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1
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [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: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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2
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Xu Q, Li L, Zhu R. T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker? Curr Allergy Asthma Rep 2025; 25:18. [PMID: 40091122 DOI: 10.1007/s11882-025-01199-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
PURPOSE OF REVIEW This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy. RECENT FINDINGS Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.
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Affiliation(s)
- Qingxiu Xu
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Le Li
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Rongfei Zhu
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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3
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Iyyanar S, Ravi SN. Vaccine Development T-cell (MHC-I) Epitopes Identification Against the Indian HCV Genotype: An Approach Based on Immunoinformatic. Mol Biotechnol 2025:10.1007/s12033-025-01398-5. [PMID: 39994132 DOI: 10.1007/s12033-025-01398-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 01/30/2025] [Indexed: 02/26/2025]
Abstract
Hepatitis C virus (HCV) infects approximately 58 million individuals worldwide, often progressing to chronic liver disease, cirrhosis, and hepatocellular carcinoma. The viral envelope glycoproteins E1 and E2 are critical for HCV entry and serve as primary targets for neutralizing antibodies. Recent advancements in cryo-electron tomography have provided high-resolution structures (3.5 Å) of the E1E2 heterodimer, revealing interactions between the E1 and E2 ectodomains, as well as neutralizing antibody complexes (e.g., AR4A, AT1209, IGH505). This structural information facilitates the design of a synthetic peptide vaccine targeting conserved E1 and E2 regions. We suggest developing a vaccine tailored to the HLA-A*24:02 allele, the most prevalent in the Indian population. Epitope candidates will be screened using immunoinformatics tools, incorporating epitopes derived from epitope mapping with 7t6x protein structure modeling. Molecular docking studies will identify high-affinity interactions with human MHC-Class I alleles, using tools such as AutoDock and HADDOCK. GROMACS molecular dynamics simulations will assess peptide-HLA binding stability and dynamics. Among ten screened epitopes, KWEYVVLLF and QWQVLPCSF emerged as the most promising based on their toxicity profiles, conservation, and docking scores with HLA-A*24:02 (- 9.3 kcal/mol for KWEYVVLLF and - 225.34 kcal/mol for QWQVLPCSF). Molecular dynamics simulations indicated that the KWEY segment of KWEYVVLLF underwent structural changes, while the VVLLF region maintained stable binding to Chain A, suggesting immunogenic potential. These epitopes represent strong candidates for T-cell-based vaccines, and the reverse vaccinology approach, supported by computational tools, offers a population-specific strategy for HCV vaccine development, advancing precision immunotherapy.
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Affiliation(s)
- Sridevi Iyyanar
- Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Sai Nandhini Ravi
- Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai, Tamil Nadu, India.
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Machraoui S, Hakmaoui A, Errafii K, Knidiri M, Essaadouni L, Krati K, Admou B. HLA Class I (A and B) Allele Polymorphism in a Moroccan Population Infected with Hepatitis C Virus. Curr Issues Mol Biol 2024; 46:14080-14094. [PMID: 39727970 DOI: 10.3390/cimb46120842] [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: 11/05/2024] [Revised: 11/28/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatitis C virus (HCV) infection is one of the major health burdens worldwide. Its course depends on the virus itself and the host's immune responses. The latter are conditioned by immunogenetic factors, in particular human leukocyte antigens (HLAs), whose role in determining the outcome of infection varies according to populations and ethnic groups. The current study attempted to investigate the possible relationship between HLA-A and HLA-B allele polymorphism and its impacts on the clinical outcome of HCV for a better understanding of disease susceptibility and clearance. A cross-sectional and comparative study was carried out on 40 patients with hepatitis C and 100 ethnically matched healthy control subjects originating from southern Morocco. HLA class I alleles were typed using the high-resolution PCR-SSO method. The prevalence of certain HLA class I alleles differed significantly between HCV-infected individuals and healthy controls. In particular, HLA-A*02:01 was less prevalent in chronic HCV infection (p = 0.002), indicating a potential protective effect, while the higher prevalence of HLA-A*68:02, A*66:01 B*15:03, B*41:02, B*44:03, and B*50:01 in patients could indicate a predisposing factor. These findings support the association of these immunogenetic markers with HCV infection, indicating their possible role in determining clinical and genotype forms as well as the outcome of HCV infection. Thus, an in-depth analysis of these alleles could lead to a better understanding of HCV pathogenesis and potential targeted interventions.
