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Ali AA, Tabll AA. Unlocking potential: Virus-like particles as a promising strategy for effective HCV vaccine development. Virology 2025; 602:110307. [PMID: 39580887 DOI: 10.1016/j.virol.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of prophylactic vaccine is essential for HCV global eradication. Despite over three decades of research, no effective vaccine for HCV has been developed, primarily due to the virus's genetic diversity, immune evasion mechanisms, and incomplete understanding of protective immunity. However, Virus-Like Particles (VLPs) offer a promising approach to overcoming these challenges. VLPs mimic the structure of native virus but without the infectious genome, making them safe and non-infectious vaccines candidates. The capability of VLPs to incorporate neutralizing and conformational epitopes, and engage humoral and cellular immune responses, positions them as a promising tool for overcoming challenges associated with the HCV vaccine development. This review examines the challenges and immunological considerations for HCV vaccine development and provides an overview of the VLPs-based vaccines development. It also discusses future directions and public health implications of HCV vaccine development.
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Affiliation(s)
- Ahmed A Ali
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, (NRC), 12622, Cairo, Egypt.
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, 12622, Cairo, Egypt; Egyptian Centre for Research and Regenerative Medicine (ECRRM), 11517, Cairo, Egypt.
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2
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Machraoui S, Errafii K, Oujamaa I, Belghali MY, Hakmaoui A, Lamjadli S, Eddehbi FE, Brahim I, Haida Y, Admou B. Frequency of the Main Human Leukocyte Antigen A, B, DR, and DQ Loci Known to Be Associated with the Clearance or Persistence of Hepatitis C Virus Infection in a Healthy Population from the Southern Region of Morocco: A Preliminary Study. Diseases 2024; 12:106. [PMID: 38785761 PMCID: PMC11120154 DOI: 10.3390/diseases12050106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 05/25/2024] Open
Abstract
Hepatitis C Virus (HCV) infection represents a significant global health challenge, with its natural course largely influenced by the host's immune response. Human Leukocyte Antigen (HLA) molecules, particularly HLA class I and II, play a crucial role in the adaptive immune response against HCV. The polymorphism of HLA molecules contributes to the variability in immune response, affecting the outcomes of HCV infection. This study aims to investigate the frequency of HLA A, B, DR, and DQ alleles known to be associated with HCV clearance or persistence in a healthy Moroccan population. Conducted at the University Hospital Center Mohammed VI, Marrakech, this study spanned from 2015 to 2022 and included 703 healthy Moroccan individuals. HLA class I and II typing was performed using complement-dependent cytotoxicity and polymerase chain reaction-based methodologies. The results revealed the distinct patterns of HLA-A, B, DRB1, and DQB1 alleles in the Moroccan population. Notably, alleles linked to favorable HCV outcomes, such as HLA-DQB1*0301, DQB1*0501, and DRB1*1101, were more prevalent. Conversely, alleles associated with increased HCV susceptibility and persistence, such as HLA-DQB1*02 and DRB1*03, were also prominent. Gender-specific variations in allele frequencies were observed, providing insights into genetic influences on HCV infection outcomes. The findings align with global trends in HLA allele associations with HCV infection outcomes. The study emphasizes the role of host genetics in HCV infection, highlighting the need for further research in the Moroccan community, including HCV-infected individuals. The prevalence of certain HLA alleles, both protective and susceptibility-linked, underscores the potential for a national HLA data bank in Morocco.
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Affiliation(s)
- Safa Machraoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Ider Oujamaa
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Moulay Yassine Belghali
- Department of Biology, Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdellah University, Fez 30003, Morocco;
| | - Abdelmalek Hakmaoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Saad Lamjadli
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Fatima Ezzohra Eddehbi
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Ikram Brahim
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Yasmine Haida
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Brahim Admou
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
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Tang Y, Yao W, Hang hu, Xiong W, Mei H, Hu Y. TGF-β blocking combined with photothermal therapy promote tumor targeted migration and long-term antitumor activity of CAR-T cells. Mater Today Bio 2023; 20:100615. [PMID: 37063775 PMCID: PMC10090704 DOI: 10.1016/j.mtbio.2023.100615] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 04/03/2023] Open
Abstract
TGF-β is widely existed in tumor microenvironment, taking part in tumorigenesis process including angiogenesis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. It inhibited the activation, proliferation, migration and differentiation of T cells, in which way caused a limited therapeutic effects of chimeric antigen receptor T (CAR-T) towards solid tumor such as lymphoma. To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma. Based on amphipathic hydroxyethyl starch-polycaprolactone (HES-PCL), LY and photosensitizer indocyanine green (ICG) were co-loaded in HES-PCL to achieve LY/ICG@HES-PCL nanoparticle. The enhanced function of CAR-T benefited from LY/ICG@HES-PCL were verified through lymphoma Raji cells in vitro and Nod scid gamma mice engrafted with the Raji cells in vivo. LY was targeted transported to tumor site and accelerated release by mild ICG photothermal. Chemokines CXCL9/10/11 at the tumor site relevant to CAR-T migration and chemokines receptor CXCR3 of CAR-T could be up-regulated by LY, thus facilitated the enhanced accumulation of CAR-T at lymphoma site. T effector memory cells differentiation could also be accelerated by LY/ICG@HES-PCL. Combined therapy of LY/ICG@HES-PCL and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ICG@HES-PCL facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.
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Kardani K, Sadat SM, Kardani M, Bolhassani A. The next generation of HCV vaccines: a focus on novel adjuvant development. Expert Rev Vaccines 2021; 20:839-855. [PMID: 34114513 DOI: 10.1080/14760584.2021.1941895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Considerable efforts have been made to treat and prevent acute and chronic infections caused by the hepatitis C virus (HCV). Current treatments are unable to protect people from reinfection. Hence, there is a need for development of both preventive and therapeutic HCV vaccines. Many vaccine candidates are in development to fight against HCV, but their efficacy has so far proven limited partly due to low immunogenicity. AREAS COVERED We explore development of novel and powerful adjuvants to achieve an effective HCV vaccine. The basis for developing strong adjuvants is to understand the innate immunity pathway, which subsequently stimulates humoral and cellular immune responses. We have also investigated immunogenicity of developed adjuvants that have been used in recent studies available in online databases such as PubMed, PMC, ScienceDirect, Google Scholar, etc. EXPERT OPINION Adjuvants are used as a part of vaccine formulation to boost vaccine immunogenicity and antigen delivery. Several FDA-approved adjuvants are used in licensed human vaccines. Unfortunately, no adjuvant has yet been proven to boost HCV immune responses to the extent needed for an effective vaccine. One of the promising approaches for developing an effective adjuvant is the combination of various adjuvants to trigger several innate immune responses, leading to activation of adaptive immunity.[Figure: see text].
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Affiliation(s)
- Kimia Kardani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Mehdi Sadat
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Mona Kardani
- Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, 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, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Bonilla CM, McGrath NA, Fu J, Xie C. Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus. HEPATOMA RESEARCH 2020; 6:68. [PMID: 33134550 PMCID: PMC7597818 DOI: 10.20517/2394-5079.2020.58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) has one of highest mortalities globally amongst cancers, but has limited therapeutic options once in the advanced stage. Hepatitis B or C virus infection are the most common drivers for HCC carcinogenesis, triggering chronic liver inflammation and adding to the complexity of the immune microecosystem of HCC. The emergence of immunotherapy has afforded a new avenue of therapeutic options for patients with advanced HCC with a history of hepatitis B or C virus infection. This article reviews the change of immunity elicited by hepatitis B or C virus infection, the immune feature of HCC, and the clinical evidence for immunotherapy in advanced HCC and discusses future directions in this field.
