, London WC2R 2LS, UK; (F.D.); (S.N.)
| | - Ariane Düx
- Epidemiology of Highly Pathogenic Microorganisms, Robert Koch Institute, 13353 Berlin, Germany;
| | - Silke Riesle-Sbarbaro
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Angelika Lander
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Annette Wahlbrink
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Nicole Kromarek
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Stuart Neil
- Department of Infectious Diseases, King’s College London, London WC2R 2LS, UK; (F.D.); (S.N.)
| | - Emmanuel Couacy-Hymann
- Laboratoire National d’Appui au Développement Agricole, Bingerville BP 206, Côte d’Ivoire;
| | - Joseph Prescott
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
| | - Andreas Kurth
- Centre for Biological Threats and Special Pathogens, Robert Koch Institute, 13353 Berlin, Germany; (M.B.); (U.V.); (S.R.-S.); (A.L.); (A.W.); (N.K.); (J.P.)
- Correspondence:
| |
Collapse
|
|
3
|
Masoomikarimi M, Garmabi B, Alizadeh J, Kazemi E, Azari Jafari A, Mirmoeeni S, Dargahi M, Taheri N, Jafari R. Advances in immunotherapy for COVID-19: A comprehensive review. Int Immunopharmacol 2021; 93:107409. [PMID: 33581501 PMCID: PMC7826020 DOI: 10.1016/j.intimp.2021.107409] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/06/2021] [Accepted: 01/15/2021] [Indexed: 12/21/2022]
Abstract
COVID-19 is an acute respiratory syndrome caused by SARS-COV-2 which has now become a huge pandemic worldwide. The immunopathogenesis of COVID-19 has been established that increased serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and reduction of the CD4+ and the CD8+ T lymphocyte populations, are the most reported immunological findings in these patients. High levels of other inflammatory cytokines and chemokines such as IL-2 and IL-8 with an increased number of neutrophils and eosinophils may induce immune abnormalities in patients with COVID-19. There is growing evidence to obtain a deeper understanding of the immunopathogenesis of COVID-19 which will lay the foundation for the development of new potential therapies. However, specific and non-specific immunotherapies such as convalescent plasma (CP) are widely performed to treat patients with severe COVID-19, there is no definitive evidence to suggest the effectiveness of these treatments. Hence, this review aimed to highlight the current and most recent studies to identify the new immunotherapeutics for COVID-19 disease.
Collapse
Affiliation(s)
- Masoomeh Masoomikarimi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Garmabi
- Study and Treatment of Circadian Rhythms Research Center, Shahroud University of Medical Sciences, Shahroud, Iran; School of Medicine, Shahroud University of Medical Sciences. Shahroud, Iran
| | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Erfan Kazemi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Amirhossein Azari Jafari
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | | | - Motahareh Dargahi
- School of Medicine, Shahroud University of Medical Sciences. Shahroud, Iran
| | - Niloofar Taheri
- School of Medicine, Shahroud University of Medical Sciences. Shahroud, Iran
| | - Reza Jafari
- School of Medicine, Shahroud University of Medical Sciences. Shahroud, Iran.
| |
Collapse
|
|
4
|
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
|
|
5
|
Nakamura I, Furuichi Y, Sugimoto K. Restoration of natural killer cell activity by interferon-free direct-acting antiviral combination therapy in chronic hepatitis C patients. Hepatol Res 2018; 48:855-861. [PMID: 29732688 DOI: 10.1111/hepr.13186] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 04/24/2018] [Accepted: 04/25/2018] [Indexed: 02/06/2023]
Abstract
AIM Interferon-free direct-acting antiviral (DAA) therapy is an effective treatment for chronic hepatitis C (CH(C)) patients. Activity of natural killer (NK) cells was reported to be impaired in patients with hepatitis C virus infection. The aim of this study was to examine whether DAA therapy could restore NK activity in patients with CH(C). METHODS Direct-acting antiviral therapy was given to 31 CH(C) patients as asunaprevir/daclatasvir (ASV/DCV) (n = 15), ledipasvir/sofosbuvir (n = 7), ombitasvir/paritaprevir/ritonavir (n = 6), or elbasvir/grazoprevir (n = 3). Prior to therapy (0M), at the completion of the therapy (EOT), and at 24 weeks after completion (AFTER), NK activity and the frequency of CD56dim NK and CD56bright NK cells in peripheral blood were estimated by Cr release assay and flow cytometry. Statistical analysis was carried out by anova and the Mann-Whitney U-test. RESULTS In one of the ASV/DCV-treated patients, treatment was stopped 12 weeks after initiation of therapy because of viral breakthrough. The anova showed that NK activity significantly improved at EOT (vs. 0M, P < 0.01) and at AFTER (vs. 0M, P < 0.001) in 30 patients with sustained virologic response. It also showed that the frequency of CD56dim NK cells was significantly increased at EOT and at AFTER (vs. 0M, P < 0.05). In addition, the NK activity ratio (AFTER/0M) had no significant difference between patient groups with higher and lower Fibrosis-4 scores. CONCLUSION Direct-acting antiviral therapy in CH(C) patients could improve NK activity by increasing the frequency of CD56dim NK cells. Additionally, our results might imply that DAAs therapy could reduce the risk of hepatocarcinogenesis by restoring innate immune responses.
Collapse
Affiliation(s)
- Ikuo Nakamura
- Department of Gastroenterology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan
- Department of Gastroenterology, Tokyo Medical University, Tokyo, Japan
| | | | | |
Collapse
|
|
6
|
. A, Nasrul E, Miro S. Level of Interferon-gamma and Interleukin-12 in Several
Genotypes of HCV Infections. JOURNAL OF MEDICAL SCIENCES 2018. [DOI: 10.3923/jms.2018.180.185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
|
|
7
|
Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans.
Collapse
Affiliation(s)
- Jijing Shi
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | - Yuanyuan Li
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | | | - Xuexiu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 460000, China
| | - Fu-Sheng Wang
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
| |
Collapse
|
|
8
|
Potential Hepatoprotective Role of Galectin-3 during HCV Infection in End-Stage Renal Disease Patients. DISEASE MARKERS 2017; 2017:6275987. [PMID: 28487598 PMCID: PMC5405569 DOI: 10.1155/2017/6275987] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/24/2017] [Accepted: 02/26/2017] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus infection (HCV), one of the greatest causes of liver disease, is a frequent complication in patients with end-stage renal disease (ESRD) on dialysis. ESRD is defined as decreased glomerular filtration and also accompanied by impaired function of the immune system. Galectin-3 is a β-galactoside-binding lectin, involved in various biological processes including pathogenesis of chronic renal disease. The aim of our study was to estimate disease severity in ESRD HCV+ patients and analyze the serum concentrations of IL-1β, IL-4, IL-23, and IL-6; anti-HCV antibodies; and galectin-3. Also, we attempted to determine potential correlation between galectin-3 level and parameters of disease severity ALT and AST. Our results showed decreased levels of ALT and AST (p = 0.00), demonstrating less liver destruction in ESRD HCV+ patients in comparison to HCV+ patients. Increased levels of IL-6 (p = 0.03) implicate a hepatoprotective role of IL-6 in these patients. Also, level of galectin-3 (p = 0.00) in the serum of ESRD HCV+ patients was higher than that of HCV+ patients. This alteration was accompanied with negative correlation between galectin-3 and AST and ALT, respectively (p = 0.029; p = 0.033). The presence of increased systemic levels of IL-6 and Gal-3 in ESRD HCV+ patients may be an attempt to counteract or limit ongoing proinflammatory processes and to downregulate chronic inflammation, suggesting the new aspects of HCV infection in ESRD patients.
Collapse
|
|
9
|
Zupin L, Polesello V, Alberi G, Moratelli G, Crocè SL, Masutti F, Pozzato G, Crovella S, Segat L. MBL2 Genetic Variants in HCV Infection Susceptibility, Spontaneous Viral Clearance and Pegylated Interferon Plus Ribavirin Treatment Response. Scand J Immunol 2017; 84:61-9. [PMID: 27136459 DOI: 10.1111/sji.12444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 04/24/2016] [Indexed: 01/21/2023]
Abstract
Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection.