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Affiliation(s)
- Safa Machraoui
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
- 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
| | - Abdelmalek Hakmaoui
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Mehdi Knidiri
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Lamiaa Essaadouni
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
| | - Khadija Krati
- Gastroenterology Department, Arrazi Hospital, Mohammed VI University Hospital Center, Marrakech 40000, Morocco
| | - Brahim Admou
- Laboratory of Immunology and Human Leukocyte Antigen, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
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5
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Nagarathinam K, Scheck A, Labuhn M, Ströh LJ, Herold E, Veselkova B, Tune S, Cramer JT, Rosset S, Vollers SS, Bankwitz D, Ballmaier M, Böning H, Roth E, Khera T, Ahsendorf-Abidi HP, Dittrich-Breiholz O, Obleser J, Nassal M, Jäck HM, Pietschmann T, Correia BE, Krey T. Epitope-focused immunogens targeting the hepatitis C virus glycoproteins induce broadly neutralizing antibodies. SCIENCE ADVANCES 2024; 10:eado2600. [PMID: 39642219 PMCID: PMC11623273 DOI: 10.1126/sciadv.ado2600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 11/04/2024] [Indexed: 12/08/2024]
Abstract
Hepatitis C virus (HCV) infection causes ~290,000 annual human deaths despite the highly effective antiviral treatment available. Several viral immune evasion mechanisms have hampered the development of an effective vaccine against HCV, among them the remarkable conformational flexibility within neutralization epitopes in the HCV antigens. Here, we report the design of epitope-focused immunogens displaying two distinct HCV cross-neutralization epitopes. We show that these immunogens induce a pronounced, broadly neutralizing antibody response in laboratory and transgenic human antibody mice. Monoclonal human antibodies isolated from immunized human antibody mice specifically recognized the grafted epitopes and neutralized four diverse HCV strains. Our results highlight a promising strategy for developing HCV immunogens and provide an encouraging paradigm for targeting structurally flexible epitopes to improve the induction of neutralizing antibodies.
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Affiliation(s)
- Kumar Nagarathinam
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Andreas Scheck
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Maurice Labuhn
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Luisa J. Ströh
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Elisabeth Herold
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Barbora Veselkova
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Sarah Tune
- Department of Psychology, University of Lübeck, 23562 Lübeck, Germany
- Center of Brain, Behavior, and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | | | - Stéphane Rosset
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Sabrina S. Vollers
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Dorothea Bankwitz
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Matthias Ballmaier
- Central Research Facility Cell Sorting, Hannover Medical School, 30625 Hannover, Germany
| | - Heike Böning
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Edith Roth
- Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tanvi Khera
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | | | | | - Jonas Obleser
- Department of Psychology, University of Lübeck, 23562 Lübeck, Germany
- Center of Brain, Behavior, and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | - Michael Nassal
- Department of Internal Medicine 2/Molecular Biology, University Hospital Freiburg, 79106 Freiburg, Germany
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Thomas Pietschmann
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, 30625 Hannover, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, 30625 Hannover, Germany
| | - Bruno E. Correia
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Thomas Krey
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, 38124 Braunschweig, Germany
- Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany
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6
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Layug PJ, Vats H, Kannan K, Arsenio J. Sex differences in CD8 + T cell responses during adaptive immunity. WIREs Mech Dis 2024; 16:e1645. [PMID: 38581141 DOI: 10.1002/wsbm.1645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 02/08/2024] [Accepted: 03/14/2024] [Indexed: 04/08/2024]
Abstract