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Affiliation(s)
- Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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7
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Smits M, Zoldan K, Ishaque N, Gu Z, Jechow K, Wieland D, Conrad C, Eils R, Fauvelle C, Baumert TF, Emmerich F, Bengsch B, Neumann-Haefelin C, Hofmann M, Thimme R, Boettler T. Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination. J Clin Invest 2020; 130:998-1009. [PMID: 31697649 DOI: 10.1172/jci129642] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 10/31/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.
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Affiliation(s)
- Maike Smits
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Naveed Ishaque
- Digital Health Center, Berlin Institute of Health (BIH) and Charité Universitätsmedizin, Berlin, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Zuguang Gu
- German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katharina Jechow
- Digital Health Center, Berlin Institute of Health (BIH) and Charité Universitätsmedizin, Berlin, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik Wieland
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Christian Conrad
- Digital Health Center, Berlin Institute of Health (BIH) and Charité Universitätsmedizin, Berlin, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Roland Eils
- Digital Health Center, Berlin Institute of Health (BIH) and Charité Universitätsmedizin, Berlin, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Catherine Fauvelle
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France
| | - Thomas F Baumert
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France.,Pole Hépato-digestif, Institut Hopitalo-Universitaire, Hopitaux Universitaires Strasbourg, Strasbourg, France
| | - Florian Emmerich
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Institute for Transfusion Medicine and Gene Therapy, University Medical Center, University of Freiburg, Freiburg, Germany
| | - Bertram Bengsch
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maike Hofmann
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Binder B, Thimme R. CD4+ T cell responses in human viral infection: lessons from hepatitis C. J Clin Invest 2020; 130:595-597. [PMID: 31904589 DOI: 10.1172/jci133222] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver disease as a result of chronic hepatitis C virus (HCV) infection is a global problem. While some HCV infections resolve spontaneously, viral persistence associates with compromised T cell immunity. In this issue of the JCI, Chen et al. and Coss et al. explored virus-specific CD4+ T cell response during HCV infection. Both studies evaluated the HCV-specific T cells of patients with different courses of infection. Chen et al. revealed that initial CD4+ T cell responses are similar during early infection and that T cell failure resulted from loss of the virus-specific T cells themselves. Coss et al. showed that HCV-specific CD4+ T cells temporarily recovered in some women following childbirth. These studies contribute to our understanding of CD4+ T cell functionality during different natural courses of infection, with the notable implication that restoring CD4+ T cell immunity might contribute to controlling HCV infection.
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Affiliation(s)
- Benedikt Binder
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.,IMM-PACT Clinician Scientist Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
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9
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Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines (Basel) 2020; 8:vaccines8010090. [PMID: 32079254 PMCID: PMC7157504 DOI: 10.3390/vaccines8010090] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.
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Affiliation(s)
- Joshua D. Duncan
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
- Correspondence:
| | - Richard A. Urbanowicz
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Alexander W. Tarr
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Jonathan K. Ball
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
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10
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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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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12
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Dawood RM, Moustafa RI, Abdelhafez TH, El-Shenawy R, El-Abd Y, Bader El Din NG, Dubuisson J, El Awady MK. A multiepitope peptide vaccine against HCV stimulates neutralizing humoral and persistent cellular responses in mice. BMC Infect Dis 2019; 19:932. [PMID: 31690267 PMCID: PMC6833294 DOI: 10.1186/s12879-019-4571-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 10/16/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Although DAAs hold promise to significantly reduce rates of chronic HCV infections, its eradication still requires development of an effective vaccine. Prolonged T cell responses and cross neutralizing antibodies are ideal for vaccination against the infection. We aimed to design and synthesize a 6 multi epitope peptide vaccine candidate and provide evidence for production of extended cellular and neutralizing Abs in mice. METHODS Six peptides derived from conserved epitopes in E1, E2 (n = 2),NS4B, NS5A and NS5B were designed, synthesized in a multiple antigenic peptide (MAP) form and administered w/o adjuvant to BALB/c mice as HCVp6-MAP at doses ranging from 800 ng to 16 μg. Humoral responses to structural epitopes were assayed by ELISA at different times after injection. ELISpot assay was used to evaluate IFN ɣ producing CD4+/ CD8+ T- lymphocytes at extended durations i.e. > 20 weeks. Viral neutralization by mice sera was tested for genotypes 2a (JFH1) and a chimeric 2a/4a virus (ED43/JFH1) in HCVcc culture. RESULTS HCVp6-MAP confers potent viral neutralization and specific cellular responses at > 1600 ng/ animal for at least 20 weeks. CONCLUSION We report on a promising anti HCV vaccine for future studies on permissive hosts and in clinical trials.
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Affiliation(s)
- Reham M Dawood
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt.
| | - Rehab I Moustafa
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Tawfeek H Abdelhafez
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Reem El-Shenawy
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Yasmine El-Abd
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Noha G Bader El Din
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Jean Dubuisson
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Mostafa K El Awady
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
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13
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Gomaa AF, Wahba MO, Hafez RAEL, Eldaly OM, Badran SG. Assessment of the role of interleukin 17A and interleukin 17F in chronic hepatitis C virus infection in Egyptian patients. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2019. [DOI: 10.4103/ejim.ejim_119_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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14
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Irshad M, Gupta P, Irshad K. Immunopathogenesis of Liver Injury During Hepatitis C Virus Infection. Viral Immunol 2019; 32:112-120. [PMID: 30817236 DOI: 10.1089/vim.2018.0124] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The present report describes current concepts about the mechanism of liver cell injury caused by host immune response against hepatitis C virus (HCV) infection in human beings. This report is based on the observations from experimental studies and follow-up actions on human liver diseases. The results from different investigations suggest that liver injury depends on the presentation of viral antigen and the level of host immune response raised against HCV-related peptides. Both innate and adaptive immunity are triggered to counter the viral onset. During development of host immunity, the cell-mediated immune response involving CD4+ Th1 cells and CD8+ cytotoxic T-lymphocyte (CTL) cells were found to play a major role in causing liver damage. The hepatic Innate lymphoid cells (ILCs) subsets are involved in the immune regulation of different liver diseases: viral hepatitis, mechanical liver injury, and fibrosis. Humoral immunity and natural killer (NK) cell action also contributed in liver cell injury by antibody-dependent cellular cytotoxicity (ADCC). In fact, immunopathogenesis of HCV infection is a complex phenomenon where regulation of immune response at several steps decides the possibility of viral elimination or persistence. Regulation of immune response was noted starting from viral-host interaction to immune reaction cascade engaged in cell damage. The activation or suppression of interferon-stimulated genes, NK cell action, CTL inducement by regulatory T cells (Treg), B cell proliferation, and so on was demonstrated during HCV infection. Involvement of HLA in antigen presentation, as well as types of viral genotypes, also influenced host immune response against HCV peptides. The combined effect of all these effector mechanisms ultimately decides the progression of viral onset to acute or chronic infection. In conclusion, immunopathogenesis of liver injury after HCV infection may be ascribed mainly to host immune response. Second, it is cell-mediated immunity that plays a predominant role in liver cell damage.