Collapse
Affiliation(s)
- L Zupin
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - V Polesello
- Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy
| | - G Alberi
- Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy
| | - G Moratelli
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - S L Crocè
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - F Masutti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - G Pozzato
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - S Crovella
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.,Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy
| | - L Segat
- Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy
| |
Collapse
|
|
10
|
Zupin L, Polesello V, Alberi G, Moratelli G, Crocè SL, Masutti F, Pozzato G, Crovella S, Segat L. CD209 promoter polymorphisms associate with HCV infection and pegylated-interferon plus ribavirin treatment response. Mol Immunol 2016; 76:49-54. [PMID: 27348632 DOI: 10.1016/j.molimm.2016.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 11/25/2022]
Abstract
Hepatitis C is a severe liver disease caused by hepatitis C virus that could persist in the host causing progression towards chronic disease in about 80% of the cases. Pegylated-interferon plus ribavirin was the gold standard therapy, however treatment's response was quite variable among individuals and different host/viral factors may play a role in disease outcome. The cluster of differentiation 209 (CD209 antigen) is a component of the innate immune system able to recognize HCV and consequently activating the immune response. We enrolled 203 Italian HCV infected patients and 220 healthy controls investigating if five promoter polymorphisms within CD209 gene (encoding for CD209 antigen) correlated with HCV infection susceptibility, spontaneous viral clearance and interferon treatment response. CD209 -939G>A and -871A>G polymorphisms associated with HCV infection susceptibility, while, CD209 -871A>G and -336A>G polymorphisms associated with response to treatment. In conclusion, CD209 polymorphisms could play a role in the susceptibility to HCV infection as well as interferon treatment response in our study population from North-East of Italy.
Collapse
Affiliation(s)
- Luisa Zupin
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
| | - Vania Polesello
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Giulia Alberi
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Giulia Moratelli
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Saveria Lory Crocè
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Flora Masutti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Pozzato
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Sergio Crovella
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Ludovica Segat
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| |
Collapse
|
|
11
|
Nakamura I, Asano T, Asabe S, Ando M, Sano T, Miyata Y, Taira J, Sugimoto K, Imai Y, Moriyasu F, Imawari M. Restoration of natural killer cell activity by pegylated interferon-alpha/ribavirin therapy in chronic hepatitis C patient. Hepatol Res 2015; 45:107-12. [PMID: 24606027 DOI: 10.1111/hepr.12322] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 02/28/2014] [Accepted: 03/05/2014] [Indexed: 02/08/2023]
Abstract
AIM The combination therapy of pegylated interferon-α and ribavirin (PEG IFN/RBV) is one of the effective treatments for chronic hepatitis C (CHC) patients. Natural killer (NK)-cell activity was reported to be impaired in patients with hepatitis C virus (HCV). The aim of this study was to examine whether PEG IFN/RBV therapy could restore NK activity in CHC patients. METHODS In 19 CHC patients, PEG IFN/RBV therapy was performed. Just before (0M), at 3 months of the therapy (3M) and at 6 months after completion of the therapy (6M), NK activity and the frequency of NK cells, CD56(dim) NK cells and CD56(bright) NK cells in peripheral blood was estimated by creatinine release assay and flow cytometry. Statistical analysis was performed by anova and Mann-Whitney U-test. RESULTS anova showed that NK activity significantly improved at 6M (vs 0M, P < 0.05) in the patients studied and in the patients with sustained virological response (SVR). It also showed that frequency of CD56(bright) NK cells was significantly increased at 6M (vs 0M, P < 0.05) in the patients studied and in the SVR group. However, no significant change in NK activity and frequency of CD56(bright) NK cells were detected in non-SVR group. Furthermore, NK activity ratio (6M/0M) in the SVR group was revealed to be higher compared with that in the non-SVR group by analysis using Mann-Whitney U-test (P < 0.05). CONCLUSION PEG IFN/RBV therapy in CHC patients could improve NK activity by increasing the frequency of CD56(bright) NK cells in SVR patients. Our study also revealed that eradication of HCV could restore NK-cell activity.
Collapse
Affiliation(s)
- Ikuo Nakamura
- Department of Gastroenterology, Tokyo Medical University, Tokyo, Japan; Division of Gastroenterology, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Valva P, Gismondi MI, Casciato PC, Galoppo M, Lezama C, Galdame O, Gadano A, Galoppo MC, Mullen E, De Matteo EN, Preciado MV. Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection. Clin Microbiol Infect 2014; 20:O998-1009. [PMID: 24942073 DOI: 10.1111/1469-0691.12728] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/23/2014] [Accepted: 06/15/2014] [Indexed: 12/17/2022]
Abstract
Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.
Collapse
Affiliation(s)
- P Valva
- Laboratory of Molecular Biology, Pathology Division, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Granato M, Lacconi V, Peddis M, Di Renzo L, Valia S, Rivanera D, Antonelli G, Frati L, Faggioni A, Cirone M. Hepatitis C virus present in the sera of infected patients interferes with the autophagic process of monocytes impairing their in-vitro differentiation into dendritic cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:1348-55. [DOI: 10.1016/j.bbamcr.2014.04.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/25/2014] [Accepted: 04/01/2014] [Indexed: 12/31/2022]
|
|
14
|
Dichamp I, Abbas W, Kumar A, Di Martino V, Herbein G. Cellular activation and intracellular HCV load in peripheral blood monocytes isolated from HCV monoinfected and HIV-HCV coinfected patients. PLoS One 2014; 9:e96907. [PMID: 24809719 PMCID: PMC4014560 DOI: 10.1371/journal.pone.0096907] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 04/13/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND During HCV infection, the activation status of peripheral blood monocytes and its impact on HCV replication are poorly understood. We hypothesized that a modified activation of peripheral blood monocytes in HIV-HCV coinfected compared to HCV monoinfected patients may contribute to different monocytes reservoirs of HCV replication. METHODS We performed a case-control analysis involving HCV-infected patients with and without HIV coinfection. In peripheral blood mononuclear cells (PBMCs), peripheral blood lymphocytes (PBLs) and peripheral blood monocytes isolated from HCV monoinfected and HIV-HCV coinfected patients, intracellular HCV load and a marker of cellular activation, nuclear factor-kappaB (NF-κB) activation, were quantified using intracellular detection of HCV-core protein and electrophoretic mobility shift assay, respectively. RESULTS Intracellular HCV loads were higher in monocytes isolated from HIV-HCV coinfected patients than in those of monoinfected patients. Among PBMCs isolated from HIV-HCV coinfected patients, intracellular HCV loads were higher in monocytes compared to PBLs. Cellular activation as measured by NF-κB activation was higher in monocytes isolated from HIV-HCV coinfected patients than in those of monoinfected patients. CONCLUSIONS Our results reveal the peripheral blood monocytes as an important extrahepatic reservoir for HCV in HIV-HCV coinfected patients and indicate a potential association between the activation state of monocytes and the size of the HCV reservoir in HIV-HCV coinfected patients.
Collapse
Affiliation(s)
- Isabelle Dichamp
- Pathogens and Inflammation Department, UPRES EA4266, SFR FED 4234, University of Franche-Comté, Besancon, France
- Department of Virology, CHRU Besançon, Besançon, France
| | - Wasim Abbas
- Pathogens and Inflammation Department, UPRES EA4266, SFR FED 4234, University of Franche-Comté, Besancon, France
- Department of Virology, CHRU Besançon, Besançon, France
| | - Amit Kumar
- Pathogens and Inflammation Department, UPRES EA4266, SFR FED 4234, University of Franche-Comté, Besancon, France
- Department of Virology, CHRU Besançon, Besançon, France
| | - Vincent Di Martino
- Pathogens and Inflammation Department, UPRES EA4266, SFR FED 4234, University of Franche-Comté, Besancon, France
- Department of Hepatology, CHRU Besançon, Besançon, France
| | - Georges Herbein
- Pathogens and Inflammation Department, UPRES EA4266, SFR FED 4234, University of Franche-Comté, Besancon, France
- Department of Virology, CHRU Besançon, Besançon, France
| |
Collapse
|
|
15
|
Characterization of CD4⁺ T-cell immune activation and interleukin 10 levels among HIV, hepatitis C virus, and HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr 2014; 64:232-40. [PMID: 24131865 DOI: 10.1097/qai.0b013e31829c6de0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND HIV/hepatitis C virus (HCV)-coinfected patients have accelerated liver disease compared with HCV monoinfection. In HIV-positive patients with viral suppression, data comparing inflammatory cytokines and immune activation between HIV/HCV coinfection with chronic hepatitis C (CHC) to HIV/HCV-seropositive patients with cleared HCV are limited. METHODS Fifty-nine age- and sex-matched patients were stratified: (1) HIV monoinfection (n = 15); (2) HCV monoinfection with CHC (n = 15); (3) HIV/HCV coinfection with CHC (n = 14); and (4) HIV/HCV seropositive with cleared HCV (n = 15). All HIV-positive patients had undetectable HIV viremia, and median CD4 was 420 cells per microliter. Liver fibrosis was assessed in each subject using transient elastography. Cells were collected for CD4 and CD8 immune activation (CD38/HLA-DR) markers via flow cytometry and plasma for luminex-multiplex cytokine assays. RESULTS CD38⁺HLA-DR⁺ expression on CD4⁺ T cells was significantly increased in HIV/HCV coinfection with CHC (7%) versus HCV monoinfection (4%) (P = 0.012). CD4⁺ total HLA-DR⁺ expression was significantly increased in HIV/HCV coinfection with CHC (43%) versus HIV monoinfection (31%) (P = 0.010) and HIV/HCV seropositive with cleared HCV (38%) (P = 0.046). Total CD4⁺CD38⁺ and CD4⁺CD38⁺HLA-DR⁻ expression was significantly higher in HIV monoinfection (23% and 18%) than HCV moninfection (13%, P = 0.002% and 9%, P = 0.001, respectively). Interleukin 10 levels were significantly lower in HIV monoinfection versus HIV/HCV coinfection with CHC (P = 0.0002). In multivariate analysis, severe fibrosis was associated with lower expression of CD4⁺CD38⁺HLA-DR⁺ and CD4⁺ total CD38⁺ than mild-moderate fibrosis (P = 0.03 and 0.03, respectively). CONCLUSIONS CD4 immune activation with HLA-DR⁺ expression in HIV/HCV coinfection with well-controlled HIV may arise from chronic HCV viremia. Conversely, CD4⁺CD38⁺ expression may be driven by underlying HIV infection. CD4 immune activation was unexpectedly found to be associated with decreased liver fibrosis.
