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Martín-Escolano R, Vidal-Alcántara EJ, Crespo J, Ryan P, Real LM, Lazo-Álvarez JI, Cabezas-González J, Macías J, Arias-Loste MT, Cuevas G, Virseda-Berdices A, Briz V, Resino S, Jiménez-Sousa MÁ, Fernández-Rodríguez A. Immunological and senescence biomarker profiles in patients after spontaneous clearance of hepatitis C virus: gender implications for long-term health risk. Immun Ageing 2023; 20:62. [PMID: 37978401 PMCID: PMC10655350 DOI: 10.1186/s12979-023-00387-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND About 25% of patients with acute hepatitis C virus (HCV) infection show spontaneous clearance within the first six months of infection but may remain at risk of inflammaging, aging, and liver and non-liver disease complications. This study evaluated the differences in the plasma levels of immune checkpoints (ICs) and senescence-associated secretory phenotype (SASP) biomarkers between patients who had spontaneously eliminated HCV infection (SC group) and individuals without evidence of HCV infection (C group). METHODS We performed a multicenter retrospective study of 56 individuals: 32 in the SC and 24 in the C groups. ICs and SASP proteins were analyzed using a Luminex 200TM analyzer. The statistical analysis used Generalized Linear Models with gamma distribution (log-link) adjusted by significant variables and sex. RESULTS 13 ICs (BTLA, CD137(4-1BB), CD27, CD28, CD80, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, and TIM-3) and 13 SASP proteins (EGF, Eotaxin, IL-1alpha, IL-1RA, IL-8, IL-13, IL-18, IP-10, SDF-1alpha, HGF, beta-NGF, PLGF-1, and SCF) were significantly higher in SC group after approximately more than two years of HCV clearance. After stratifying by sex, differences remained significant for males, which showed higher levels for 13 ICs and 4 SASP proteins in SC. While only PD-L2 was significantly higher in SC women, and no differences in SASP were found. CONCLUSIONS Higher plasma levels of different IC and SASP proteins were found in individuals after more than two years of HCV clearance, mainly in men. Alterations in these molecules might be associated with an increased risk of developing liver and non-hepatic diseases.
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Affiliation(s)
- Rubén Martín-Escolano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain
| | - Erick Joan Vidal-Alcántara
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Traslational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Pablo Ryan
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Internal Medicine Service, Hospital Universitario Infanta Leonor, Facultad de Medicina, Universidad Complutense de Madrid, Gregorio Marañón Health Research Institute, Madrid, Spain
| | - Luis Miguel Real
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen de Valme Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - Juan Ignacio Lazo-Álvarez
- Internal Medicine Service, Hospital Universitario Infanta Leonor, Facultad de Medicina, Universidad Complutense de Madrid, Gregorio Marañón Health Research Institute, Madrid, Spain
| | - Joaquín Cabezas-González
- Gastroenterology and Hepatology Department, Clinical and Traslational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Juan Macías
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen de Valme Facultad de Medicina, Universidad de Sevilla, Seville, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, Clinical and Traslational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Guillermo Cuevas
- Internal Medicine Service, Hospital Universitario Infanta Leonor, Facultad de Medicina, Universidad Complutense de Madrid, Gregorio Marañón Health Research Institute, Madrid, Spain
| | - Ana Virseda-Berdices
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Veronica Briz
- Laboratory of Reference and Research On Viral Hepatitis, National Center for Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, Madrid, Majadahonda, 28220, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal. Int J Mol Sci 2020; 21:ijms21207473. [PMID: 33050486 PMCID: PMC7589490 DOI: 10.3390/ijms21207473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.
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Hakim MS, Rahmadika N, Jariah ROA. Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy. Rev Med Virol 2019; 30:e2094. [DOI: 10.1002/rmv.2094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/06/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Mohamad S. Hakim
- Department of Microbiology, Faculty of Medicine, Public Health and NursingUniversitas Gadjah Mada Yogyakarta Indonesia
| | - Nofri Rahmadika
- Infectious Disease Research Center, Faculty of MedicineUniversitas Padjadjaran Bandung Indonesia
| | - Rizka O. A. Jariah
- Department of Health Science, Faculty of Vocational StudiesUniversitas Airlangga Surabaya Indonesia
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Lombardi A, Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharmacol Ther 2019; 50:872-884. [PMID: 31378985 DOI: 10.1111/apt.15449] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/21/2019] [Accepted: 07/13/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionised the oncological landscape in the last few years. Possible applications include the treatment of hepatocellular carcinoma and cholangiocarcinoma. Unfortunately, new immune-related adverse effects have been associated with the use of these agents and the liver is one of the organs most frequently involved. AIMS To provide a general overview of the potential impact of immune checkpoint inhibitors on the liver METHODS: We reviewed the literature and abstracts/presentations on immune checkpoint inhibitors at most relevant hepatology meetings over the last 5 years. RESULTS The role of immune checkpoint inhibitors has been investigated both for the treatment of viral hepatitis and primary liver cancer. Hepatocellular carcinoma and chronic hepatitis B show the greatest potential for treatment with these drugs in the near future. However, immune-related adverse events involving the liver are a growing concern related to their widespread use. CONCLUSIONS Immune checkpoint inhibitors represent an exciting new class of drugs with currently limited application in malignant and non-malignant liver disease. Caution must be exercised on the emergence of potentially severe immune adverse reactions.