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Affiliation(s)
- Mohammad Irshad
- 1 Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Priyanka Gupta
- 2 Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Khushboo Irshad
- 3 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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15
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Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
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16
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Konstantinides P, Alexopoulou A, Hadziyannis E, Kanellopoulou T, Dourakis SP. Interleukin-17A and B-cell activating factor in chronic hepatitis C patients with or without asymptomatic mixed cryoglobulinemia: effects of antiviral treatment and correlations with vitamin D. Ann Gastroenterol 2018; 31:705-711. [PMID: 30386121 PMCID: PMC6191865 DOI: 10.20524/aog.2018.0310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 08/23/2018] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Several studies have provided conflicting results regarding the immune responses in chronic hepatitis C (CHC) patients with mixed cryoglobulinemia (MC). The importance of B-cell activating factor (BAFF) in MC has been described, but the role of interleukin (IL)-17A is less clear. METHODS Serum concentrations of IL-17A, BAFF and 25-OH vitamin D were measured in CHC patients at baseline, end of treatment, and 6 months post-treatment with pegylated interferon-α and ribavirin, versus 12 healthy controls. RESULTS Thirty-four patients (20 male, mean age 40.7±9.2 years, 12 of genotype 1 or 4, 22 of genotype 2 or 3) were included, of whom 64.7% achieved a sustained virological response (SVR). MC was detected in 52.9% of the patients. Higher levels of both cytokines were found in patients with MC compared to those without. Patients who achieved SVR had higher pretreatment IL-17A and lower BAFF levels compared to those without SVR. IL-17A was downregulated during and following treatment in responders, whereas upregulation was observed in non-responders. CHC patients demonstrated low vitamin D levels compared to HC. Moreover, the changes in IL-17A over the treatment period were significantly associated with vitamin D changes (β=-0.04, SE=0.02, P=0.046). No difference in IL-17A, BAFF and vitamin D values was seen between patients with cirrhosis (n=14) and those without. CONCLUSIONS CHC patients with asymptomatic MC have increased levels of IL-17A and BAFF. IL-17A levels decline significantly while BAFF increases during treatment in responders. An interplay between IL-17A and vitamin D concentrations was revealed during the antiviral treatment.
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Affiliation(s)
- Polydoros Konstantinides
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Alexandra Alexopoulou
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Theoni Kanellopoulou
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Spyridon P. Dourakis
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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17
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Lampejo T, Agarwal K, Carey I. Interferon-free direct-acting antiviral therapy for acute hepatitis C virus infection in HIV-infected individuals: A literature review. Dig Liver Dis 2018; 50:113-123. [PMID: 29233687 DOI: 10.1016/j.dld.2017.11.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 10/29/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
Dramatic rises in hepatitis C virus (HCV) coinfection rates in human immunodeficiency virus (HIV)-infected individuals have been observed recently, largely attributable to increasing recreational drug use combined with increased testing for HCV. In the era of direct-acting antiviral (DAA) therapy, treatment of acute HCV infection in HIV-infected individuals with short durations of these drugs may potentially reduce the disease and economic burden associated with HCV infection as well as reducing the likelihood of onward HCV transmission. We performed an extensive literature search of PubMed, Embase and Google Scholar up to 05 September 2017 for clinical trials of acute HCV infection in HIV-infected individuals. In the studies identified, rates of sustained virologic response at 12 weeks post-treatment (SVR12) ranged from 21% with 6 weeks of therapy up to 92% with 12 weeks of therapy with sofosbuvir and ribavirin. Ledipasvir/sofosbuvir for 6 weeks achieved an SVR of 77%. No HIV-related events occurred regardless of whether patients were receiving antiretroviral therapy (ART) and DAAs were well tolerated. Data is currently limited with regards to optimal regimens and durations of therapy, which need to be tailored based on potential interactions with concurrent ART and consideration for the fact that patients with higher baseline HCV RNA levels may require an extended duration of treatment.
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Affiliation(s)
- Temi Lampejo
- Institute of Liver Studies, King's College Hospital, London, United Kingdom.
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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18
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Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis. Int J Mol Sci 2017; 18:ijms18071517. [PMID: 28703774 PMCID: PMC5536007 DOI: 10.3390/ijms18071517] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/03/2017] [Accepted: 07/04/2017] [Indexed: 12/21/2022] Open
Abstract
Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.
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19
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Cachem FCOF, Dias AS, Monteiro C, Castro JR, Fernandes G, Delphim L, Almeida AJ, Tavares F, Maciel AMA, Amendola-Pires MM, Brandão-Mello CE, Bento CAM. The proportion of different interleukin-17-producing T-cell subsets is associated with liver fibrosis in chronic hepatitis C. Immunology 2017; 151:167-176. [PMID: 28140446 DOI: 10.1111/imm.12720] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 12/13/2022] Open
Abstract
Studies have suggested the pivotal role of T helper type 1 (Th1) -related cytokines on the outcome of hepatitis C virus (HCV) infection. Nevertheless, the role of different interleukin-17 (IL-17) -secreting T cells on chronic hepatitis C (CHC) is less clear. Here, the in vivo IL-1β, IL-6, and IL-17 levels were positively correlated with both alanine transaminase (ALT) levels and hepatic lesions. When compared with the control group, CHC patients showed a lower proportion of IL-17-secreting (CD4+ and CD8+ ) T cells capable of simultaneously producing IL-21. Moreover, the percentage of IL-10-secreting Th17 cells was also lower in CHC patients. Notably, advanced liver lesions were observed among those patients with lower percentage levels of IL-17-producing T cells positive for IL-21, interferon-γ (IFN-γ) and IL-10. In contrast, the severity of hepatic damage was associated with peripheral single IL-17+ T cells. The percentage of IL-17+ IL-21- IFN-γ+ (CD4+ and CD8+ ) T-cell phenotypes was positively associated with plasma CD14 levels. Finally, elevated levels of circulating CD14 were detected among CHC patients with extensive liver damage. In summary, although preliminary, our results suggest that a balance between different IL-17-producing T cells, associated with peripheral levels of CD14, may be a progress marker for liver disease in chronically HCV-infected patients.
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Affiliation(s)
- Fabio C O F Cachem
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.,Department of Microbiology, Immunology and Parasitology, UERJ, Rio de Janeiro, Brazil
| | - Aleida S Dias
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Clarice Monteiro
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.,Department of Microbiology, Immunology and Parasitology, UERJ, Rio de Janeiro, Brazil
| | - José Roberto Castro
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gabriel Fernandes
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Letícia Delphim
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adilson J Almeida
- Division of Gastroenterology & Hepatology, Internal Medicine Department, HUGG, UNIRIO, Rio de Janeiro, Brazil
| | - Felipe Tavares
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alessandra M A Maciel
- Division of Gastroenterology & Hepatology, Internal Medicine Department, HUGG, UNIRIO, Rio de Janeiro, Brazil
| | - Marcia M Amendola-Pires
- Division of Gastroenterology & Hepatology, Internal Medicine Department, HUGG, UNIRIO, Rio de Janeiro, Brazil
| | - Carlos E Brandão-Mello
- Division of Gastroenterology & Hepatology, Internal Medicine Department, HUGG, UNIRIO, Rio de Janeiro, Brazil
| | - Cleonice A M Bento
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.,Department of Microbiology, Immunology and Parasitology, UERJ, Rio de Janeiro, Brazil
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20
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Muraro E, Merlo A, Martorelli D, Cangemi M, Dalla Santa S, Dolcetti R, Rosato A. Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4 + T Cells. Front Immunol 2017; 8:197. [PMID: 28289418 PMCID: PMC5327441 DOI: 10.3389/fimmu.2017.00197] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 02/09/2017] [Indexed: 12/18/2022] Open
Abstract
CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors.