Collapse
|
|
16
|
The role of chemokines in acute and chronic hepatitis C infection. Cell Mol Immunol 2013; 11:25-40. [PMID: 23954947 DOI: 10.1038/cmi.2013.37] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/08/2013] [Accepted: 07/14/2013] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C imposes a significant burden on global healthcare. Chronic infection is associated with progressive inflammation of the liver which typically manifests in cirrhosis, organ failure and cancer. By virtue of elaborate evasion strategies, hepatitis C virus (HCV) succeeds as a persistent human virus. It has an extraordinary capacity to subvert the immune response enabling it to establish chronic infections and associated liver disease. Chemokines are low molecular weight chemotactic peptides that mediate the recruitment of inflammatory cells into tissues and back into the lymphatics and peripheral blood. Thus, they are central to the temporal and spatial distribution of effector and regulatory immune cells. The interactions between chemokines and their cognate receptors help shape the immune response and therefore, have a major influence on the outcome of infection. However, chemokines represent a target for modulation by viruses including the HCV. HCV is known to modulate chemokine expression in vitro and may therefore enable its survival by subverting the immune response in vivo through altered leukocyte chemotaxis resulting in impaired viral clearance and the establishment of chronic low-grade inflammation. In this review, the roles of chemokines in acute and chronic HCV infection are described with a particular emphasis placed on chemokine modulation as a means of immune subversion. We provide an in depth discussion of the part played by chemokines in mediating hepatic fibrosis while addressing the potential applications for these chemoattractants in prognostic medicine.
Collapse
|
|
17
|
Ghosh M, Solanki AK, Roy K, Dhoke RR, Ashish, Roy S. Carrier protein influences immunodominance of a known epitope: implication in peptide vaccine design. Vaccine 2013; 31:4682-8. [PMID: 23928464 DOI: 10.1016/j.vaccine.2013.06.110] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 06/10/2013] [Accepted: 06/14/2013] [Indexed: 11/29/2022]
Abstract
We investigated how the processing of a given antigen by antigen presenting cells (APC) is dictated by the conformation of the antigen and how this governs the immunodominance hierarchy. To address the question, a known immunodominant sequence of bacteriophage lambda repressor N-terminal sequence 12-26 [λR(12-26)] was engineered at the N and C termini of a heterologous leishmanial protein, Kinetoplastid membrane protein-11 (KMP-11); the resulting proteins were defined as N-KMP-11 and C-KMP-11 respectively. The presence of λR(12-26) in N-KMP-11 and C-KMP-11 was established by western blot analysis with antibody to λR(12-26) peptide. N-KMP-11 but not C-KMP-11 could stimulate the anti λR(12-26) T-cell clonal population very efficiently in the presence of APCs. Priming of BALB/c mice with N-KMP-11 or C-KMP-11 generated similar levels of anti-KMP-11 IgG, but anti-λR(12-26) specific IgG was observed only upon priming with N-KMP-11. Interestingly, uptake of both N-KMP-11 and C-KMP-11 by APCs was similar but catabolism of N-KMP-11 but not C-KMP-11 was biphasic and fast at the initial time point. Kratky plots of small angle X-ray scattering showed that while N-KMP-11 adopts flexible Gaussian type of topology, C-KMP-11 prefers Globular nature. To show that KMP-11 is not unique as a carrier protein, an epitope (SPITBTNLBTMBK) of Plasmodium yoelii (PY) apical membrane protein 1[AMA-1 (136-148)], is placed at the C and N terminals of a dominant T-cell epitope of ovalbumin protein OVA(323-339) and the resulting peptides are defined as PY-OVA and OVA-PY respectively. Interestingly, only OVA-PY could stimulate anti-OVA T-cells and produce IgG response upon priming of BALB/c mice with it. Thus for rational design of peptide vaccine it is important to place the dominant epitope appropriately in the context of the carrier protein.
Collapse
Affiliation(s)
- Moumita Ghosh
- Division of Infectious diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | | | | | | | | | | |
Collapse
|
|
18
|
|
|
19
|
Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, Sulkowski M, Marro SO, Anderson J, He B, Kansra V, McPhee F, Wind-Rotolo M, Grasela D, Selby M, Korman AJ, Lowy I. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One 2013; 8:e63818. [PMID: 23717490 PMCID: PMC3661719 DOI: 10.1371/journal.pone.0063818] [Citation(s) in RCA: 197] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 04/04/2013] [Indexed: 01/09/2023] Open
Abstract
UNLABELLED Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naïve and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted. TRIAL REGISTRATION ClinicalTrials.gov NCT00703469.
Collapse
|
|
20
|
Valva P, Casciato P, Lezama C, Galoppo M, Gadano A, Galdame O, Galoppo MC, Mullen E, De Matteo E, Preciado MV. Serum apoptosis markers related to liver damage in chronic hepatitis C: sFas as a marker of advanced fibrosis in children and adults while M30 of severe steatosis only in children. PLoS One 2013; 8:e53519. [PMID: 23326448 PMCID: PMC3543432 DOI: 10.1371/journal.pone.0053519] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 11/29/2012] [Indexed: 12/16/2022] Open
Abstract
Background Liver biopsy represents the gold standard for evaluating damage and progression in patients with chronic hepatitis C (CHC); however, developing noninvasive tests that can predict liver injury represents a growing medical need. Considering that hepatocyte apoptosis plays a role in CHC pathogenesis; the aim of our study was to evaluate the presence of different apoptosis markers that correlate with liver injury in a cohort of pediatric and adult patients with CHC. Methods Liver biopsies and concomitant serum samples from 22 pediatric and 22 adult patients with CHC were analyzed. Histological parameters were evaluated. In serum samples soluble Fas (sFas), caspase activity and caspase-generated neoepitope of the CK-18 proteolytic fragment (M30) were measured. Results sFas was associated with fibrosis severity in pediatric (significant fibrosis p = 0.03, advanced fibrosis p = 0.01) and adult patients (advanced fibrosis p = 0.02). M30 levels were elevated in pediatric patients with severe steatosis (p = 0.01) while in adults no relation with any histological variable was observed. Caspase activity levels were higher in pediatric samples with significant fibrosis (p = 0.03) and they were associated with hepatitis severity (p = 0.04) in adult patients. The diagnostic accuracy evaluation demonstrated only a good performance for sFas to evaluate advanced fibrosis both in children (AUROC: 0.812) and adults (AUROC: 0.800) as well as for M30 to determine steatosis severity in children (AUROC: 0.833). Conclusions Serum sFas could be considered a possible marker of advanced fibrosis both in pediatric and adult patient with CHC as well as M30 might be a good predictor of steatosis severity in children.