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Affiliation(s)
- Andrea Lombardi
- Division of Infectious Diseases II and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Mario U Mondelli
- Division of Infectious Diseases II and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
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Dustin LB. Innate and Adaptive Immune Responses in Chronic HCV Infection. Curr Drug Targets 2018; 18:826-843. [PMID: 26302811 DOI: 10.2174/1389450116666150825110532] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) remains a public health problem of global importance, even in the era of potent directly-acting antiviral drugs. In this chapter, I discuss immune responses to acute and chronic HCV infection. The outcome of HCV infection is influenced by viral strategies that limit or delay the initiation of innate antiviral responses. This delay may enable HCV to establish widespread infection long before the host mounts effective T and B cell responses. HCV's genetic agility, resulting from its high rate of replication and its error prone replication mechanism, enables it to evade immune recognition. Adaptive immune responses fail to keep up with changing viral epitopes. Neutralizing antibody epitopes may be hidden by decoy structures, glycans, and lipoproteins. T cell responses fail due to changing epitope sequences and due to exhaustion, a phenomenon that may have evolved to limit immune-mediated pathology. Despite these difficulties, innate and adaptive immune mechanisms do impact HCV replication. Immune-mediated clearance of infection is possible, occurring in 20-50% of people who contract the disease. New developments raise hopes for effective immunological interventions to prevent or treat HCV infection.
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Affiliation(s)
- Lynn B Dustin
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom
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Abstract
PURPOSE The aim of this study is to investigate the T-lymphocyte subpopulation and expression of programmed cell death-1 (PD-1), toll-like receptor (TLR)3, TLR4, and interferon (INF)-γ to illustrate the relationship between hepatitis B e antigen (HBeAg) and persistent hepatitis B virus (HBV) infection. METHODS Blood was taken from normal subjects into anticoagulation tubes to separate peripheral blood mononuclear cells (PBMCs). The PBMCs were divided into four groups and cultured with various concentrations of HBeAg for 72 h. Changes in the T-cell subset were analyzed through cell counting by flow cytometry, and expression of TLR3, TLR4, and PD-1 was assessed by flow cytometry and Western blot. The concentration of IFN-γ was analyzed using enzyme-linked immunospot (ELISPOT) experiments. RESULTS PBMCs were stimulated with various concentrations of HBeAg for 72 h and assayed by flow cytometry to determine CD4+ and CD8+ cell counts. The relative frequencies of CD4+ and CD8+ subpopulations and the CD4+/CD8+ ratio decreased compared with the control group, and T-cell impairment was significantly associated with higher HBeAg load. TLR3, TLR4, and PD-1 protein expression was assessed using flow cytometry and Western blotting. Expression of TLR3, TLR4, and PD-1 increased with increasing concentration of HBeAg. ELISPOT experiments were used to determine the concentration of IFN-γ. IFN-γ production in treatment groups was lower than in the control group. Comparing IFN-γ production in treatment groups, IFN-γ production in PBMCs stimulated with high dose of HBeAg was lower than for those stimulated with low-dose HBeAg. CONCLUSIONS HBeAg can inhibit proliferation of lymphocytes, increase TLR3, TLR4, and PD-1 expression, and decrease IFN-γ production. This may be one of the molecular mechanisms of HBV immune tolerance.
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Sugden PB, Cameron B, Mina M, Lloyd AR. Protection against hepatitis C infection via NK cells in highly-exposed uninfected injecting drug users. J Hepatol 2014; 61:738-45. [PMID: 24845613 DOI: 10.1016/j.jhep.2014.05.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 04/17/2014] [Accepted: 05/06/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS HCV seroprevalence surveys in longstanding injecting drug users (IDUs) reveal a small minority who remain seronegative, with some exhibiting HCV-specific cellular immunity. This study aimed to characterise this immunity, assess associations with risk behaviours and protection against infection. METHODS A nested case-control series from a prospective cohort of seronegative IDUs was selected with incident cases (IN; n = 28) matched by demographics and risk behaviour to exposed uninfected (EU) subjects (n = 28). Samples were assayed for natural killer (NK) cell phenotypes and function, HCV-specific IFNγ in ELISpot, and HCV-specific CD4 T effector responses. IL28B and HLA-C/KIR2DL3 genotypes were tested. RESULTS Numbers of activated (CD69(+)) NK cells in the mature CD56(dim)CD16(+) subset, and cytotoxic (NKp30(+)) cells in the CD56(bright)CD16(+) subset were higher in the EU subjects (p = 0.040, p = 0.038 respectively). EU subjects had higher frequencies of interferon gamma (IFNγ) producing NK cells, and lower frequencies of CD107a expression (p = 0.003, p = 0.015 respectively). By contrast, the frequency, magnitude, and breadth of HCV-specific CD4 and CD8 T cell responses did not differ, nor did IL28B, HLA-C, or KIR2DL3 allele frequencies. CONCLUSIONS Sustained NK cell activation contributes to protection against HCV infection. HCV-specific cellular immunity is prevalent in EU subjects but does not appear to be protective.