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Affiliation(s)
- Elena Muraro
- Immunopathology and Cancer Biomarkers, Traslational Research Department, IRCCS, C.R.O. National Cancer Institute, Aviano, Pordenone, Italy
| | - Anna Merlo
- Department of Immunology and Blood Transfusions, San Bortolo Hospital, Vicenza, Italy
| | - Debora Martorelli
- Immunopathology and Cancer Biomarkers, Traslational Research Department, IRCCS, C.R.O. National Cancer Institute, Aviano, Pordenone, Italy
| | - Michela Cangemi
- Immunopathology and Cancer Biomarkers, Traslational Research Department, IRCCS, C.R.O. National Cancer Institute, Aviano, Pordenone, Italy
| | | | - Riccardo Dolcetti
- Immunopathology and Cancer Biomarkers, Traslational Research Department, IRCCS, C.R.O. National Cancer Institute, Aviano, Pordenone, Italy
- Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD, Australia
| | - Antonio Rosato
- Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Padova, Italy
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21
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Keoshkerian E, Hunter M, Cameron B, Nguyen N, Sugden P, Bull R, Zekry A, Maher L, Seddiki N, Zaunders J, Kelleher A, Lloyd AR. Hepatitis C-specific effector and regulatory CD4 T-cell responses are associated with the outcomes of primary infection. J Viral Hepat 2016; 23:985-993. [PMID: 27558465 DOI: 10.1111/jvh.12576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/29/2016] [Indexed: 12/31/2022]
Abstract
Clearance of primary hepatitis C virus (HCV) infection has been associated with strong and broadly targeted cellular immune responses. This study aimed to characterize HCV-specific CD4+ effector and regulatory T-cell numbers and cytokine production during primary infection. Antigen-specific CD4+ T-cell responses were investigated in a longitudinal cohort of subjects from pre-infection to postoutcome, including subjects who cleared [n=12] or became chronically infected [n=17]. A cross-sectional cohort with previously cleared, or chronic infection [n=15 for each], was also studied. Peripheral blood mononuclear cells were incubated with HCV antigens and surface stained for T-effector (CD4+CD25high CD134+CD39-) and T-regulatory (CD4+CD25high CD134+CD39+) markers, and culture supernatants assayed for cytokine production. Contrary to expectations, the breadth and magnitude of the HCV-specific CD4+ T-cell responses were higher in subjects who became chronically infected. Subjects who cleared the virus had HCV-specific CD4+ T-cell responses dominated by effector T cells and produced higher levels of IFN-γ, in contrast to HCV-specific CD4+ T-cell responses dominated by regulatory T cells and more IL-10 production in those who became chronically infected. Better understanding of the role of antigen-specific CD4+ T-cell responses in primary HCV will further define pathogenesis and help guide development of a preventative vaccine.
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Affiliation(s)
- E Keoshkerian
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
| | - M Hunter
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - B Cameron
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - N Nguyen
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - P Sugden
- UNSW Australia, SOMS (Infection and Immunology Research Centre, IIRC), Kensington, NSW, Australia
| | - R Bull
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
| | - A Zekry
- UNSW Australia, St George and Sutherland Clinical School, Sydney, NSW, Australia
| | - L Maher
- UNSW Australia, Kirby Institute (Viral Hepatitis Epidemiology and Prevention Program VHEPP), Kensington, NSW, Australia
| | - N Seddiki
- The Vaccine Research Institute (VRI), INSERM, Créteil, France
| | - J Zaunders
- UNSW Australia, Kirby Institute (Immunovirology and Pathogenesis Program, IVPP), Kensington, NSW, Australia
| | - A Kelleher
- UNSW Australia, Kirby Institute (Immunovirology and Pathogenesis Program, IVPP), Kensington, NSW, Australia
| | - A R Lloyd
- UNSW Australia, Kirby Institute (Viral Immunology Systems Program, VISP) and School of Medical Sciences (SOMS), Kensington, NSW, Australia
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22
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Meng P, Zhao S, Niu X, Fu N, Su S, Wang R, Zhang Y, Qiao L, Nan Y. Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses. Int J Mol Sci 2016; 17:1070. [PMID: 27428948 PMCID: PMC4964446 DOI: 10.3390/ijms17071070] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/27/2016] [Accepted: 06/29/2016] [Indexed: 12/21/2022] Open
Abstract
Interleukin-23 (IL-23) and its downstream factor IL-17 are the key cytokines involved in immune and inflammatory response in chronic liver diseases. This study aimed to investigate the role and molecular mechanisms of the IL-23/Th17 axis in chronic hepatitis C virus (HCV) infection, and the efficacy of IL-23/Th17 modulation in response to anti-HCV therapy. Sixty-six HCV-infected patients and 20 healthy controls were enrolled. The patients received PegIFNa-2a and ribavirin therapy for at least 48 weeks. The plasma level of IL-23 and the number of IL-17A-, IFN-γ-, and IL-21-producing peripheral blood mononuclear cells (PBMCs) at baseline and 12, 24, and 48 weeks following treatment were determined. The mRNA level of Th17 immune-associated molecules in PBMCs was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) following treatment with IL-23 agonist or antagonist. Our data showed that, compared to healthy controls, HCV-infected patients had an increased plasma level of IL-23 and increased frequencies of IL-17A- and IFN-γ-producing PBMCs, whereas the HCV patients exhibited a reduced number of IL-21-producing PBMCs. However, the baseline frequencies of IL-21-producing PBMCs were markedly higher in HCV patients who achieved rapid virological response (RVR) than those without RVR. Additionally, the mRNA expressions of IL-21, IFN-γ, myxovirus resistance protein A (MxA), and suppressor of cytokine signaling 3 (SOCS3) were significantly upregulated in PBMCs, while FoxP3 expression was suppressed by IL-23 agonist. Thus, the IL-23/Th17 axis plays an important role in development of chronic HCV infection and antiviral response. IL-23 may enhance the antiviral activity of interferon-based therapy by modulating the expression of Th17 cells-associated molecules in HCV-infected patients.
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Affiliation(s)
- Ping Meng
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Suxian Zhao
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Xuemin Niu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Na Fu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Shanshan Su
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Rongqi Wang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Yuguo Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research (WIMR), the University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China.
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23
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Yoshio S, Kanto T. Host-virus interactions in hepatitis B and hepatitis C infection. J Gastroenterol 2016; 51:409-20. [PMID: 26894594 DOI: 10.1007/s00535-016-1183-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 02/06/2016] [Indexed: 02/04/2023]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-λ3), remains to be elucidated. Human BDCA3(+)DCs have also been shown to be a potent producer of IFN-λ3 in HCV infection, suggesting the possibility that BDCA3(+)DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.
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Affiliation(s)
- Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, 272-8516, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, 272-8516, Japan.