Collapse
Affiliation(s)
- Pamela Valva
- Laboratory of Molecular Biology, Pathology Division, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Zignego AL, Giannini C, Gragnani L, Piluso A, Fognani E. Hepatitis C virus infection in the immunocompromised host: a complex scenario with variable clinical impact. J Transl Med 2012; 10:158. [PMID: 22863056 PMCID: PMC3441205 DOI: 10.1186/1479-5876-10-158] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 07/11/2012] [Indexed: 02/07/2023] Open
Abstract
The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist.
Collapse
Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.
| | | | | | | | | |
Collapse
|
|
22
|
Vidalino L, Doria A, Quarta SM, Crescenzi M, Ruvoletto M, Frezzato F, Trentin L, Turato C, Parolin MC, Ghirardello A, Iaccarino L, Cavalletto L, Chemello L, Gatta A, Pontisso P. SERPINB3 expression on B-cell surface in autoimmune diseases and hepatitis C virus-related chronic liver infection. Exp Biol Med (Maywood) 2012; 237:793-802. [PMID: 22829702 DOI: 10.1258/ebm.2012.012024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
SERPINB3 is a serine protease inhibitor with pleiotropic functions. It is involved in several physiological and pathological processes, where it appears to exert antiapoptotic effects. Little is known about its expression on immune system cells, the major players in mechanisms of viral defense and autoimmune disorders. The aim of this study was to characterize the expression of SERPINB3 on the surface of peripheral blood mononuclear cell subsets in both normal subjects and in patients with chronic viral infections and autoimmune diseases. Sixty-two patients were analyzed by flow cytometric analysis, including 45 with hepatitis C virus (HCV)-related chronic liver disease and 17 with systemic lupus erythematosus (SLE). SERPINB3 was expressed on B lymphocytes in 79% of the controls, in 32% of the HCV-infected patients and in none of the SLE patients. Surface localization of SERPINB3 was confirmed by confocal microscopy. SERPINB3 positivity was associated with CD27 reactivity (r = 0.98), but not to other activation molecules (CD69, CD71, CD86 and CXCR3). SERPINB3 is physiologically expressed on the surface of CD27(+) B lymphocytes, but its expression is reduced in HCV viral infection and not detectable in SLE patients. These results may suggest a role for SERPINB3 in B-cell defects typically found in viral infections and autoimmune disorders.
Collapse
Affiliation(s)
- Laura Vidalino
- Department of Medicine, University of Padua, Via Giustiniani 2, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Tseng KC, Ho YC, Hsieh YH, Lai NS, Wen ZH, Li C, Wu SF. Elevated frequency and function of regulatory T cells in patients with active chronic hepatitis C. J Gastroenterol 2012; 47:823-33. [PMID: 22367277 DOI: 10.1007/s00535-012-0544-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 01/11/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Regulatory T cells (Tregs) play a pivotal role in the persistence of hepatitis C virus infection. The aim of this study was to evaluate the frequency and function of Tregs in patients with chronic hepatitis C (CHC). METHODS We enrolled 44 CHC patients with elevated alanine aminotransferase (ALT) levels (CH group), 13 CHC patients with persistent normal ALT levels (PNALT group), and 14 age-matched healthy subjects (HS group; controls). Tregs were identified as CD4+, CD25+, and forkhead box P3 (Foxp3)+ T lymphocytes, using three-color fluorescence-activated cell sorting (FACS). The frequency of Tregs was determined by calculating the percentage of CD4+CD25(high) T cells among CD4 T cells. CD127 and CD45RA were also analyzed for subsets of Tregs. The levels of serum transforming growth factor (TGF)-β and interleukin (IL)-10 in immunosuppressive assays were detected by enzyme-linked immunosorbent assay (ELISA). The immunosuppressive abilities of Tregs were evaluated by measuring their ability to inhibit the proliferation of effector cells. RESULTS Higher proportions of Tregs were found in the CH and PNALT groups compared with the HS group. The populations of CD127 low/negative and CD45RA negative cells were higher in the CH group than in the PNALT group. The expressions of IL-10 and TGF-β in the CH and PNALT groups were significantly higher than those in the HS group. In addition, the immunosuppressive ability of Tregs from the CH group was increased relative to that in the PNALT and the HS group. CONCLUSIONS CHC patients, irrespective of liver function, had higher frequencies of Tregs than healthy subjects; however, only CHC patients with inflammation showed enhanced immunosuppressive function of Tregs.
Collapse
Affiliation(s)
- Kuo-Chih Tseng
- Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Chia-Yi, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Villacres MC, Kono N, Mack WJ, Nowicki MJ, Anastos K, Augenbraun M, Liu C, Landay A, Greenblatt RM, Gange SJ, Levine AM. Interleukin 10 responses are associated with sustained CD4 T-cell counts in treated HIV infection. J Infect Dis 2012; 206:780-9. [PMID: 22693231 DOI: 10.1093/infdis/jis380] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non-AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART). METHODS A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2-4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation. RESULTS Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation. CONCLUSIONS Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
Collapse
Affiliation(s)
- Maria C Villacres
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Kanto T, Inoue M, Oze T, Miyazaki M, Sakakibara M, Kakita N, Matsubara T, Higashitani K, Hagiwara H, Iio S, Katayama K, Mita E, Kasahara A, Hiramatsu N, Takehara T, Hayashi N. Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients. J Gastroenterol 2012; 47:169-78. [PMID: 21947705 DOI: 10.1007/s00535-011-0466-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 08/03/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy. METHODS Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined. RESULTS Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR. CONCLUSIONS In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.
Collapse
Affiliation(s)
- Tatsuya Kanto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Spontaneous clearance of hepatitis C virus in vertically infected children. Eur J Pediatr 2012; 171:253-8. [PMID: 21735055 DOI: 10.1007/s00431-011-1517-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 06/09/2011] [Indexed: 02/08/2023]
Abstract
UNLABELLED Spontaneous viral clearance of hepatitis C virus (HCV) has been reported to occur in children with vertical HCV infection. However, factors which are associated with or predispose for clearance are largely unknown. In this case series we retrospectively analyzed laboratory parameters associated with spontaneous clearance of HCV in vertically infected children. The charts of six patients with documented spontaneous viral clearance by the age of 5 years were reviewed regarding clinical course, liver function tests (LFTs) and trend of HCV gene copy numbers. Spontaneous viral elimination was observed between the 25th and 52nd months of age. All patients had elevated LFTs, which peaked before 20 months of life. Peak LFT elevation was followed by normalization of LFTs and decline in viral load. These findings suggest that, in vertically HCV-infected children, a potent inflammatory response in the liver precedes viral clearance. Therefore, temporarily elevated LFTs, followed by a decline of viral load may be indicative of a near viral clearance in early childhood. CONCLUSION Further investigations regarding the development of optimal treatment algorithms should take into account factors, which are associated with possible spontaneous viral resolution, such as viral genotype, favourable host factors as well as direct and indirect parameters of antiviral immunity, and the individual course of viral replication.
Collapse
|
|
27
|
Tu Z, Hamalainen-Laanaya HK, Nishitani C, Kuroki Y, Crispe IN, Orloff MS. HCV core and NS3 proteins manipulate human blood-derived dendritic cell development and promote Th 17 differentiation. Int Immunol 2011; 24:97-106. [PMID: 22190574 DOI: 10.1093/intimm/dxr104] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) chronic infection is characterized by low-level or undetectable cellular immune response against HCV antigens. HCV proteins affect various intracellular events and modulate immune responses, although the mechanisms that mediate these effects are not fully understood. In this study, we examined the effect of HCV proteins on the differentiation of human peripheral blood monocytes to dendritic cells (DCs). The HCV core (HCVc) and non-structural 3 (NS3) proteins inhibited the expression of CD1a, CD1b and DC-SIGN during monocyte differentiation to DCs, while increasing some markers characteristic of macrophages (CD14 and HLA-DR) and also PD-L1 expression. Meanwhile, HCVc and NS3 could induce differentiating monocytes to secrete IL-10. However, anti-IL-10 mAb could not reverse HCVc and NS3 inhibition of monocyte differentiation into DCs. The HCVc and NS3 proteins increased IL-6 secretion both in immature and in fully differentiated DCs and also promoted CD4+ T-cell IL-17 production. Since T(h) 17 cells are active in many examples of immunopathology, these effects may contribute to HCV autoimmune responses in chronically infected patients.