Biological sex is an important variable that influences the immune system's susceptibility to infectious and non-infectious diseases and their outcomes. Sex dimorphic features in innate and adaptive immune cells and their activities may help to explain sex differences in immune responses. T lymphocytes in the adaptive immune system are essential to providing protection against infectious and chronic inflammatory diseases. In this review, T cell responses are discussed with focus on the current knowledge of biological sex differences in CD8+ T cell mediated adaptive immune responses in infectious and chronic inflammatory diseases. Future directions aimed at investigating the molecular and cellular mechanisms underlying sex differences in diverse T cell responses will continue to underscore the significance of understanding sex differences in protective immunity at the cellular level, to induce appropriate T cell-based immune responses in infection, autoimmunity, and cancer. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Paul Jerard Layug
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Centre for Proteomics and Systems Biology, Winnipeg, Manitoba, Canada
| | - Harman Vats
- Manitoba Centre for Proteomics and Systems Biology, Winnipeg, Manitoba, Canada
- Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Kamali Kannan
- Manitoba Centre for Proteomics and Systems Biology, Winnipeg, Manitoba, Canada
- Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Janilyn Arsenio
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Centre for Proteomics and Systems Biology, Winnipeg, Manitoba, Canada
- Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
- Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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7
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Costa GL, Sautto GA. Exploring T-Cell Immunity to Hepatitis C Virus: Insights from Different Vaccine and Antigen Presentation Strategies. Vaccines (Basel) 2024; 12:890. [PMID: 39204016 PMCID: PMC11359689 DOI: 10.3390/vaccines12080890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
The hepatitis C virus (HCV) is responsible for approximately 50 million infections worldwide. Effective drug treatments while available face access barriers, and vaccine development is hampered by viral hypervariability and immune evasion mechanisms. The CD4+ and CD8+ T-cell responses targeting HCV non-structural (NS) proteins have shown a role in the viral clearance. In this paper, we reviewed the studies exploring the relationship between HCV structural and NS proteins and their effects in contributing to the elicitation of an effective T-cell immune response. The use of different vaccine platforms, such as viral vectors and virus-like particles, underscores their versability and efficacy for vaccine development. Diverse HCV antigens demonstrated immunogenicity, eliciting a robust immune response, positioning them as promising vaccine candidates for protein/peptide-, DNA-, or RNA-based vaccines. Moreover, adjuvant selection plays a pivotal role in modulating the immune response. This review emphasizes the importance of HCV proteins and vaccination strategies in vaccine development. In particular, the NS proteins are the main focus, given their pivotal role in T-cell-mediated immunity and their sequence conservation, making them valuable vaccine targets.
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Affiliation(s)
| | - Giuseppe A. Sautto
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA;
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8
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Reisch C, Nickel S, Tautenhahn HM. Building up a model family for inflammations. J Math Biol 2024; 89:29. [PMID: 39012511 PMCID: PMC11252204 DOI: 10.1007/s00285-024-02126-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 05/17/2024] [Accepted: 07/07/2024] [Indexed: 07/17/2024]
Abstract
The paper presents an approach for overcoming modeling problems of typical life science applications with partly unknown mechanisms and lacking quantitative data: A model family of reaction-diffusion equations is built up on a mesoscopic scale and uses classes of feasible functions for reaction and taxis terms. The classes are found by translating biological knowledge into mathematical conditions and the analysis of the models further constrains the classes. Numerical simulations allow comparing single models out of the model family with available qualitative information on the solutions from observations. The method provides insight into a hierarchical order of the mechanisms. The method is applied to the clinics for liver inflammation such as metabolic dysfunction-associated steatohepatitis or viral hepatitis where reasons for the chronification of disease are still unclear and time- and space-dependent data is unavailable.