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Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections. Gastroenterology 2016; 150:696-706.e3. [PMID: 26584604 DOI: 10.1053/j.gastro.2015.11.005] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 10/08/2015] [Accepted: 11/01/2015] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Follicular T-helper (Tfh) cells contribute to pathogen-specific antibody responses by providing maturation signals to B cells. In mice with viral infections, virus-specific Tfh cells expand and are required to contain the infection. However, less is known about human virus-specific Tfh cells or their functions during infection. We investigated whether virus-specific CD4+ T cells from patients with hepatitis C virus (HCV) infection had phenotypic or functional features of Tfh cells and contribute to the production of HCV-specific antibodies. METHODS We collected blood samples from patients with acute and chronic HCV infection and healthy individuals (controls). We performed MHC class II tetramer analyses, assays to detect intracellular cytokines in response to HCV exposure, and analyses to quantify HCV-specific antibodies. In addition, we collected liver tissues from patients with chronic HCV infection or nonviral liver disease to analyze markers of Tfh cells. RESULTS HCV-specific CD4+ T cells from patients with acute HCV infection expressed markers of Tfh cells and secreted interleukin 21 in response to HCV exposure. Longitudinal analyses of HCV-specific T-cell responses and antibody responses showed an association between expression of inducible T-cell co-stimulator and induction of virus-specific antibodies in patients with acute HCV infection. Markers of Tfh cells were barely detectable in the peripheral blood samples from patients with chronic HCV infection, but were detected in liver tissues. CONCLUSIONS Virus-specific Tfh cells can be detected in blood samples from patients with acute HCV infection; inducible T-cell co-stimulator expression correlates with production of HCV-specific antibodies. In patients with chronic infection, Tfh cells seem to disappear from the blood but are detectable in the liver.
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Affiliation(s)
- Bijan Raziorrouh
- Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany
| | - Kathrin Sacher
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
| | - Rajiv G Tawar
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France
| | - Florian Emmerich
- University Hospital Freiburg, Institute for Cell and Gene Therapy, Freiburg, Germany
| | | | - Thomas F Baumert
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
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25
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Apweiler R, Bairoch A, Wu CH, Barker WC, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin MJ, Natale DA, O'Donovan C, Redaschi N, Yeh LSL. Host-virus interactions in hepatitis B and hepatitis C infection. J Gastroenterol 2016; 32:D115-9. [PMID: 14681372 PMCID: PMC308865 DOI: 10.1093/nar/gkh131] [Citation(s) in RCA: 2363] [Impact Index Per Article: 262.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-λ3), remains to be elucidated. Human BDCA3(+)DCs have also been shown to be a potent producer of IFN-λ3 in HCV infection, suggesting the possibility that BDCA3(+)DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.
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Affiliation(s)
- Rolf Apweiler
- The EMBL Outstation--European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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26
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Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
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Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
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27
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Kaźmierczak J, Caraballo Cortes K, Bukowska-Ośko I, Radkowski M. Virus-Specific Cellular Response in Hepatitis C Virus Infection. Arch Immunol Ther Exp (Warsz) 2015; 64:101-10. [PMID: 26429740 DOI: 10.1007/s00005-015-0364-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 06/08/2015] [Indexed: 12/15/2022]
Abstract
Studies performed on chimpanzees and humans have revealed that strong, multispecific and sustained CD4(+) and CD8(+) T cell immune responses is a major determinant of hepatitis C virus (HCV) clearance. However, spontaneous elimination of the virus occurs in minority of infected individuals and cellular response directed against HCV antigens is not persistent in individuals with chronic infection. This review presents characteristics of the HCV-specific T cell response in patients with different clinical course of infection, including acute and chronic infection, persons who spontaneously eliminated HCV and non-infected subjects exposed to HCV. Detection of HCV-specific response, especially in non-infected subjects exposed to HCV, may be indicative of HCV prevalence in population and rate of spontaneous viral clearance. Understanding the mechanisms and role of HCV-specific cellular immune response would contribute to better understanding of HCV epidemiology, immunopathogenesis and may help to design an effective vaccine.
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Affiliation(s)
- Justyna Kaźmierczak
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland.
| | - Kamila Caraballo Cortes
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
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28
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T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis 2015; 6:e1694. [PMID: 25789969 PMCID: PMC4385920 DOI: 10.1038/cddis.2015.42] [Citation(s) in RCA: 273] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 01/02/2015] [Accepted: 01/19/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the ‘exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4+ and CD8+ T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8+ T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.
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29
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Rossi LMG, Escobar-Gutierrez A, Rahal P. Advanced molecular surveillance of hepatitis C virus. Viruses 2015; 7:1153-88. [PMID: 25781918 PMCID: PMC4379565 DOI: 10.3390/v7031153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/05/2015] [Accepted: 02/20/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted.
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Affiliation(s)
- Livia Maria Gonçalves Rossi
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
| | | | - Paula Rahal
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
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Yang ZZ, Liang AB, Ansell SM. T-cell-mediated antitumor immunity in B-cell non-Hodgkin lymphoma: activation, suppression and exhaustion. Leuk Lymphoma 2015; 56:2498-504. [PMID: 25651421 DOI: 10.3109/10428194.2015.1011640] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The tumor microenvironment in B-cell non-Hodgkin lymphoma (NHL) comprises not only malignant cells but also significant numbers of normal immune cells. The intratumoral immune infiltrate includes T-lymphocytes that appear to target the malignant clone. Despite immunologically recognizing the lymphoma cells, the intratumoral T-cells are unable to eradicate the malignant cells and the lymphoma commonly progresses. Recent data has identified mechanisms whereby activated intratumoral T-cells are suppressed or become exhausted due to chronic antigen stimulation. A clearer understanding of these mechanisms will allow for strategies to overcome them and improve the outcome of patients with lymphoma.
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Affiliation(s)
- Zhi-Zhang Yang
- a Division of Hematology and Internal Medicine, Mayo Clinic , Rochester , MN , USA
| | - Ai-Bin Liang
- b Department of Hematology , Tongji Hospital, Tongji University , Shanghai , China
| | - Stephen M Ansell
- a Division of Hematology and Internal Medicine, Mayo Clinic , Rochester , MN , USA
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31
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Lokhande MU, Thimme R, Klenerman P, Semmo N. Methodologies for the Analysis of HCV-Specific CD4(+) T Cells. Front Immunol 2015; 6:57. [PMID: 25767470 PMCID: PMC4341113 DOI: 10.3389/fimmu.2015.00057] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 01/29/2015] [Indexed: 12/16/2022] Open
Abstract
Virus-specific CD4+ T cells play a major role in viral infections, such as hepatitis C virus (HCV). Viral clearance is associated with vigorous and multi-specific CD4+ T-cell responses, while chronic infection has been shown to be associated with weak or absent T-cell responses. Most of these studies have used functional assays to analyze virus-specific CD4+ T-cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4+ T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analyzed in detail. A novel assay, in which virus-specific CD4+ T-cell frequencies can be determined by de novo CD154 (CD40 ligand) expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4+ T cells will be discussed in this review.
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Affiliation(s)
- Megha U Lokhande
- Hepatology, Department of Clinical Research, University of Bern , Bern , Switzerland
| | - Robert Thimme
- Department of Gastroenterology and Hepatology, University Hospital of Freiburg , Freiburg , Germany
| | - Paul Klenerman
- NIHR Biomedical Research Centre, Oxford and Peter Medawar Building for Pathogen Research, University of Oxford , Oxford , UK
| | - Nasser Semmo
- Hepatology, Department of Clinical Research, University of Bern , Bern , Switzerland ; Department of Hepatology, University Clinic of Visceral Surgery and Medicine , Inselspital, Bern , Switzerland
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32
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Ma L, Zhou Y, Zhang Y, Li Y, Guo Y, He Y, Wang J, Lian J, Hao C, Moorman JP, Yao ZQ, Zhou Y, Jia Z. Role of A20 in interferon-α-mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C. Immunology 2015; 143:670-8. [PMID: 24965710 DOI: 10.1111/imm.12350] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 06/12/2014] [Accepted: 06/23/2014] [Indexed: 01/01/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.