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MESH Headings
- Adult
- Antigens, CD/immunology
- Antigens, Differentiation, T-Lymphocyte/immunology
- Drug Users/psychology
- Female
- Gene Expression Profiling
- Hepatitis C/etiology
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/prevention & control
- Humans
- Interferons
- Interleukins/genetics
- Interleukins/immunology
- Killer Cells, Natural/immunology
- Lectins, C-Type/immunology
- Lymphocyte Activation/immunology
- Male
- Natural Cytotoxicity Triggering Receptor 3/immunology
- Receptors, KIR2DL3/genetics
- Receptors, KIR2DL3/immunology
- Risk-Taking
- Substance Abuse, Intravenous/complications
- Substance Abuse, Intravenous/genetics
- Substance Abuse, Intravenous/immunology
- Substance Abuse, Intravenous/psychology
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Affiliation(s)
- Peter B Sugden
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Barbara Cameron
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.
| | - Michael Mina
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
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Dustin LB, Cashman SB, Laidlaw SM. Immune control and failure in HCV infection--tipping the balance. J Leukoc Biol 2014; 96:535-48. [PMID: 25015956 DOI: 10.1189/jlb.4ri0214-126r] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver. Whereas epitope evolution contributes to escape from T cell-mediated immunity, chronic high antigen load may also blunt the T cell response by activating exhaustion or tolerance mechanisms. The evasive maneuvers of HCV limit sterilizing humoral immunity through rapid evolution of decoy epitopes, epitope masking, stimulation of interfering antibodies, lipid shielding, and cell-to-cell spread. Whereas the majority of HCV infections progress to chronic hepatitis with persistent viremia, at least 20% of patients spontaneously clear the infection. Most of these are protected from reinfection, suggesting that protective immunity to HCV exists and that a prophylactic vaccine may be an achievable goal. It is therefore important that we understand the correlates of protective immunity and mechanisms of viral persistence.
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Affiliation(s)
- Lynn B Dustin
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Oxford, United Kingdom
| | - Siobhán B Cashman
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Oxford, United Kingdom
| | - Stephen M Laidlaw
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Oxford, United Kingdom
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Abdel-Hakeem MS, Shoukry NH. Protective immunity against hepatitis C: many shades of gray. Front Immunol 2014; 5:274. [PMID: 24982656 PMCID: PMC4058636 DOI: 10.3389/fimmu.2014.00274] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/27/2014] [Indexed: 12/11/2022] Open
Abstract
The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada ; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University , Cairo , Egypt
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada ; Département de Médecine, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada
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Larrubia JR, Moreno-Cubero E, Lokhande MU, García-Garzón S, Lázaro A, Miquel J, Perna C, Sanz-de-Villalobos E. Adaptive immune response during hepatitis C virus infection. World J Gastroenterol 2014; 20:3418-3430. [PMID: 24707125 PMCID: PMC3974509 DOI: 10.3748/wjg.v20.i13.3418] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 09/28/2013] [Accepted: 11/29/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.
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Local blockade of epithelial PDL-1 in the airways enhances T cell function and viral clearance during influenza virus infection. J Virol 2013; 87:12916-24. [PMID: 24067957 DOI: 10.1128/jvi.02423-13] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
In order to maintain the gas exchange function of the lung following influenza virus infection, a delicate orchestration of positive and negative regulatory pathways must be maintained to attain viral eradication while minimizing local inflammation. The programmed death receptor 1 ligand/programmed death receptor 1 (PDL-1/PD-1) pathway plays an important immunoregulatory role, particularly in the context of T cell function. Here, we have shown that influenza virus infection of primary airway epithelial cells strongly enhances PDL-1 expression and does so in an alpha interferon receptor (IFNAR) signaling-dependent manner. PD-1 is expressed primarily on effector T cells in the lung, compared to effector memory and central memory cells, and shortly after influenza virus infection, an increased number of PD-1(+) T cells are recruited to the airways. Using in vitro cocultures of airway epithelial cells and T cells and in vivo models of influenza virus infection, we have demonstrated that blockade of airway epithelial PDL-1 improves CD8 T cell function, defined by increased production of gamma interferon (IFN-γ) and granzyme B and expression of CD107ab. Furthermore, PDL-1 blockade in the airways served to accelerate influenza virus clearance and enhance infection recovery. Our findings suggest that local manipulation of the PDL-1/PD-1 axis in the airways may represent a therapeutic alternative during acute influenza virus infection.
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Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 2013; 110:15001-6. [PMID: 23980172 DOI: 10.1073/pnas.1312772110] [Citation(s) in RCA: 137] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.