Collapse
Affiliation(s)
- Zhengkun Tu
- Department of Surgery, Division of Solid Organ Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | | | | | | | | | | |
Collapse
|
|
28
|
Helle F, Duverlie G, Dubuisson J. The hepatitis C virus glycan shield and evasion of the humoral immune response. Viruses 2011; 3:1909-32. [PMID: 22069522 PMCID: PMC3205388 DOI: 10.3390/v3101909] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 09/28/2011] [Accepted: 10/01/2011] [Indexed: 12/14/2022] Open
Abstract
Despite the induction of effective immune responses, 80% of hepatitis C virus (HCV)-infected individuals progress from acute to chronic hepatitis. In contrast to the cellular immune response, the role of the humoral immune response in HCV clearance is still subject to debate. Indeed, HCV escapes neutralizing antibodies in chronically infected patients and reinfection has been described in human and chimpanzee. Studies of antibody-mediated HCV neutralization have long been hampered by the lack of cell-culture-derived virus and the absence of a small animal model. However, the development of surrogate models and recent progress in HCV propagation in vitro now enable robust neutralization assays to be performed. These advances are beginning to shed some light on the mechanisms of HCV neutralization. This review summarizes the current state of knowledge of the viral targets of anti-HCV-neutralizing antibodies and the mechanisms that enable HCV to evade the humoral immune response. The recent description of the HCV glycan shield that reduces the immunogenicity of envelope proteins and masks conserved neutralizing epitopes at their surface constitutes the major focus of this review.
Collapse
Affiliation(s)
- François Helle
- Laboratory of Virology, EA4294, Jules Verne University of Picardie, Amiens 80000, France; E-Mail:
| | - Gilles Duverlie
- Laboratory of Virology, EA4294, Jules Verne University of Picardie, Amiens 80000, France; E-Mail:
- Virology Department, Amiens University Hospital Center, South Hospital, Amiens 80000, France
| | - Jean Dubuisson
- Inserm U1019, CNRS UMR8204, Center for Infection and Immunity of Lille (CIIL), Institut Pasteur de Lille, Université Lille Nord de France, Lille 59021, France; E-Mail:
| |
Collapse
|
|
29
|
Abstract
The human immune system is under constant challenge from many viruses, some of which the body is successfully able to clear. Other viruses have evolved to escape the host immune responses and thus persist, leading to the development of chronic diseases. Dendritic cells are professional antigen-presenting cells that play a major role in both innate and adaptive immunity against different pathogens. This review focuses on the interaction of different chronic viruses with dendritic cells and the viruses' ability to exploit this critical cell type to their advantage so as to establish persistence within the host.
Collapse
Affiliation(s)
- Saifur Rahman
- Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | | | | |
Collapse
|
|
30
|
R753Q single-nucleotide polymorphism impairs toll-like receptor 2 recognition of hepatitis C virus core and nonstructural 3 proteins. Transplantation 2010; 89:811-5. [PMID: 20090572 DOI: 10.1097/tp.0b013e3181cbac18] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) core and nonstructural (NS) 3 proteins induce inflammation and immunity through a toll-like receptor (TLR) 2-dependent pathway. Individuals with the R753Q single-nucleotide polymorphism (SNP) in the TLR2 gene have increased the risk of allograft failure after liver transplantation for chronic hepatitis C. METHODS To test the hypothesis that R753Q SNP impairs TLR2 recognition of HCV proteins, a series of in vitro experiments were performed wherein stable clones of wild-type TLR2-deficient human embryonic kidney (HEK) 293 cells and HEK293 cells transfected with wild-type (HEK293-TLR2) or variant TLR2 genes (HEK293-TLR2-R753Q) were stimulated with HCV core and NS3 proteins. Cellular activation was assessed by nuclear factor-kappa B-driven luciferase activity, cytokine secretion, and gene upregulation. RESULTS Compared with TLR2-deficient HEK293 cells, HEK293-TLR2 cells had marked nuclear factor-kappa B-driven luciferase activity, had modest to marked upregulation in TLR2 signaling-associated genes, and secreted large quantities of interleukin-8 during exposure to HCV core and NS3 proteins. In contrast, HEK293-TLR2-R753Q cells did not respond to stimulation with HCV and behaved similarly like TLR2-deficient HEK293 cells. CONCLUSION R753Q SNP impairs TLR2-mediated immune recognition of HCV core and NS3 proteins. This biologic defect may account for the predisposition of patients to develop allograft failure after liver transplantation for chronic hepatitis C.
Collapse
|
|
31
|
Castellanos M, Cinza Z, Dorta Z, Veliz G, Vega H, Lorenzo I, Ojeda S, Dueñas-Carrera S, Alvarez-Lajonchere L, Martínez G, Ferrer E, Limonta M, Linares M, Ruiz O, Acevedo B, Torres D, Márquez G, Herrera L, Arús E. Immunization with a DNA vaccine candidate in chronic hepatitis C patients is safe, well tolerated and does not impair immune response induction after anti-hepatitis B vaccination. J Gene Med 2010; 12:107-16. [PMID: 19866482 DOI: 10.1002/jgm.1407] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND In the present study, we evaluated the safety of CIGB-230, a novel vaccine candidate based on the mixture of a plasmid for DNA immunization, expressing hepatitis C virus (HCV) structural antigens, with a recombinant HCV Core protein. METHODS Fifteen HCV chronically-infected volunteers with detectable levels of HCV RNA genotype 1b, who were nonresponders to previous treatment with interferon plus ribavirin, were intramuscularly injected with CIGB-230 on weeks 0, 4, 8, 12, 16 and 20. Individuals were also immunized at weeks 28, 32 and 36 with a recombinant vaccine against hepatitis B. Adverse events were recorded and analyzed. Blood samples were taken every 4 weeks up to month 12 for hematological, biochemical, virological and immunological analysis. RESULTS All patients completed the treatment with CIGB-230. Adverse events were only slight (83.6%) or moderate (16.4%). No significant differences in hematological and biochemical parameters, including serum aminotransferases, were detected between the baseline and post-treatment state. Induction of a CD4+ T lymphocyte response against a particular region in HCV E1, spanning amino acids 230-312 in HCV polyprotein, was detected in 42.8% of patients during treatment with CIGB-230. The ability of T cells to proliferate in response to mitogenic stimulation was not weakened. Most individuals (78.6%) were seroprotected after anti-hepatitis B vaccination and 42.8% were hyper-responders (antibody titers > 100 UI/ml). No anti-mitochondrial, anti-nuclear and anti-extractable nuclear antigen antibodies were generated during immunization with CIGB-230. CONCLUSIONS Vaccination with CIGB-230 in HCV chronically-infected individuals was safe, well tolerated and did not impair the ability to respond to non-HCV antigens.
Collapse
|
|
32
|
Salem ML, El-Demellawy M, El-Azm ARA. The potential use of Toll-like receptor agonists to restore the dysfunctional immunity induced by hepatitis C virus. Cell Immunol 2010; 262:96-104. [PMID: 20338549 DOI: 10.1016/j.cellimm.2010.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Accepted: 03/02/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a major public health concern with approximately 3% of the world's population is infected, posing social, economical and health burden. Less than 20% of the infected individuals clear the virus during the acute infection, while the rest develop chronic infection. The treatment of choice for HCV infection is pegylated interferon-alpha (IFN-alpha) in combination with ribavarin. Despite the cost and side effects of this treatment regimen, many patients fail this therapy and develop persistent HCV infection, leading to cirrhosis and hepatocellular carcinoma. Although the mechanisms underlying the failure to resolve HCV infection are poorly understood, the incapability of patients to develop effective anti-HCV immunity is a potential cause. We hypothesize that the dysfunctional anti-HCV immunity is due to the emergence of immunosuppressive cells coinciding with a decrease in the stimulatory dendritic cells (DCs) and natural killer (NK) cells. We further hypothesize that applying agents that can correct the imbalance between the immunosuppressive cells and stimulatory cells can results in resolution of chronic HCV. In this review article, we will discuss potential approaches, focusing on the use of Toll-like receptor agonists, to block the suppressive effects of the regulatory cells and restore the stimulatory effects of DCs and NK cells.