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Affiliation(s)
- Li Ma
- Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
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Losikoff PT, Mishra S, Terry F, Gutierrez A, Ardito MT, Fast L, Nevola M, Martin WD, Bailey-Kellogg C, De Groot AS, Gregory SH. HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients. J Hepatol 2015; 62:48-55. [PMID: 25157982 DOI: 10.1016/j.jhep.2014.08.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 07/14/2014] [Accepted: 08/17/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Spontaneous resolution of hepatitis C virus (HCV) infection depends upon a broad T cell response to multiple viral epitopes. However, most patients fail to clear infections spontaneously and develop chronic disease. The elevated number and function of CD3(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg)) in HCV-infected patients suggest a role of Treg cells in impaired viral clearance. The factors contributing to increased Treg cell activity in chronic hepatitis C cases remain to be delineated. METHODS Immunoinformatics tools were used to predict promiscuous, highly-conserved HLA-DRB1-restricted immunogenic consensus sequences (ICS), each composed of multiple T cell epitopes. These sequences were synthesized and added to cultures of peripheral blood mononuclear cells (PBMCs), derived from patients who resolved HCV infection spontaneously, patients with persistent infection, and non-infected individuals. The cells were collected and following 5days incubation, quantified and characterized by flow cytometry. RESULTS One immunogenic consensus sequence (ICS), HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not in patients who spontaneously cleared HCV or in non-infected individuals. An analogous human peptide (p7_794), on the other hand, induced a significant increase in Treg cells among PBMCs derived from both HCV-infected and non-infected individuals. JanusMatrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome. CONCLUSIONS A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3(+)CD4(+)CD25(+)FoxP3(+) natural Treg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C.
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Affiliation(s)
- Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Sasmita Mishra
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | | | - Andres Gutierrez
- Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | | | - Loren Fast
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Martha Nevola
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | | | | | - Anne S De Groot
- EpiVax, Inc., Providence, RI, USA; Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
| | - Stephen H Gregory
- Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
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Asghar K, Ashiq MT, Zulfiqar B, Mahroo A, Nasir K, Murad S. Indoleamine 2,3-dioxygenase expression and activity in patients with hepatitis C virus-induced liver cirrhosis. Exp Ther Med 2014; 9:901-904. [PMID: 25667650 PMCID: PMC4316896 DOI: 10.3892/etm.2014.2146] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 10/21/2014] [Indexed: 12/20/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme. It plays a key role in various malignancies, infection and autoimmune diseases. IDO induces immunosuppression through the depletion of tryptophan and its downstream metabolites. Hepatitis C virus (HCV) has infected more than 12 million individuals in Pakistan. The aim of the present study was to assess the expression and activity of IDO in HCV-infected patients. The functional enzymatic activity of IDO was measured by colorimetric assay. Serum samples from 100 HCV-infected patients were taken to examine IDO activity and samples from 100 healthy volunteers were used as controls. Liver sections from patients with HCV (n=35) and healthy controls (n=5) were used for immunohistochemical studies. Immunohistochemical analysis revealed that IDO was overexpressed in 28 of 35 (80%) cirrhotic liver samples, whereas 5 of 35 (14.2%) cases presented moderate and 2 of 35 (5.7%) cases presented mild expression of IDO. The enzymatic activity of IDO was significantly higher in the serum samples of HCV-infected patients as compared with those in the control. These data indicate that the expression of IDO correlated with the pathogenesis of disease. In summary, it is suggested that the high expression of IDO in the progressively cirrhotic livers of HCV-infected patients might contribute to the development of hepatocellular carcinoma. IDO may characterize a novel therapeutic target against HCV.
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Affiliation(s)
- Kashif Asghar
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - M Taimour Ashiq
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Bilal Zulfiqar
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Amnah Mahroo
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Kaenat Nasir
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
| | - Sheeba Murad
- Molecular Immunology Research Group, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Islamabad 44000, Pakistan
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35
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Raziorrouh B, Heeg M, Kurktschiev P, Schraut W, Zachoval R, Wendtner C, Wächtler M, Spannagl M, Denk G, Ulsenheimer A, Bengsch B, Pircher H, Diepolder HM, Grüner NH, Jung MC. Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules. PLoS One 2014; 9:e105703. [PMID: 25144233 PMCID: PMC4140833 DOI: 10.1371/journal.pone.0105703] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 07/22/2014] [Indexed: 01/01/2023] Open
Abstract
Background T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure. Methods The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production. Results CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-γ, IL-2 and TNF-α secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control. Conclusion HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation.
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Affiliation(s)
- Bijan Raziorrouh
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
- * E-mail:
| | - Malte Heeg
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
- Department of Nephrology/Rheumatology, University of Göttingen, Göttingen, Germany
| | - Peter Kurktschiev
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | - Winfried Schraut
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | - Reinhart Zachoval
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | | | - Martin Wächtler
- Medical Department, Klinikum München-Schwabing, Munich, Germany
| | - Michael Spannagl
- Laboratory of Immunogenetics/Molecular Diagnostics, University of LMU Munich, Munich, Germany
| | - Gerald Denk
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | - Axel Ulsenheimer
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | - Bertram Bengsch
- Medical Department II, University of Freiburg, Freiburg, Germany
| | | | - Helmut M. Diepolder
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
| | - Norbert H. Grüner
- Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany
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TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. Leukemia 2014; 28:1872-84. [PMID: 24569779 DOI: 10.1038/leu.2014.84] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/17/2014] [Accepted: 02/03/2014] [Indexed: 12/16/2022]
Abstract
Transforming growth factor beta (TGF-β) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-β-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-β inhibits Tm cells, and TGF-β mediated exhaustion is associated with upregulation of CD70. We found that TGF-β upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-β is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-β-induced exhaustion of effector Tm cells. Both TGF-β-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-β-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.
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Fernandez-Ponce C, Dominguez-Villar M, Aguado E, Garcia-Cozar F. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. PLoS One 2014; 9:e85191. [PMID: 24465502 PMCID: PMC3896374 DOI: 10.1371/journal.pone.0085191] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 11/30/2013] [Indexed: 12/11/2022] Open
Abstract
Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127(low)PD-1(high)TIM-3(high) regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.