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Affiliation(s)
- Cordula Reisch
- Institute for Partial Differential Equations, Technische Universität Braunschweig, Universitätsplatz 2, 38106, Braunschweig, Germany.
| | - Sandra Nickel
- Clinic for Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Liebigstrasse 20, 04103, Leipzig, Germany
| | - Hans-Michael Tautenhahn
- Clinic for Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Liebigstrasse 20, 04103, Leipzig, Germany
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9
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [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: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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10
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Pierce BG, Felbinger N, Metcalf M, Toth EA, Ofek G, Fuerst TR. Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development. Viruses 2024; 16:803. [PMID: 38793684 PMCID: PMC11125608 DOI: 10.3390/v16050803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/02/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatitis C virus (HCV) is a major medical health burden and the leading cause of chronic liver disease and cancer worldwide. More than 58 million people are chronically infected with HCV, with 1.5 million new infections occurring each year. An effective HCV vaccine is a major public health and medical need as recognized by the World Health Organization. However, due to the high variability of the virus and its ability to escape the immune response, HCV rapidly accumulates mutations, making vaccine development a formidable challenge. An effective vaccine must elicit broadly neutralizing antibodies (bnAbs) in a consistent fashion. After decades of studies from basic research through clinical development, the antigen of choice is considered the E1E2 envelope glycoprotein due to conserved, broadly neutralizing antigenic domains located in the constituent subunits of E1, E2, and the E1E2 heterodimeric complex itself. The challenge has been elicitation of robust humoral and cellular responses leading to broad virus neutralization due to the relatively low immunogenicity of this antigen. In view of this challenge, structure-based vaccine design approaches to stabilize key antigenic domains have been hampered due to the lack of E1E2 atomic-level resolution structures to guide them. Another challenge has been the development of a delivery platform in which a multivalent form of the antigen can be presented in order to elicit a more robust anti-HCV immune response. Recent nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both the cellular and humoral components of the immune system. This review focuses on recent advances in understanding the E1E2 heterodimeric structure to facilitate a rational design approach and the potential for development of a multivalent nanoparticle-based HCV E1E2 vaccine. Both aspects are considered important in the development of an effective HCV vaccine that can effectively address viral diversity and escape.
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Affiliation(s)
- Brian G. Pierce
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Nathaniel Felbinger
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Matthew Metcalf
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Eric A. Toth
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
| | - Gilad Ofek
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Thomas R. Fuerst
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA; (B.G.P.); (N.F.); (M.M.); (E.A.T.); (G.O.)
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
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11
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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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12
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Das S, Behera P, Shewale DJ, Bodele J, Das S, Karande AA. Development of an effective single-chain variable fragment recognizing a novel epitope in the hepatitis C virus E2 protein that restricts virus entry into hepatocytes. Arch Virol 2024; 169:112. [PMID: 38683226 DOI: 10.1007/s00705-024-06024-4] [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: 09/15/2023] [Accepted: 03/09/2024] [Indexed: 05/01/2024]
Abstract
Previously, we reported a neutralizing monoclonal antibody, A8A11, raised against a novel conserved epitope within the hepatitis C virus (HCV) E2 protein, that could significantly reduce HCV replication. Here, we report the nucleotide sequence of A8A11 and demonstrate the efficacy of a single-chain variable fragment (scFv) protein that mimics the antibody, inhibits the binding of an HCV virus-like particle to hepatocytes, and reduces viral RNA replication in a cell culture system. More importantly, scFv A8A11 was found to effectively restrict the increase of viral RNA levels in the serum of HCV-infected chimeric mice harbouring human hepatocytes. These results suggest a promising approach to neutralizing-antibody-based therapeutic interventions against HCV infection.