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Bukh J. Animal models for the study of hepatitis C virus infection and related liver disease. Gastroenterology 2012; 142:1279-1287.e3. [PMID: 22537434 DOI: 10.1053/j.gastro.2012.02.016] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 02/09/2012] [Accepted: 02/15/2012] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) causes liver-related death in more than 300,000 people annually. Treatments for patients with chronic HCV are suboptimal, despite the introduction of directly acting antiviral agents. There is no vaccine that prevents HCV infection. Relevant animal models are important for HCV research and development of drugs and vaccines. Chimpanzees are the best model for studies of HCV infection and related innate and adaptive host immune responses. They can be used in immunogenicity and efficacy studies of HCV vaccines. The only small animal models of robust HCV infection are T- and B- cell deficient mice with human chimeric livers. Although these mice cannot be used in studies of adaptive immunity, they have provided new insights into HCV neutralization, interactions between virus and receptors, innate host responses, and therapeutic approaches. Recent progress in developing genetically humanized mice is exciting, but these models only permit studies of specific steps in the HCV life cycle and have limited or no viral replication.
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Affiliation(s)
- Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
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14
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Thimme R, Binder M, Bartenschlager R. Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol Rev 2012; 36:663-83. [PMID: 22142141 DOI: 10.1111/j.1574-6976.2011.00319.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/07/2011] [Accepted: 11/25/2011] [Indexed: 12/24/2022] Open
Affiliation(s)
- Robert Thimme
- Department of Medicine II, University Medical Center Freiburg, Freiburg, Germany
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15
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Bes M, Sauleda S, Casamitjana N, Piron M, Campos-Varela I, Quer J, Cubero M, Puig L, Guardia J, Esteban JI. Reversal of nonstructural protein 3-specific CD4(+) T cell dysfunction in patients with persistent hepatitis C virus infection. J Viral Hepat 2012; 19:283-94. [PMID: 22404727 DOI: 10.1111/j.1365-2893.2011.01549.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatitis C virus (HCV)-specific T cell responses are essential for HCV control, and chronic infection is characterized by functionally altered antigen-specific T cells. It has been proposed that the early inactivation of specific CD4(+) T cell responses may be involved in establishment of HCV persistence. We have investigated whether HCV-specific CD4(+) T cells dysfunction can be reversed in vitro. Nonstructural protein 3 (NS3) and core-specific CD4(+) T cells from eight chronically infected and eight spontaneously resolved HCV individuals were selected through transient CD154 (CD40 ligand) expression, and their functional profile (IFN-γ, IL-2, TNF-α, IL-10 and IL-4 production by enzyme-linked immunospot assay, cytometric bead array and intracellular cytokine staining, and proliferation by carboxy-fluorescein diacetate succinimidyl ester dilution assay) was determined both ex vivo and after in vitro expansion of sorted CD154-expressing cells in the absence of specific antigen in IL-7/IL-15-supplemented medium. Ex vivo bulk CD4(+) T cells from chronic patients expressed CD154 in most cases, albeit at lower frequencies than those of resolved patients (0.11%vs 0.41%; P = 0.01), when stimulated with NS3, but not core, although they had a markedly impaired capacity to produce IL-2 and IFN-γ. Antigen-free in vitro expansion of NS3-specific CD154(+) cells from chronic patients restored IFN-γ and IL-2 production and proliferation to levels similar to those of patients with spontaneously resolved infection. Hence, NS3-specific CD4(+) T cell response can be rescued in most chronic HCV patients by in vitro expansion in the absence of HCV-specific antigen. These results might provide a rationale for adoptive immunotherapy.
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Affiliation(s)
- M Bes
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
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16
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HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients. J Transl Med 2012; 92:295-304. [PMID: 22042085 DOI: 10.1038/labinvest.2011.157] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hyper-expression of programmed death-1 (PD-1) is a hallmark of exhausted T cells. In chronic hepatitis-B virus (HBV)-infected patients, PD-1 upregulation on T cells was often observed. The mechanism of it has not been fully understood. In this study, we examined the dynamic changes of PD-1 expression on T cells during the natural history of chronic HBV infection and explored the signaling pathway of PD-1 upregulation by the hepatitis-B core antigen (HBcAg). Sixty-seven chronic HBV-infected patients were categorized into an immune tolerance group, an immune clearance group and an inactive virus carrier group, and 20 healthy volunteers were chosen as normal control group. Peripheral blood mononuclear cells from patients and healthy volunteers, and T lymphocytes from healthy volunteers were separated. Results showed that the PD-1 expression level on CD4(+)T cells in every phase of chronic HBV infection was significantly higher than that in healthy volunteers, whereas such effects were not observed on CD8(+)T cells. In the immune clearance phase, a positive correlation was found between serum HBV DNA level and the PD-1 expression level on CD4(+)T cells. In all phases, no correlation was shown between serum alanine amino transferase (ALT) level and PD-1 expression level. Phosphorylation of JNK, ERK and AKT was induced by HBcAg, and inhibitors of JNK, ERK and PI3K/AKT significantly decreased the HBcAg-induced PD-1 upregulation on CD4(+)T cells. In conclusion, the PD-1 expression level on CD4(+)T cells was upregulated in every phase of chronic HBV infection, which was induced by HBcAg through JNK, ERK and PI3K/AKT signaling pathways.