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Affiliation(s)
- Cecilia Fernandez-Ponce
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Margarita Dominguez-Villar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Enrique Aguado
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Francisco Garcia-Cozar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
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Eberhardt MK, Barry PA. Pathogen manipulation of cIL-10 signaling pathways: opportunities for vaccine development? Curr Top Microbiol Immunol 2014; 380:93-128. [PMID: 25004815 DOI: 10.1007/978-3-662-43492-5_5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Interleukin-10 (IL-10) is a tightly regulated, pleiotropic cytokine that has profound effects on all facets of the immune system, eliciting cell-type-specific responses within cells expressing the IL-10 receptor (IL-10R). It is considered a master immune regulator, and imbalances in IL-10 expression, resulting from either inherent or infectious etiologies, have far reaching clinical ramifications. Regarding infectious diseases, there has been accumulating recognition that many pathogens, particularly those that establish lifelong persistence, share a commonality of their natural histories: manipulation of IL-10-mediated signaling pathways. Multiple viral, bacterial, protozoal, and fungal pathogens appear to have evolved mechanisms to co-opt normal immune functions, including those involving IL-10R-mediated signaling, and immune effector pathways away from immune-mediated protection toward environments of immune evasion, suppression, and tolerance. As a result, pathogens can persist for the life of the infected host, many of whom possess otherwise competent immune systems. Because of pathogenic avoidance of immune clearance, persistent infections can exact incalculable physical and financial costs, and represent some of the most vexing challenges for improvements in human health. Enormous benefits could be gained by the development of efficient prevention and/or therapeutic strategies that block primary infection, or clear the infection. There are now precedents that indicate that modalities focusing on pathogen-mediated manipulation of IL-10 signaling may have clinical benefit.
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Affiliation(s)
- Meghan K Eberhardt
- Center for Comparative Medicine, University of California, Davis, CA, 95616, USA
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Overexpression of Regulatory T Cells Type 1 (Tr1) Specific Markers in a Patient with HCV-Induced Hepatocellular Carcinoma. ISRN HEPATOLOGY 2013; 2013:928485. [PMID: 27335834 PMCID: PMC4890904 DOI: 10.1155/2013/928485] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 07/24/2013] [Indexed: 01/14/2023]
Abstract
Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection.
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Langhans B, Krämer B, Louis M, Nischalke HD, Hüneburg R, Staratschek-Jox A, Odenthal M, Manekeller S, Schepke M, Kalff J, Fischer HP, Schultze JL, Spengler U. Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C. J Hepatol 2013; 59:229-35. [PMID: 23624000 DOI: 10.1016/j.jhep.2013.04.011] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/04/2013] [Accepted: 04/07/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. METHODS Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. RESULTS We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. CONCLUSIONS Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.
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Affiliation(s)
- Bettina Langhans
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
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Adeyemo O, Doi H, Reddy KR, Kaplan DE. Impact of oral silymarin on virus- and non-virus-specific T-cell responses in chronic hepatitis C infection. J Viral Hepat 2013; 20:453-62. [PMID: 23730838 PMCID: PMC3675799 DOI: 10.1111/jvh.12050] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 11/01/2012] [Indexed: 01/26/2023]
Abstract
Silymarin displays anti-inflammatory effects on T lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T cells while increasing anti-inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon nonresponders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in (3) H-thymidine proliferation assays, IFNγ ELISPOT and IL-10 ELISPOT. The frequency of CD4(+) CD25(hi) and CD4(+) foxp3(+) regulatory T cells, serum cytokine levels, serum IP-10 and lymphocyte interferon-stimulated gene expression were also quantified at baseline and week 20. Thirty-two patients were recruited (10; placebo, 11; 420 mg three times a day, 11; 700 mg three times a day). Serum ALT and HCV RNA titres did not change in any group. HCV-specific CD4(+) T-cell proliferation and the frequency of IFNγ- and IL-10-producing T cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNγ and phytohaemagglutinin-induced T-cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T cells was identified, these data confirm that high-dose oral silymarin exerts modest nonspecific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation.
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Affiliation(s)
- Oluwasayo Adeyemo
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - Hiroyoshi Doi
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - K. Rajender Reddy
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
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Abstract
BACKGROUND Bezafibrate exerts multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-α, which modulates the expression of key genes of lipid transport, lipoprotein metabolism as well as inflammation. The aim of the present study was to assess the efficacy and safety of bezafibrate in patients with advanced chronic hepatitis C. MATERIALS AND METHODS A total of 34 patients received oral bezafibrate treatment (400 mg/day) on the basis of a prospective observational open-label study design. Clinical, biochemical and virological data were evaluated during a mean treatment duration of 19 months. In a subpopulation (n=8), cytokine expression analysis was carried out and compared with an hepatitis C virus treatment-naive control group (n=7). RESULTS A significant improvement in aspartate aminotransferase (P=0.007), alanine aminotransferase (P<0.0001), alkaline phosphatase (P=0.001), γ-glutamyltranspeptidase levels (P=0.001) and aspartate aminotransferase-to-platelets ratio index Score (P=0.026) could be found at the end of observation. No significant effect on viral load was observed. Bezafibrate treatment for at least 4 months markedly increased interferon-γ expression compared with the treatment-naive patients (4.81 vs. 1.63 arbitrary units; P=0.005), whereas tumour necrosis factor-α and interleukin-6 levels were not significantly influenced. CONCLUSION This observational study provides evidence that bezafibrate is effective for patients with advanced chronic hepatitis C by reducing liver enzymes significantly and should be further evaluated as a potentially beneficial maintenance therapy.
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Howell J, Angus P, Gow P, Visvanathan K. Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment. J Gastroenterol Hepatol 2013; 28:766-76. [PMID: 23432473 DOI: 10.1111/jgh.12170] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a significant global health problem, affecting over 150 million people worldwide. While the critical role of the adaptive immune system in HCV infection is well-established, the importance of the innate immune system in HCV infection has only been recognized in more recent years. Toll-like receptors form the cornerstone of the innate immune response, and there is considerable evidence for their crucial role in hepatitis C infection. This review outlines recent advances made in our understanding of the role of Toll-like receptor function in HCV infection, exploring how HCV manipulates host immunity to evade immune clearance and establish persistent infection despite leading to inflammatory hepatic damage.
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Affiliation(s)
- Jessica Howell
- Liver Transplant Unit, Austin Hospital, Victoria, Australia.
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Schmidt J, Blum HE, Thimme R. T-cell responses in hepatitis B and C virus infection: similarities and differences. Emerg Microbes Infect 2013; 2:e15. [PMID: 26038456 PMCID: PMC3630955 DOI: 10.1038/emi.2013.14] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 02/13/2013] [Accepted: 02/17/2013] [Indexed: 01/05/2023]
Abstract
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are global health problems affecting 600 million people worldwide. Indeed, HBV and HCV are hepatotropic viruses that can cause acute and chronic liver disease progressing to liver cirrhosis and even hepatocellular carcinoma. Furthermore, co-infections of HBV and HCV with HIV are emerging worldwide. These co-infections are even more likely to develop persistent infection and are difficult to treat. There is growing evidence that virus-specific CD4+ and CD8+ T-cell responses play a central role in the outcome and pathogenesis of HBV and HCV infection. While virus-specific T-cell responses are able to successfully clear the virus in a subpopulation of patients, failure of these T-cell responses is associated with the development of viral persistence. In this review article, we will discuss similarities and differences in HBV- and HCV-specific T-cell responses that are central in determining viral clearance, persistence and liver disease.
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Affiliation(s)
- Julia Schmidt
- Department of Medicine II, University Hospital Freiburg , D-79106 Freiburg, Germany
| | - Hubert E Blum
- Department of Medicine II, University Hospital Freiburg , D-79106 Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg , D-79106 Freiburg, Germany
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Abstract
Natural killer (NK) cells are effector cells of the innate immune system and are important in the control of viral infections. Their relevance is reflected by the multiple mechanisms evolved by viruses to evade NK cell-mediated immune responses. Over recent years, our understanding of the interplay between NK cell immunity and viral pathogenesis has improved significantly. Here, we review the role of NK cells in the control of four important viral infections in humans: cytomegalovirus, influenza virus, HIV-1, and hepatitis C virus.