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Affiliation(s)
- Soma Das
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
| | - Padmanava Behera
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India
| | - Dipeshwari J Shewale
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
| | - Janhavi Bodele
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Anjali A Karande
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
- Centre For Human Genetics, Biotech Park, Bangalore, 560012, India
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13
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Woo J, Choi Y. Biomarkers in Detection of Hepatitis C Virus Infection. Pathogens 2024; 13:331. [PMID: 38668286 PMCID: PMC11054098 DOI: 10.3390/pathogens13040331] [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: 04/01/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
| | - Youkyung Choi
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA 30329-4018, USA;
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Mondal A, Sarkar A, Das D, Sengupta A, Kabiraj A, Mondal P, Nag R, Mukherjee S, Das C. Epigenetic orchestration of the DNA damage response: Insights into the regulatory mechanisms. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 387:99-141. [PMID: 39179350 DOI: 10.1016/bs.ircmb.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
Abstract
The DNA damage response (DDR) is a critical cellular mechanism that safeguards genome integrity and prevents the accumulation of harmful DNA lesions. Increasing evidence highlights the intersection between DDR signaling and epigenetic regulation, offering profound insights into various aspects of cellular function including oncogenesis. This comprehensive review explores the intricate relationship between the epigenetic modifications and DDR activation, with a specific focus on the impact of viral infections. Oncogenic viruses, such as human papillomavirus, hepatitis virus (HBV or HCV), and Epstein-Barr virus have been shown to activate the DDR. Consequently, these DNA damage events trigger a cascade of epigenetic alterations, including changes in DNA methylation patterns, histone modifications and the expression of noncoding RNAs. These epigenetic changes exert profound effects on chromatin structure, gene expression, and maintenance of genome stability. Importantly, elucidation of the viral-induced epigenetic alterations in the context of DDR holds significant implications for comprehending the complexity of cancer and provides potential targets for therapeutic interventions.
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Affiliation(s)
- Atanu Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | | | - Dipanwita Das
- Virus Unit [NICED-ICMR], ID and BG Hospital, Kolkata, India
| | - Amrita Sengupta
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Aindrila Kabiraj
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Payel Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Rachayita Nag
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India.
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15
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English K, Kwan R, Holz LE, McGuffog C, Krol JMM, Kempe D, Kaisho T, Heath WR, Lisowski L, Biro M, McCaughan GW, Bowen DG, Bertolino P. A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs. Nat Commun 2024; 15:1261. [PMID: 38341416 PMCID: PMC10858872 DOI: 10.1038/s41467-024-45612-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
While CD4+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions.
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Affiliation(s)
- Kieran English
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
| | - Rain Kwan
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Lauren E Holz
- Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Claire McGuffog
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Jelte M M Krol
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
- Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Daryan Kempe
- EMBL Australia, Single Molecule Science node, School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - William R Heath
- Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Leszek Lisowski
- Children's Medical Research Institute, Translational Vectorology Research Unit, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Maté Biro
- EMBL Australia, Single Molecule Science node, School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Geoffrey W McCaughan
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
| | - Patrick Bertolino
- Centenary Institute and The University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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16
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Tsukanov VV, Savchenko AA, Cherepnin MA, Vasyutin AV, Kasparov EV, Belenyuk VD, Tonkikh JL, Borisov AG. Subpopulation composition of blood T-helpers in hepatitis C patients with genotype 1 or 3. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:168-176. [DOI: 10.21518/ms2023-447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Introduction. Despite advances in treatment, the problem of chronic viral hepatitis C (CVHC) remains very relevant for Russia. There is a debate about which of the most common genotypes in our country: 1 or 3, has a more aggressive course of CVHC. Patients with CVHC exhibit dysfunction of T-cell immunity, many aspects of which remain unclear.Aim. To research the subpopulation composition of blood T-helpers in patients with genotypes 1 and 3 of chronic viral hepatitis C (CVHC) depending on the severity of clinical and morphological manifestations.Materials and methods. Clinical, laboratory examination and determination of liver fibrosis by elastometry using the METAVIR scale were performed in 297 patients with CVHC genotype 1, 231 patients with CVHC genotype 3, and 20 healthy individuals in the control group. The study of the subpopulation composition of T-helpers in the blood by flow cytometry (Navios, Beckman Coulter, USA) with the determination of markers CD3, CD4, CD45R0 and CD62L was carried out in 74 patients with CVHC genotype 1, 70 patients with CVHC genotype 3 and 20 people in the control group.Results. Naive T-helpers (CD3+CD4+CD45RO-CD62L+), T-helpers of central (CD3+CD4+CD45R0+CD62L+) and effector memory (CD3+CD4+CD45R0+CD62L–) in the blood decreased with an increase in the severity of fibrosis and inflammation activity in the liver in both examined groups. In patients with CVHC genotype 3, the content of TEMRA T-helpers (CD3+CD4+CD45R0-CD62L-) in the blood under these conditions sharply decreased (Kruskal – Wallis test, respectively, p = 0.04 and p = 0.02). In patients with CVHC genotype 1, no such patterns were registered (Kruskal – Wallis test, respectively, p = 0.8 and p = 0.87).Conclusion. A direct correlation was determined between the deterioration of the indicators of the blood T-helpers subpopulation composition with an increase in the severity of fibrosis and inflammation activity in the liver in patients with chronic hepatitis C, which had some differences in patients with genotypes 1 and 3.