Collapse
MESH Headings
- Adjuvants, Immunologic/therapeutic use
- Antiviral Agents/therapeutic use
- Dendritic Cells/immunology
- Enzyme Inhibitors/therapeutic use
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Immunity, Innate
- Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
- Interferon-alpha/therapeutic use
- Killer Cells, Natural/immunology
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Ribavirin/therapeutic use
- T-Lymphocytes, Regulatory/immunology
- Toll-Like Receptors/agonists
- Toll-Like Receptors/immunology
Collapse
Affiliation(s)
- Mohamed L Salem
- Surgery Department and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
| | | | | |
Collapse
|
|
33
|
Short-Term Administration of the CCR5 Antagonist Vicriviroc to Patients With HIV and HCV Coinfection Is Safe and Tolerable. J Acquir Immune Defic Syndr 2010; 53:78-85. [DOI: 10.1097/qai.0b013e3181bb28dc] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
34
|
Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat 2009; 16:883-94. [PMID: 19566789 DOI: 10.1111/j.1365-2893.2009.01144.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatitis D virus (HDV) or delta hepatitis has mainly been studied in Asian and Mediterranean cohorts, but data on virological and clinical characteristics of HDV-infected Central and Northern European patients are limited. We investigated virological patterns, as well as biochemical and clinical features of liver disease in 258 HDV infected patients recruited over a period of 15 years at Hannover Medical School. Virological parameters were compared to 2083 anti-HDV negative hepatitis B surface antigen (HBsAg) positive individuals. In this cohort, (i) HDV infection was associated with both suppressed hepatitis B virus (HBV) and hepatitis C virus (HCV) replication, (ii) the suppression of HBV-DNA and HCV-RNA was not related to HDV-RNA replication, (iii) mean HBsAg levels did not significantly differ between HBV-monoinfected patients and individuals with delta hepatitis, (iv) HCV coinfection was rather frequent as about one third of our delta hepatitis patients tested anti-HCV positive, however, without being associated with more advanced liver disease, (v) delta hepatitis patients presented in a high frequency with an advanced stage of liver disease, and (vi) the course of delta hepatitis did not differ between Turkish-born, Eastern European (EE)-born and German-born patients. In summary, in this cohort of patients which is the largest so far Central European single centre group of delta hepatitis patients, we confirm the presence of frequently severe disease and describe novel virological profiles which require consideration in the management of this difficult to treat group of patients.
Collapse
Affiliation(s)
- B Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | | | | | | | | |
Collapse
|
|
35
|
Castello G, Scala S, Palmieri G, Curley SA, Izzo F. HCV-related hepatocellular carcinoma: From chronic inflammation to cancer. Clin Immunol 2009; 134:237-50. [PMID: 19910258 DOI: 10.1016/j.clim.2009.10.007] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2009] [Revised: 10/16/2009] [Accepted: 10/16/2009] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem because of its incidence and pathogenicity. It might evolve into chronic disease, cirrhosis, and/or hepatocellular carcinoma (HCC) and the outcome is mainly determined by the host immune response. For viral clearance, combined innate and adaptive immune responses are required; resolution requires a vigorous, durable, polyclonal CD4(+) and CD8(+) T-cell response, with an increase in virus-specific CD8(+) T cells or cytotoxic T lymphocytes. Failure of efficient immune response can lead to chronic inflammation, tissue remodeling through cell growth, apoptosis and/or necrosis and induction of oxidative stress. Development of fibrosis and/or cirrhosis plus a microenvironment conducive to genomic instability mutations will promote neoplastic transformation. System governance derives from cellular (regulatory cells) and humoral (cytokines and chemokines) immune networks. Therefore, HCC pathogenesis may be a model to study the disease progression from chronic inflammation to cancer allowing design of new strategies targeting the immune response, thereby modifying disease outcome.
Collapse
|
|
36
|
Márquez M, Fernández-Gutiérrez C, Montes-de-Oca M, Blanco MJ, Brun F, Rodríguez-Ramos C, Girón-González JA. Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. Clin Exp Immunol 2009; 158:219-29. [PMID: 19737142 DOI: 10.1111/j.1365-2249.2009.04005.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The objectives of this work were the analysis of the functional characteristics of circulating monocytes and T lymphocytes in patients with liver cirrhosis, and evaluation of the relationship with an increased exposure to antigens due to bacterial translocation. Forty patients with liver cirrhosis (20 with compensated cirrhosis and 20 with ascitic decompensation) and 20 healthy control subjects were studied. Bacterial translocation was evaluated by serum levels of lipopolysaccharide binding protein (LBP). Macrophage activation was studied by CD40 antigen expression. T lymphocytes were analysed for activation (CD25(+), CD122(+)), effector function (CD8(+)CD45RO(+)CD57(+)), apoptosis (CD95(+)) and regulatory abilities, either by analysis of the membrane expression of co-stimulatory molecules CD80, CD86 and CD28, or by quantification of regulatory T cells CD4(+)CD25(high)forkhead box P3 (FoxP3). The percentage of activated monocytes and T lymphocytes in patients was increased significantly. The proportions of effector senescent cells and of those near to apoptosis were also significantly higher. With respect to these proportions, there were no significant differences between patients in function of the presence or absence of decompensation or in function of the increased or normal values of LBP. Conversely, those patients with elevated levels of LBP presented a significantly higher frequency of regulatory T cells than those with normal levels. In conclusion, patients with liver cirrhosis showed an intensive activation state with a higher percentage of cells committed to activation-induced death, even in non-advanced stages. It is possible that bacterial permeability and endotoxaemia contribute to the expansion of those lymphocyte populations implicated in the prevention of a more severe antigen-induced immunopathology.
Collapse
Affiliation(s)
- M Márquez
- Infectious Diseases Units, Internal Medicine, Hospital Universitario Puerta del Mar, Cadiz, Spain
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Kottilil S, Yan MY, Reitano KN, Zhang X, Lempicki R, Roby G, Daucher M, Yang J, Cortez KJ, Ghany M, Polis MA, Fauci AS. Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells. Hepatology 2009; 50:34-45. [PMID: 19551908 PMCID: PMC2736098 DOI: 10.1002/hep.23055] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
UNLABELLED Coinfection with hepatitis C virus (HCV) is present in one-third of all human immunodeficiency virus (HIV)-infected individuals in the United States and is associated with rapid progression of liver fibrosis and poor response to pegylated interferon (IFN) and ribavirin. In this study we examined gene expression profiles in peripheral blood mononuclear cells (PBMCs) from different groups of individuals who are monoinfected or coinfected with HIV and HCV. Data showed that HIV and HCV viremia up-regulate genes associated with immune activation and immunoregulatory pathways. HCV viremia is also associated with abnormalities in all peripheral immune cells, suggesting a global effect of HCV on the immune system. Interferon-alpha-induced genes were expressed at a higher level in PBMCs from HIV-infected individuals. HCV and HIV infections leave distinct profiles or gene expression of immune activation in PBMCs. HIV viremia induces an immune activated state; by comparison, HCV infection induces immunoregulatory and proinflammatory pathways that may contribute to progression of liver fibrosis. CONCLUSION An aberrant type-I IFN response seen exclusively in HIV-infected individuals could be responsible for the poor therapeutic response experienced by HIV/HCV coinfected individuals receiving interferon-alpha-based current standard of care.
Collapse
Affiliation(s)
- Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Meier V, Ramadori G. Hepatitis C virus virology and new treatment targets. Expert Rev Anti Infect Ther 2009; 7:329-50. [PMID: 19344246 DOI: 10.1586/eri.09.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease. An estimated 130 million people worldwide are persistently infected with HCV. Almost half of patients who have chronic HCV infection cannot be cured with the standard treatment consisting of pegylated IFN-alpha and ribavirin. For those patients who do not respond to this standard antiviral therapy, there is currently no approved treatment option available. Recent progress in structure determination of HCV proteins and development of a subgenomic replicon system enables the development of a specifically targeted antiviral therapy for hepatitis C. Many HCV-specific compounds are now under investigation in preclinical and clinical trials.
Collapse
Affiliation(s)
- Volker Meier
- Universitätsmedizin Göttingen, Abteilung für Gastroenterologie und Endokrinologie, Göttingen, Germany
| | | |
Collapse
|
|
39
|
Affiliation(s)
- Mathis Heydtmann
- Liver Research Laboratories, Institute for Biomedical Research, Birmingham University, Birmingham B15 2TT, United Kingdom.
| |
Collapse
|
|
40
|
Osna NA. Hepatitis C virus and ethanol alter antigen presentation in liver cells. World J Gastroenterol 2009; 15:1201-1208. [PMID: 19291820 PMCID: PMC2658850 DOI: 10.3748/wjg.15.1201] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2008] [Revised: 01/14/2009] [Accepted: 01/21/2009] [Indexed: 02/06/2023] Open
Abstract
Alcoholic patients have a high incidence of hepatitis C virus (HCV) infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV-induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex (MHC) class I- and class II-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class I and class II in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine profile to the suppressive phenotype of interleukin-10 (IL-10) and transforming growth factor beta (TGFbeta) predominance, preventing cell maturation and allostimulation capacity. The synergistic action of ethanol with HCV results in the suppression of MHC class II-restricted antigen presentation. In addition, ethanol metabolism and HCV proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class I-restricted antigen presentation. Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics.