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17
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Abstract
HCV has the tendency to persist in the majority of infected patients despite the presence of virus-specific CD8+ T-cell responses. The HCV-specific CD8+ T-cell pool consists of heterogenous subsets that can be elegantly distinguished by CD127 expression. Indeed, HCV-specific CD8+ T cells with high levels of CD127 expression are characterized by features consistent with memory differentiation, while HCV-specific CD8+ T cells with low levels of CD127 expression display an exhausted phenotype characterized by the coexpression of PD-1 and other inhibitory receptors. In this article, the current knowledge about the phenotypes and differentiation profiles of HCV-specific CD8+ T cells is summarized. Clearly, the differentiation of HCV-specific CD8+ T cells in chronic HCV infection results from complex virus–host interactions, and both viral and immunological factors shape the HCV-specific CD8+ T-cell pool.
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Affiliation(s)
- Bertram Bengsch
- University of Freiburg, Freiburg, Germany; Uniklinik Freiburg, Hugstetter Street, 55, 79106 Freiburg, Germany
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18
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Abstract
The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.
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Barnaba V. Hepatitis C virus infection: a "liaison a trois" amongst the virus, the host, and chronic low-level inflammation for human survival. J Hepatol 2010; 53:752-61. [PMID: 20673595 DOI: 10.1016/j.jhep.2010.06.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2010] [Revised: 05/20/2010] [Accepted: 06/09/2010] [Indexed: 01/26/2023]
Abstract
This review covers the various aspects of the immune system that allows the relationship between the hepatitis-C virus, the host and chronic low-level inflammation, to be highly flexible and able to defend the host from persistent infections. This ambiguity mainly stems from the property of the immune system that can be both protective and harmful. Immunity cannot be fully protective without producing a certain degree of damage (acute hepatitis resulting in resolving HCV infection). In addition, the balance between protection and tissue damage is critical for the development of chronic HCV infection. The establishment of a state of chronic low-level inflammation is instrumental to limit liver immunopathology, to limit viral spread, and ultimately to ensure a long-lasting survival of the host. It is dictated by a fine equilibrium maintained by multiple immunologic mechanisms, including: sensory perception of innate immunity, virus-specific T and B cell functions, control of immune responses, and finally the balance between immunity and immunopathology that has principally evolved to favor the survival of the species.
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Affiliation(s)
- Vincenzo Barnaba
- Departimento of Medicina Interna, Sapienza Università di Roma, Fondazione Andrea Cesalpino, Fondazione Cenci Bolognetti, Italy.
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20
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Yamashiro H, Yoshizaki S, Tadaki T, Egawa K, Seo N. Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol 2010; 88:757-67. [DOI: 10.1189/jlb.0309156] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Affiliation(s)
| | - Shinji Yoshizaki
- Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | | | - Naohiro Seo
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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21
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Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 2010; 6:e1000947. [PMID: 20548953 PMCID: PMC2883597 DOI: 10.1371/journal.ppat.1000947] [Citation(s) in RCA: 305] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 05/10/2010] [Indexed: 02/07/2023] Open
Abstract
Exhausted CD8+ T cell responses during chronic viral infections are defined by a complex expression pattern of inhibitory receptors. However, very little information is currently available about the coexpression patterns of these receptors on human virus-specific CD8+ T cells and their correlation with antiviral functions, T cell differentiation and antigen recognition. We addressed these important aspects in a cohort of 38 chronically HCV infected patients and found a coexpression of inhibitory receptors such as 2B4, CD160 and KLRG1 in association with PD-1 in about half of the HCV-specific CD8+ T cell responses. Importantly, this exhaustive phenotype was associated with low and intermediate levels of CD127 expression, an impaired proliferative capacity, an intermediate T cell differentiation stage and absence of sequence variations within the corresponding epitopes, indicating ongoing antigen triggering. In contrast, a low expression of inhibitory receptors by the remaining HCV-specific CD8+ T cells occurred in concert with a CD127hi phenotype, an early T cell differentiation stage and presence of viral sequence variations within the corresponding epitopes. In sum, these results suggest that T cell exhaustion contributes to the failure of about half of HCV-specific CD8+ T cell responses and that it is determined by a complex interplay of immunological (e.g. T cell differentiation) and virological (e.g. ongoing antigen triggering) factors. About 170 million people are infected with hepatitis C virus (HCV), which may cause severe liver disease and liver cancer. Upon acute infection, only about 30% of patients are able to eliminate the virus spontaneously while about 70% of patients develop chronic infection. It is known that a successful immune response against HCV depends on virus-specific CD8+ T cells. However, during chronic infection, these cells are impaired in their antiviral function. In this study, we found that the exhaustion is characterized by the expression of multiple inhibitory receptors, such as PD-1, 2B4, CD160 and KLRG1. Of note, the coexpression of these receptors depends on the ongoing recognition of the viral antigen and the maturation stage of the T cell. The remaining virus-specific T cell responses that are not exhausted do not recognize the virus present in the patients any more due to viral mutations, indicating viral escape. Thus, they fail to exert antiviral activity, although they share characteristics of fully functional memory T cells. In sum, we have found that T cell exhaustion contributes to the failure of about half of HCV-specific CD8+ T cell responses and that it is determined by a complex interplay of immunological and virological factors. These findings will be important to consider in the design of new antiviral vaccination strategies.