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Affiliation(s)
- V. V. Tsukanov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. A. Savchenko
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - M. A. Cherepnin
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. V. Vasyutin
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - E. V. Kasparov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - V. D. Belenyuk
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - Ju. L. Tonkikh
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. G. Borisov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
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Dravid P, Murthy S, Attia Z, Cassady C, Chandra R, Trivedi S, Vyas A, Gridley J, Holland B, Kumari A, Grakoui A, Cullen JM, Walker CM, Sharma H, Kapoor A. Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection. PLoS Pathog 2023; 19:e1011697. [PMID: 37812637 PMCID: PMC10602381 DOI: 10.1371/journal.ppat.1011697] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/26/2023] [Accepted: 09/19/2023] [Indexed: 10/11/2023] Open
Abstract
Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.
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Affiliation(s)
- Piyush Dravid
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Satyapramod Murthy
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Zayed Attia
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Cole Cassady
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Rahul Chandra
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Sheetal Trivedi
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Ashish Vyas
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - John Gridley
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Brantley Holland
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Anuradha Kumari
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Arash Grakoui
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - John M. Cullen
- North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, United States of America
| | - Christopher M. Walker
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Himanshu Sharma
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Amit Kapoor
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
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18
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Toth EA, Andrianov AK, Fuerst TR. Prospects for developing an Hepatitis C virus E1E2-based nanoparticle vaccine. Rev Med Virol 2023; 33:e2474. [PMID: 37565536 PMCID: PMC10626635 DOI: 10.1002/rmv.2474] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/12/2023]
Abstract
Globally, more than 58 million people are chronically infected with Hepatitis C virus (HCV) with 1.5 million new infections occurring each year. An effective vaccine for HCV is therefore a major unmet medical and public health need. Since HCV rapidly accumulates mutations, vaccines must elicit the production of broadly neutralising antibodies (bnAbs) in a reproducible fashion. Decades of research have generated a number of HCV vaccine candidates. Based on the available data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice, but robust induction of humoral and cellular responses leading to virus neutralisation has not yet been achieved. One issue that has arisen in developing an HCV vaccine (and many other vaccines as well) is the platform used for antigen delivery. The majority of viral vaccine trials have employed subunit vaccines. However, subunit vaccines often have limited immunogenicity, as seen for HCV, and thus multiple formats must be examined in order to elicit a robust anti-HCV immune response. Nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both arms of the immune system. This review discusses the potential for development of a nanoparticle-based HCV E1E2 vaccine, with an emphasis on the potential benefits of such an approach along with the major challenges facing the incorporation of E1E2 into nanoparticulate delivery systems and how those challenges can be addressed.