Collapse
|
|
41
|
Carpentier A, Conti F, Carrière M, Aoudjehane L, Miroux C, Moralès O, Calmus Y, Groux H, Auriault C, Pancré V, Delhem N, Podevin P. Analysis of gene transcription in sera during chronic hepatitis C infection. J Med Virol 2009; 81:473-80. [PMID: 19152403 DOI: 10.1002/jmv.21398] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Alternative, non-invasive techniques are necessary to monitor the progression of liver disease during chronic hepatitis C. Firstly, because serum is the most accessible material for studies using qPCR in microplates, gene transcription was compared in 219 selected genes involved in the pathogenesis of hepatitis C virus (HCV) infection between sera, PBMCs and liver samples collected simultaneously from five patients infected chronically. Secondly, using sera, gene profiles were compared between HCV-infected patients (n = 10) and healthy controls (n = 10). In addition, the influence of alcohol intake was examined in patients infected with HCV genotype-1. Firstly, amplifiable mRNAs were obtained in all samples. After amplification, significant correlations were observed between: liver versus serum; liver versus PBMCs; and serum versus PBMCs (r(2) = 0.37, r(2) = 0.54, r(2) = 0.49, respectively). A comparison of gene transcription by gene involved in T- and B-cell markers, adhesion molecules, apoptosis, liver matrix turnover and inflammation, revealed comparable, significant correlations between serum and liver, (r(2) = 0.30, r(2) = 0.60, r(2) = 0.51, r(2) = 0.51, r(2) = 0.26, and r(2) = 0.61 respectively). Secondly, a quantitative analysis of gene expression in sera between genotype-1b-infected patients and healthy controls revealed that 41 genes involved closely in T-cell activation and apoptosis were over-expressed significantly in patients infected with HCV. In these patients, alcohol consumption was associated with an increased expression of six genes involved in the inflammatory response, together with a decrease of genes associated with dendritic cell function. It is concluded that in patients infected with HCV, serum can be used to evaluate expression of liver genes. Further prospective studies are clearly needed to validate the initial results and to define the relevant genes.
Collapse
|
|
42
|
Weaver JM, Sant AJ. Understanding the focused CD4 T cell response to antigen and pathogenic organisms. Immunol Res 2009; 45:123-43. [PMID: 19198764 DOI: 10.1007/s12026-009-8095-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Immunodominance is a term that reflects the final, very limited peptide specificity of T cells that are elicited during an immune response. Recent experiments in our laboratory compel us to propose a new paradigm for the control of immunodominance in CD4 T cell responses, stating that immunodominance is peptide-intrinsic and is dictated by the off-rate of peptides from MHC class II molecules. Our studies have revealed that persistence of peptide:class II complexes both predicts and controls CD4 T cell immunodominance and that this parameter can be rationally manipulated to either promote or eliminate immune responses. Mechanistically, we have determined that DM editing in APC is a key event that is influenced by the kinetic stability of class II:peptide complexes and that differential persistence of complexes also impacts the expansion phase of the immune response. These studies have important implications for rational vaccine design and for understanding the immunological mechanisms that limit the specificity of CD4 T cell responses.
Collapse
Affiliation(s)
- Jason M Weaver
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, NY 14642, USA
| | | |
Collapse
|
|
43
|
HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 2009; 5:e1000291. [PMID: 19242562 PMCID: PMC2647842 DOI: 10.1371/journal.ppat.1000291] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Accepted: 01/08/2009] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress-mediated apoptosis CHOP was not. We found that overall levels of NF-kappaB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-kappaB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-kappaB and BCL-xL, thus sensitizing hepatocytes to apoptosis.
Collapse
|
|
44
|
Weaver JM, Lazarski CA, Richards KA, Chaves FA, Jenks SA, Menges PR, Sant AJ. Immunodominance of CD4 T cells to foreign antigens is peptide intrinsic and independent of molecular context: implications for vaccine design. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:3039-48. [PMID: 18713974 PMCID: PMC2814425 DOI: 10.4049/jimmunol.181.5.3039] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Immunodominance refers to the restricted peptide specificity of T cells that are detectable after an adaptive immune response. For CD4 T cells, many of the mechanisms used to explain this selectivity suggest that events related to Ag processing play a major role in determining a peptide's ability to recruit CD4 T cells. Implicit in these models is the prediction that the molecular context in which an antigenic peptide is contained will impact significantly on its immunodominance. In this study, we present evidence that the selectivity of CD4 T cell responses to peptides contained within protein Ags is not detectably influenced by the location of the peptide in a given protein or the primary sequence of the protein that bears the test peptide. We have used molecular approaches to change the location of peptides within complex protein Ags and to change the flanking sequences that border the peptide epitope to now include a protease site, and find that immunodominance or crypticity of a peptide observed in its native protein context is preserved. Collectively, these results suggest immunodominance of peptides contained in complex Ags is due to an intrinsic factor of the peptide, based upon the affinity of that peptide for MHC class II molecules. These findings are discussed with regard to implications for vaccine design.
Collapse
Affiliation(s)
- Jason M. Weaver
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Christopher A. Lazarski
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Katherine A. Richards
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Francisco A. Chaves
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Scott A. Jenks
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Paula R. Menges
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| | - Andrea J. Sant
- David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642
| |
Collapse
|
|
45
|
Cooper CL, Ahluwalia NK, Efler SM, Vollmer J, Krieg AM, Davis HL. Immunostimulatory effects of three classes of CpG oligodeoxynucleotides on PBMC from HCV chronic carriers. JOURNAL OF IMMUNE BASED THERAPIES AND VACCINES 2008; 6:3. [PMID: 18541039 PMCID: PMC2430961 DOI: 10.1186/1476-8518-6-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2008] [Accepted: 06/09/2008] [Indexed: 01/15/2023]
Abstract
Background Chronic hepatitis C virus (HCV) infection results from weak or absent T cell responses. Pegylated-interferon-alpha (IFN-α) and ribavirin, the standard of care for chronic HCV, have numerous immune effects but are not potent T cell activators. A potent immune activator such as TLR9 agonist CpG oligodeoxynucleotide (CpG) may complement current treatment approaches. Methods Peripheral blood mononuclear cells (PBMC) obtained from HCV chronic carriers who failed previous treatment and from healthy donors were incubated in vitro with the three main CpG classes (A, B or C), recombinant IFN-α-2b (IntronA) and/or ribavirin. Proliferation and cytokine secretion (IFN-α, IL-10 and IP-10) were evaluated. Results CpG induced proliferation and cytokine secretion in patterns expected for each CpG class with similar group means for HCV and healthy donors. IntronA and ribavirin, alone or together, had no detectable effects. IntronA and C-Class CpG together induced more IFN-α than CpG alone in most subjects. IFN-α secretion was proportional to the number of plasmacytoid dendritic cells in PBMC from healthy donors but not HCV donors in whom responses were highly heterogeneous. Conclusion The strong immune stimulatory effect of CpG on PBMC isolated from treatment-failed HCV patients suggests possible utility alone or in combination with current HCV antiviral treatment.
Collapse
|
|
46
|
Hepatitis C virus inhibits cell surface expression of HLA-DR, prevents dendritic cell maturation, and induces interleukin-10 production. J Virol 2008; 82:3320-8. [PMID: 18216090 DOI: 10.1128/jvi.02547-07] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatitis C virus (HCV) chronic infection is characterized by low-level or undetectable cellular immune responses against HCV antigens. HCV proteins have been shown to affect various intracellular events and modulate immune responses, although the precise mechanisms used to mediate these effects are not fully understood. In this study, we have examined the effect of HCV proteins on the modulation of major histocompatibility complex (MHC) class II expression and other functions important for antigen presentation in humans. Expression of an HCV(1-2962) genomic clone (HCV-FL) in human fibrosarcoma cells (HT1080) inhibited gamma interferon (IFN-gamma)-induced upregulation of human leukocyte antigen-DR (HLA-DR) cell surface expression. Furthermore, inhibition of promoter activities of MHC class II transactivator (CIITA), IFN-gamma-activated site (GAS), and HLA-DR was observed in IFN-gamma-inducible HT1080 cells expressing HCV-FL by in vitro reporter assays. Exposure of human monocyte-derived dendritic cells (DCs) to cell culture-grown HCV (HCVcc) genotype 1a (clone H77) or 2a (clone JFH1) significantly inhibited DC maturation and was associated with the production of IL-10. Furthermore, DCs exposed to HCVcc were impaired in their functional ability to stimulate antigen-specific CD4-positive (CD4(+)) and CD8(+) T-cell responses. Taken together, our results indicated that HCV can have direct and/or indirect inhibitory effects on antigen-presenting cells, resulting in reduction of antigen-specific T-cell activation. These effects may account for or contribute to the low overall level of immunogenicity of HCV observed in chronically infected patients.