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Affiliation(s)
- Bertram Bengsch
- Department of Medicine II, University of Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Bianca Seigel
- Department of Medicine II, University of Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Marianne Ruhl
- Department of Virology, University of Essen, Essen, Germany
| | - Jörg Timm
- Department of Virology, University of Essen, Essen, Germany
| | - Martin Kuntz
- Department of Medicine II, University of Freiburg, Freiburg, Germany
| | - Hubert E. Blum
- Department of Medicine II, University of Freiburg, Freiburg, Germany
| | | | - Robert Thimme
- Department of Medicine II, University of Freiburg, Freiburg, Germany
- * E-mail:
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22
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Salisch NC, Kaufmann DE, Awad AS, Reeves RK, Tighe DP, Li Y, Piatak M, Lifson JD, Evans DT, Pereyra F, Freeman GJ, Johnson RP. Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1. THE JOURNAL OF IMMUNOLOGY 2009; 184:476-87. [PMID: 19949078 DOI: 10.4049/jimmunol.0902781] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Ongoing antigenic stimulation appears to be an important prerequisite for the persistent expression of programmed death 1 (PD-1), an inhibitory TCR coreceptor of the CD28 family. Although recent publications have emphasized the utility of PD-1 as a marker for dysfunctional T cells in chronic viral infections, its dependence on antigenic stimulation potentially renders it a sensitive indicator of low-level viral replication. To explore the antigenic threshold for the maintenance of PD-1 expression on virus-specific T cells, we compared PD-1 expression on virus-specific and memory T cell populations in controlled and uncontrolled SIV and HIV-1 infection. In both controlled live attenuated SIV infection in rhesus macaques and HIV-1 infection in elite controllers, elevated levels of PD-1 expression were observed on SIV- and HIV-1-specific CD8(+) T cells. However, in contrast to chronic wild-type SIV infection and uncontrolled HIV-1 infection, controlled SIV/HIV-1 infection did not result in increased expression of PD-1 on total memory T cells. PD-1 expression on SIV-specific CD8(+) T cells rapidly decreased after the emergence of CTL escape in cognate epitopes, but was maintained in the setting of low or undetectable levels of plasma viremia in live attenuated SIV-infected macaques. After inoculation of naive macaques with a single-cycle SIV, PD-1 expression on SIV-specific CD8(+) T cells initially increased, but was rapidly downregulated. These results demonstrate that PD-1 can serve as a sensitive indicator of persistent, low-level virus replication and that generalized PD-1 expression on T lymphocytes is a distinguishing characteristic of uncontrolled lentiviral infections.
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Affiliation(s)
- Nadine C Salisch
- Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA
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23
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Adaptive immunity to hepatitis C virus. Viruses 2009; 1:276-97. [PMID: 21994550 PMCID: PMC3185498 DOI: 10.3390/v1020276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Revised: 08/14/2009] [Accepted: 08/25/2009] [Indexed: 12/23/2022] Open
Abstract
The precise role of adaptive immune responses in the clinical outcome of HCV infection is still only partially defined. Recent studies suggest that viral-host cell interactions during the acute phase of infection are essential for viral clearance or progression into chronic HCV infection. This review focuses on different aspects of the adaptive immune responses as determinants of the different outcomes of HCV infection, clearance or persistent infection, and outlines current concepts of HCV evasion strategies. Unravelling these important mechanisms of virus-host interaction will contribute to the development of novel strategies to prevent and control HCV infection.
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24
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Zhang Z, Jin B, Zhang JY, Xu B, Wang H, Shi M, Wherry EJ, Lau GKK, Wang FS. Dynamic decrease in PD-1 expression correlates with HBV-specific memory CD8 T-cell development in acute self-limited hepatitis B patients. J Hepatol 2009; 50:1163-73. [PMID: 19395117 DOI: 10.1016/j.jhep.2009.01.026] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Revised: 01/05/2009] [Accepted: 01/09/2009] [Indexed: 01/07/2023]
Abstract
BACKGROUND/AIMS Programmed death-1 (PD-1) upregulation can impair virus-specific CD8 T-cell responses during chronic viral infection. Whether and how PD-1 affects virus-specific memory CD8 T cells in humans with acute viral infection, however, remains largely undefined. METHODS The association between PD-1 expression and HBV-specific memory CD8 T-cell responses were longitudinally analyzed in eighteen patients with acute hepatitis B virus (HBV) infection, including ten patients with human leucocyte antigen (HLA)-A201 and eight with other HLA-A2 subtypes. RESULTS At clinical onset, PD-1 was significantly up-regulated and subsequently led to the functional suppression of HBV-specific effector CD8 T cells, as blocking PD-1/PD-L1 interactions in vitro enhanced their proliferation and IFN-gamma production. Following disease resolution, HBV-specific effector CD8 T cells developed into memory T cells. During this period, the dynamic PD-1 decrease was numerically correlated with the reduction of HBV-specific CD8 T-cell frequency, phenotypically with an acquisition of CCR7, CD45RA and CD127 expressions, and functionally with the increase in proliferation and IFN-gamma production of the memory T cells. CONCLUSIONS PD-1-mediated inhibitory signaling not only attenuates HBV-specific CD8 T-cell effector function during the acute phase of infection but also correlates with the development of HBV-specific memory CD8 T cells following disease resolution.