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Affiliation(s)
- Stephanie Jost
- Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02129, USA.
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Hajarizadeh B, Grebely J, Dore GJ. Case definitions for acute hepatitis C virus infection: a systematic review. J Hepatol 2012; 57:1349-60. [PMID: 22796896 DOI: 10.1016/j.jhep.2012.07.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 07/03/2012] [Accepted: 07/05/2012] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Case definitions for recent hepatitis C virus (HCV) infection vary considerably between studies. The aim of this systematic review was to characterize case definitions for recent HCV and explore the heterogeneity in studies performed to date. METHODS A systematic literature search of MEDLINE, SCOPUS, and ISI Web of Knowledge was performed covering all studies of recent HCV infection cited between January 2000 and June 2011. The criteria used by each study to define cases of recent HCV infection were extracted, structured, and analyzed. RESULTS Overall, 195 articles were included, with 87% (n=169) providing a clear case definition for recent HCV infection. The most frequently used individual criteria for defining a case included HCV antibody seroconversion (77%), alanine aminotransferase (ALT) elevation (68%), and HCV RNA detection (63%). In studies using HCV antibody seroconversion, the window period between the last negative and the first positive antibody test varied widely across studies (4 weeks to 4 years). Considerable diversity was also observed with respect to the ALT threshold used to characterize ALT elevations, ranging from 2 to 20 times the upper limit of normal. HCV antibody seroconversion was used as a single criterion in 41% of the studies, while all other studies used at least two criteria (range: 2-9). Epidemiology/surveillance studies mostly used a more sensitive case definition, whereas treatment studies, natural history studies, and diagnosis studies used more specific case definitions. CONCLUSIONS Marked heterogeneity in case definitions for recent HCV infection was observed. Although a single case definition for recent HCV is not warranted, a degree of standardization within specific study categories would enable improved cross-study comparison and more uniform evaluation of HCV prevention and management strategies.
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Affiliation(s)
- Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, The Kirby Institute, The University of New South Wales (UNSW), Sydney, NSW, Australia.
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Kondo Y, Ueno Y, Ninomiya M, Tamai K, Tanaka Y, Inoue J, Kakazu E, Kobayashi K, Kimura O, Miura M, Yamamoto T, Kobayashi T, Igarashi T, Shimosegawa T. Sequential immunological analysis of HBV/HCV co-infected patients during Peg-IFN/RBV therapy. J Gastroenterol 2012; 47:1323-1335. [PMID: 22588246 DOI: 10.1007/s00535-012-0596-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Accepted: 03/28/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The immunopathogenesis of dual chronic infection with hepatitis B virus and hepatitis C virus (HBV/HCV) remains unclear. The in vivo suppressive effects of each virus on the other have been reported. In this study we aimed to analyze the virological and immunological parameters of HBV/HCV coinfected patients during pegylated interferon/ribavirin (Peg-IFN/RBV) therapy. METHODS One patient with high HBV-DNA and high HCV-RNA titers (HBV-high/HCV-high) and 5 patients with low HBV-DNA and high HCV-RNA titers (HBV-low/HCV-high) were enrolled. Twenty patients monoinfected with HBV and 10 patients monoinfected with HCV were enrolled as control subjects.. In vitro cultures of Huh 7 cells with HBV/HCV dual infection were used to analyze the direct interaction of HBV/HCV. RESULTS Direct interaction of HBV clones and HCV could not be detected in the Huh-7 cells. In the HBV-high/HCV-high-patient, the HCV-RNA level gradually declined and HBV-DNA gradually increased during Peg-IFN/RBV therapy. Activated CD4- and CD8-positive T cells were increased at 1 month of Peg-IFN/RBV-therapy, but HBV-specific IFN-γ-secreting cells were not increased and HBV-specific interleukin (IL)-10 secreting cells were increased. The level of HBV- and HCV-specific IFN-γ-secreting cells in the HBV-high/HCV-high-patient was low in comparison to that in the HBV- or HCV-monoinfected patients. In the HBV-low/HCV-high-patient, HCV-RNA and HBV-DNA rapidly declined during Peg-IFN/RBV therapy. Activated CD4- and CD8-positive T cells were increased, and HBV- and HCV-specific IFN-γ-secreting cells were also increased during Peg-IFN/RBV-therapy. CONCLUSION The immunological responses of the HBV-high/HCV-high patient were low in comparison to the responses in HBV and HCV monoinfected patients. Moreover, the response of immune cells in the HBV-high/HCV-high patient during Peg-IFN/RBV therapy was insufficient to suppress HBV and HCV.
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Affiliation(s)
- Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai, Miyagi, Japan
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Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 2012; 3:610-20. [PMID: 23076334 PMCID: PMC3545943 DOI: 10.4161/viru.21823] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is a small, enveloped RNA virus and a major cause of chronic liver disease. Resolution of primary HCV infections depends upon the vigorous responses of CD4+ and CD8+ T cells to multiple viral epitopes. Although such broad-based responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Ostensibly, a variety of factors contribute to the diminished T cell responses observed in chronic, HCV-infected patients including impaired dendritic cell function and the induction of CD4+FoxP3+ regulatory T cells. Overwhelming evidence suggests that the complex interaction of dendritic cells and regulatory T cells plays a critical role in the pathogenesis of chronic hepatitis C.
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Affiliation(s)
- Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, RI, USA
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Brenndörfer ED, Sällberg M. Hepatitis C virus-mediated modulation of cellular immunity. Arch Immunol Ther Exp (Warsz) 2012; 60:315-29. [PMID: 22911132 DOI: 10.1007/s00005-012-0184-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Accepted: 03/09/2012] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic liver disease globally. A chronic infection can result in liver fibrosis, liver cirrhosis, hepatocellular carcinoma and liver failure in a significant ratio of the patients. About 170 million people are currently infected with HCV. Since 80 % of the infected patients develop a chronic infection, HCV has evolved sophisticated escape strategies to evade both the innate and the adaptive immune system. Thus, chronic hepatitis C is characterized by perturbations in the number, subset composition and/or functionality of natural killer cells, natural killer T cells, dendritic cells, macrophages and T cells. The balance between HCV-induced immune evasion and the antiviral immune response results in chronic liver inflammation and consequent immune-mediated liver injury. This review summarizes our current understanding of the HCV-mediated interference with cellular immunity and of the factors resulting in HCV persistence. A profound knowledge about the intrinsic properties of HCV and its effects on intrahepatic immunity is essential to be able to design effective immunotherapies against HCV such as therapeutic HCV vaccines.
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Affiliation(s)
- Erwin Daniel Brenndörfer
- Division of Clinical Microbiology F68, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
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50
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Abstract
The immune response in patients chronically infected with HCV plays a unique role during the infection because of its potential to contribute not only to viral clearance and, in some cases, protective immunity, but also to liver injury. A detailed understanding of the immunological mechanisms involved in persistence to HCV is essential to fully appreciate the complexity of the disease. In recent years, enormous progress has been made to characterize the dysfunctional natural killer cells and T cells during the chronic phase of infection. This information is important to further optimize treatment strategies based on the strengthening antiviral and immunomodulatory activities in patients chronically infected with HCV.
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Affiliation(s)
- Michelle Spaan
- Liver Unit, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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