Collapse
|
|
47
|
Kanto T, Hayashi N. Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells. Hepatol Res 2007; 37 Suppl 3:S319-26. [PMID: 17931181 DOI: 10.1111/j.1872-034x.2007.00236.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sequential activation of innate and adaptive immune response is crucial for virus elimination. We thus sought to clarify the role of innate immune system in the pathogenesis of hepatitis C virus (HCV) infection. Dendritic cells (DC) sense virus infection via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I), resulting in the secretion of type-I interferons (IFN) and inflammatory cytokines. Blood DC consist of two subsets; myeloid DC (MDC) and plasmacytoid DC (PDC). In MDC from HCV-infected patients, regardless of higher expression of TLR2, TLR4 and RIG-I compared to the controls, the levels of TLR/RIG-I-mediated IFN-beta or TNF-alpha induction are lower than those in uninfected donors. These results suggest that the signal transduction in the downstream of TLR/RIG-I in MDC is profoundly impaired in HCV infection. In response to IFN-alpha, DC are able to express MHC class-I related chain A/B (MICA/B) and activate natural killer (NK) cells following ligation of NKG2D. Interestingly, DC from HCV-infected patients are unresponsive to exogenous IFN-alpha to enhance MICA/B expression and fail to activate NK cells. Alternatively, NK cells from HCV-infected patients downregulate DC functions in the presence of human leukocyte antigen E-expressing hepatocytes by secreting interleukin (IL)-10 and transforming growth factor-beta1. Such functional alteration of NK cells in HCV infection is ascribed to the enhanced expression of inhibitory receptor NKG2A/CD94 compared to the healthy counterparts. Invariant NKT cells activated by CD1d-positive DC secrete both T-helper (Th)1 and Th2 cytokines, serving as immune regulators. The frequency of NKT cells in chronic HCV infection does not differ from those in healthy donors. Activated NKT cells produce higher levels of IL-13 but comparable levels of IFN-gamma with those from healthy subjects, showing that NKT cells are biased to Th2-type in chronic HCV infection. In conclusion, cross-talks among DC, NK cells and NKT cells are critical in shaping subsequent adaptive immune response against HCV.
Collapse
Affiliation(s)
- Tatsuya Kanto
- Department of Gastroenterology and Hepatology and Department of Dendritic Cell Biology and Clinical Applications, Osaka University Graduate School of Medicine, Osaka, Japan
| | | |
Collapse
|
|
48
|
Helle F, Goffard A, Morel V, Duverlie G, McKeating J, Keck ZY, Foung S, Penin F, Dubuisson J, Voisset C. The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein. J Virol 2007; 81:8101-11. [PMID: 17522218 PMCID: PMC1951279 DOI: 10.1128/jvi.00127-07] [Citation(s) in RCA: 170] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2007] [Accepted: 05/13/2007] [Indexed: 12/27/2022] Open
Abstract
Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with up to 5 and 11 N-linked glycans on E1 and E2, respectively. Most of the glycosylation sites on HCV envelope glycoproteins are conserved, and some of the glycans associated with these proteins have been shown to play an essential role in protein folding and HCV entry. Such a high level of glycosylation suggests that these glycans can limit the immunogenicity of HCV envelope proteins and restrict the binding of some antibodies to their epitopes. Here, we investigated whether these glycans can modulate the neutralizing activity of anti-HCV antibodies. HCV pseudoparticles (HCVpp) bearing wild-type glycoproteins or mutants at individual glycosylation sites were evaluated for their sensitivity to neutralization by antibodies from the sera of infected patients and anti-E2 monoclonal antibodies. While we did not find any evidence that N-linked glycans of E1 contribute to the masking of neutralizing epitopes, our data demonstrate that at least three glycans on E2 (denoted E2N1, E2N6, and E2N11) reduce the sensitivity of HCVpp to antibody neutralization. Importantly, these three glycans also reduced the access of CD81 to its E2 binding site, as shown by using a soluble form of the extracellular loop of CD81 in inhibition of entry. These data suggest that glycans E2N1, E2N6, and E2N11 are close to the binding site of CD81 and modulate both CD81 and neutralizing antibody binding to E2. In conclusion, this work indicates that HCV glycans contribute to the evasion of HCV from the humoral immune response.
Collapse
Affiliation(s)
- François Helle
- Institut de Biologie de Lille (UMR8161), CNRS, Université Lille I and II and Institut Pasteur de Lille, Lille, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Fan Z, Huang XL, Kalinski P, Young S, Rinaldo CR. Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2007; 14:1127-37. [PMID: 17634507 PMCID: PMC2043301 DOI: 10.1128/cvi.00141-07] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection can persist despite HCV-specific T-cell immunity and can have a more aggressive course in persons coinfected with human immunodeficiency virus type 1 (HIV-1). Defects in antigen-presenting, myeloid dendritic cells (DCs) could underlie this T-cell dysfunction. Here we show that monocyte-derived DCs from persons with chronic HCV infection, with or without HIV-1 coinfection, being treated with combination antiretroviral therapy produced lower levels of interleukin 12 (IL-12) p70 in response to CD40 ligand (CD40L), whereas the expression of DC surface activation and costimulatory molecules was unimpaired. The deficiency in IL-12 production could be overcome by addition of gamma interferon (IFN-gamma) with CD40L, resulting in very high, comparable levels of IL-12 production by DCs from HCV- and HIV-1-infected subjects. Smaller amounts of IL-12 p70 were produced by DCs treated with the immune modulators tumor necrosis factor alpha and IL-1beta, with or without IFN-gamma, and the amounts did not differ among the uninfected and infected subjects. Blocking of IL-10 with an anti-IL-10 monoclonal antibody in the CD40L-stimulated DC cultures from HCV-infected persons increased the level of IL-12 p70 production. The ability of DCs from HCV-infected persons to stimulate allogeneic CD4+ T cells or induce IL-2, IL-5, or IL-10 in a mixed lymphocyte reaction was not impaired. Thus, myeloid DCs derived from persons with chronic HCV infection or with both HCV and HIV-1 infections have defects in IL-12 p70 production related to IL-10 activity that can be overcome by treatment of the DCs with CD40L and IFN-gamma. DCs from these infected subjects have a normal capacity to stimulate CD4+ T cells. The functional effectiveness of DCs derived from HCV-infected individuals provides a rationale for the DC-based immunotherapy of chronic HCV infection.
Collapse
Affiliation(s)
- Zheng Fan
- Graduate School of Public Health and School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | | | | | | | | |
Collapse
|
|
50
|
Golden-Mason L, Castelblanco N, O'Farrelly C, Rosen HR. Phenotypic and functional changes of cytotoxic CD56pos natural T cells determine outcome of acute hepatitis C virus infection. J Virol 2007; 81:9292-8. [PMID: 17553896 PMCID: PMC1951454 DOI: 10.1128/jvi.00834-07] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Innate CD56(pos) natural killer (NK) and natural T (NT) cells comprise important hepatic antiviral effector lymphocytes whose activity is fine-tuned through surface NK receptors (NKRs). Dysregulation of NKRs in patients with long-standing hepatitis C virus (HCV) infection has been shown, but little is known regarding NKRs in acute infection. Treatment-naïve patients with acute HCV (n = 22), including 10 with spontaneous recovery, were prospectively studied. CD56(pos) NT levels were reduced early in acute HCV infection and did not fluctuate over time. In resolving HCV infection, NT cells with a more activated phenotype (lower CD158A and higher natural cytotoxicity receptor expression) at baseline predated spontaneous recovery. Moreover, NKG2A expression on CD56(+) NT cells correlated directly with circulating HCV RNA levels. Deficient interleukin-13 (IL-13) production by NT cells and reduced IL-2-activated killing (LAK) at baseline were associated with the ultimate development of persistence. These results indicate a previously unappreciated role for NT cells in acute HCV infection and identify a potential target for pharmacologic manipulation.
Collapse
Affiliation(s)
- Lucy Golden-Mason
- Division of Gastroenterology and Hepatology, Hepatitis C Center, University of Colorado at Denver Health Sciences Center, and National Jewish Hospital, Denver, Colorado, USA
| | | | | | | |
Collapse
|