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Affiliation(s)
- Zheng Zhang
- Research Centre for Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China
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25
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Burgers WA, Riou C, Mlotshwa M, Maenetje P, de Assis Rosa D, Brenchley J, Mlisana K, Douek DC, Koup R, Roederer M, de Bruyn G, Karim SA, Williamson C, Gray CM. Association of HIV-specific and total CD8+ T memory phenotypes in subtype C HIV-1 infection with viral set point. THE JOURNAL OF IMMUNOLOGY 2009; 182:4751-61. [PMID: 19342652 DOI: 10.4049/jimmunol.0803801] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8(+) T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-gamma(+) T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8(+) T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8(+) memory subpopulations. At 6-9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8(+) cells of a central memory (CD45RO(+)CD27(+)CCR7(+)) and intermediate memory (CD45RO(-)CD27(+)CCR7(-)) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO(+)CD27(-)CCR7(-)) cells. The proportions of memory subsets significantly correlated with CD38(+)CD8(+) T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8(+) T cells.
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Affiliation(s)
- Wendy A Burgers
- Division of Medical Virology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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26
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Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF. Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 2009; 8:333-45. [PMID: 19249975 DOI: 10.1586/14760584.8.3.333] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Development of an effective vaccine against the hepatitis C virus (HCV) has long been defined as a difficult challenge due to the considerable variability of this RNA virus and the observation that convalescent humans and chimpanzees could be re-infected after re-exposure. On the other hand, progress in the understanding of antiviral immune responses in patients with viral clearance has elucidated key mechanisms playing a role in the control of viral infection. Studies investigating prophylactic vaccine approaches in chimpanzees have confirmed that the induction and maintenance of strong helper and cytotoxic T-cell immune responses against multiple viral epitopes is necessary for protection against viral clearance and chronic infection. A multispecific B-cell response, resulting in rapid induction of cross-neutralizing antibodies may assist cellular responses. Therapeutic vaccine formulations currently being evaluated in clinical trials are facing the fact that the immune system of chronic carriers is impaired and needs the restoration of T-cell functions to enhance their efficacy.
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Affiliation(s)
- Françoise Stoll-Keller
- Inserm, U748 et Laboratoire de Virologie des Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé 67000 Strasbourg, France.
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27
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Diepolder HM. New insights into the immunopathogenesis of chronic hepatitis C. Antiviral Res 2009; 82:103-9. [PMID: 19428600 DOI: 10.1016/j.antiviral.2009.02.203] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Revised: 02/23/2009] [Accepted: 02/27/2009] [Indexed: 12/26/2022]
Abstract
Despite the high propensity of hepatitis C virus to establish chronic viral persistence, immune-mediated viral clearance occurs in some patients, fostering hopes that therapeutic induction of specific antiviral immune responses might be able to contribute to viral clearance in chronically infected patients. Indeed, recent clinical trials of therapeutic vaccination have provided clear proof of concept that specific immunotherapy can reduce the viral load in some patients. Further improvement of these strategies will depend on a detailed analysis of the immunopathogenesis of chronic hepatitis C. Recent advances in our understanding of the mechanisms of down-regulation of virus-specific immune responses during chronic infection, including the role of regulatory T cells and inhibitory molecules such as programmed death receptor 1, may open up new avenues for second-generation immunotherapeutic interventions.
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28
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Rutebemberwa A, Ray SC, Astemborski J, Levine J, Liu L, Dowd KA, Clute S, Wang C, Korman A, Sette A, Sidney J, Pardoll DM, Cox AL. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:8215-25. [PMID: 19050238 PMCID: PMC2773824 DOI: 10.4049/jimmunol.181.12.8215] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) is an important human pathogen that represents a model for chronic infection given that the majority of infected individuals fail to clear the infection despite generation of virus-specific T cell responses during the period of acute infection. Although viral sequence evolution at targeted MHC class I-restricted epitopes represents one mechanism for immune escape in HCV, many targeted epitopes remain intact under circumstances of viral persistence. To explore alternative mechanisms of HCV immune evasion, we analyzed patterns of expression of a major inhibitory receptor on T cells, programmed death-1 (PD-1), from the time of initial infection and correlated these with HCV RNA levels, outcome of infection, and sequence escape within the targeted epitope. We show that the level of PD-1 expression in early HCV infection is significantly higher on HCV-specific T cells from subjects who progress to chronic HCV infection than from those who clear infection. This correlation is independent of HCV RNA levels, compatible with the notion that high PD-1 expression on HCV-specific CD8 T cells during acute infection inhibits viral clearance. Viral escape during persistent infection is associated with reduction in PD-1 levels on the surface of HCV-specific T cells, supporting the necessity of ongoing antigenic stimulation of T cells for maintenance of PD-1 expression. These results support the idea that PD-1 expression on T cells specific for nonescaped epitopes contributes to viral persistence and suggest that PD-1 blockade may alter the outcome of HCV infection.
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MESH Headings
- Acute Disease
- Adult
- Antigens, CD/biosynthesis
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Viral/immunology
- Apoptosis Regulatory Proteins/biosynthesis
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/virology
- Epitopes, T-Lymphocyte/genetics
- Epitopes, T-Lymphocyte/immunology
- Female
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Mutation
- Programmed Cell Death 1 Receptor
- Prospective Studies
- RNA, Viral/genetics
- RNA, Viral/metabolism
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- T-Lymphocyte Subsets/virology
- Viral Load
- Virus Latency/genetics
- Virus Latency/immunology
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Affiliation(s)
- Alleluiah Rutebemberwa
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Stuart C. Ray
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
- Department of Oncology, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Jacquie Astemborski
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
- Department of Epidemiology, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Jordana Levine
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Lin Liu
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
- Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China 400038
| | - Kimberly A. Dowd
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Shalyn Clute
- Medarex Incorporated, 521 Cottonwood Drive, Milpitas, CA 95035, USA
| | - Changyu Wang
- Medarex Incorporated, 521 Cottonwood Drive, Milpitas, CA 95035, USA
| | - Alan Korman
- Medarex Incorporated, 521 Cottonwood Drive, Milpitas, CA 95035, USA
| | - Alessandro Sette
- La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive San Diego, California 92121
| | - John Sidney
- La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive San Diego, California 92121
| | - Drew M. Pardoll
- Department of Oncology, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
| | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
- Department of Oncology, Johns Hopkins Medical Institutions, 855 N Wolfe Street. Suite 530, Baltimore, Maryland 21205, USA
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29
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Badr G, Bédard N, Abdel-Hakeem MS, Trautmann L, Willems B, Villeneuve JP, Haddad EK, Sékaly RP, Bruneau J, Shoukry NH. Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells. J Virol 2008; 82:10017-31. [PMID: 18667516 PMCID: PMC2566289 DOI: 10.1128/jvi.01083-08] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2008] [Accepted: 07/21/2008] [Indexed: 01/01/2023] Open
Abstract
The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.
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Affiliation(s)
- Gamal Badr
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital St.-Luc, 264 Blvd. René-Lévesque Est, Local PEA-316, Montréal (Québec) H2X 1P1, Canada
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30
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Ye P, Weng ZH, Zhang SL, Zhang JA, Zhao L, Dong JH, Jie SH, Pang R, Wei RH. Programmed death-1 expression is associated with the disease status in hepatitis B virus infection. World J Gastroenterol 2008; 14:4551-7. [PMID: 18680238 PMCID: PMC2731285 DOI: 10.3748/wjg.14.4551] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To define the potential role of programmed death-1/programmed death-ligand (PD-1/PD-L) pathway in different hepatitis B virus (HBV) infection disease status; we examined the expression of PD-1 on antigen specific CD8+ T cells in peripheral blood of patients with chronic hepatitis B (CHB) and acute exacerbation of hepatitis B (AEHB) infection.
METHODS: The PD-1 level on CD8+ T lymphocytes and the number of HBV specific CD8+ T lymphocytes in patients and healthy controls (HCs) were analyzed by staining with pentameric peptide-human leukocyte antigen2 (HLA2) complexes combined with flow cytometry. Real-time quantitative polymerase chain reaction (PCR) was used to measure the serum HBV-DNA levels.
RESULTS: The level of PD-1 expression on total CD8+ T cells in CHB patients (13.86% ± 3.38%) was significantly higher than that in AEHB patients (6.80% ± 2.19%, P < 0.01) and healthy individuals (4.63% ± 1.23%, P < 0.01). Compared to AEHB patients (0.81% ± 0.73%), lower frequency of HBV-specific CD8+ T cells was detected in chronic hepatitis B patients (0.37% ± 0.43%, P < 0.05). There was an inverse correlation between the strength of HBV-specific CD8+ T-cell response and the level of PD-1 expression. Besides, there was a significant positive correlation between HBV viral load and the percentage of PD-1 expression on CD8+ T cells in CHB and AEHB subjects (R = 0.541, P < 0.01). However, PD-1 expression was not associated with disease flare-ups as indicated by alanine aminotransferase (ALT) levels (R = 0.066, P > 0.05).
CONCLUSION: Our results confirm previous reports that HBV specific CD8+ T-cell response in the peripheral blood is more intense in patients with AEHB than in chronic hepatitis B with persistent viral infection. Moreover, there is a negative correlation between the level of PD-1 and the intensity of virus specific CD8+ T cell response.
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31
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Dolganiuc A, Szabo G. T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't. J Leukoc Biol 2008; 84:614-22. [PMID: 18495782 DOI: 10.1189/jlb.1107770] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The mechanism behind the apparent lack of effective antiviral immune response in patients with chronic hepatitis C virus (HCV) infection is poorly understood. Although multiple levels of abnormalities have been identified in innate and adaptive immunity, it remains unclear if any of the subpopulations of T cells with regulatory capacity (Tregs) contribute to the induction and maintenance of HCV persistence. In this review, we summarize the current knowledge about Tregs as they relate to HCV infection.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, LRB 270J, 364 Plantation St., Worcester, MA 01605, USA.
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