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Affiliation(s)
- Eric A. Toth
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
| | - Alexander K. Andrianov
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
| | - Thomas R. Fuerst
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
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19
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Lu X, Song B, Weng W, Su B, Wu H, Cheung AKL, Zhang T, Gao Y. Characteristics of CD8 + Stem Cell-Like Memory T Cell Subset in Chronic Hepatitis C Virus Infection. Viral Immunol 2023; 36:25-32. [PMID: 36346310 DOI: 10.1089/vim.2022.0079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The dysfunction of memory CD8+ T cell cannot be reverted by successful clearance of hepatitis C virus (HCV) after direct-acting antivirals (DAAs) therapy, increasing the risk of reinfection with HCV. Stem cell-like memory T cells (Tscm) with superior properties of long-lasting, self-renewing, and multipotency contribute to the maintenance of immune function. We investigated the impact of HCV infection on CD8+ Tscm, and their possible role in disease progression, by using DAA-naive HCV-infected and human immunodeficiency virus (HIV)/HCV-coinfected cohorts. The distribution of memory CD8+ T cell subsets and the level of T cell immune activation were determined by flow cytometry. Associations between CD8+ Tscm and other memory T cell subsets, HCV viral load, as well as the level of T cell immune activation were analyzed. We observed that the proportion of CD8+ Tscm increased in both HCV and HIV/HCV individuals. The proportion of CD8+ Tscm had positive and negative correlation with CD8+ Tcm (central memory T cells) and CD8+ Tem (effector memory T cell), respectively, representing the contribution of CD8+ Tscm in T cell homeostasis. In addition, higher frequency of CD8+ Tscm indicated lower HCV viral load and less T cell immune activation in HCV infection, which suggested that CD8+ Tscm is likely associated with effective control of HCV replication for protective immunity. Considering the characteristics of Tscm, our current findings provide implications for Tscm-based vaccine design and immunotherapy development to achieve HCV elimination.
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Affiliation(s)
- Xiaofan Lu
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bingbing Song
- Department of Dermatology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Department of Dermatology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Wenjia Weng
- Department of Dermatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hao Wu
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Allen Ka Loon Cheung
- Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, China
| | - Tong Zhang
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yanqing Gao
- Department of Dermatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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20
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Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
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21
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Chao E, Chato C, Vender R, Olabode AS, Ferreira RC, Poon AFY. Molecular source attribution. PLoS Comput Biol 2022; 18:e1010649. [PMID: 36395093 PMCID: PMC9671344 DOI: 10.1371/journal.pcbi.1010649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Elisa Chao
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Connor Chato
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Reid Vender
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
- School of Medicine, Queen’s University, Kingston, Ontario, Canada
| | - Abayomi S. Olabode
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Roux-Cil Ferreira
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Art F. Y. Poon
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
- * E-mail:
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22
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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23
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Huang CH, Fan JH, Jeng WJ, Chang ST, Yang CK, Teng W, Wu TH, Hsieh YC, Chen WT, Chen YC, Sheen IS, Lin YC, Lin CY. Innate-like bystander-activated CD38 + HLA-DR + CD8 + T cells play a pathogenic role in patients with chronic hepatitis C. Hepatology 2022; 76:803-818. [PMID: 35060158 DOI: 10.1002/hep.32349] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.
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Affiliation(s)
- Chien-Hao Huang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Jian-He Fan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Shu-Ting Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chan-Keng Yang
- Division of Medical Oncology/Hematology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei Teng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Tsung-Han Wu
- Division of General Surgery, Chang-Gung Memorial Hospital, Linkou Medical Center, Taiwan
| | - Yi-Chung Hsieh
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Yi-Cheng Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - I-Shyan Sheen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Yung-Chang Lin
- Division of Medical Oncology/Hematology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Yen Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
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24
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“The Good, the Bad and the Ugly”: Interplay of Innate Immunity and Inflammation. Cell Microbiol 2022. [DOI: 10.1155/2022/2759513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Innate immunity recognizes microorganisms through certain invariant receptors named pattern recognition receptors (PRRs) by sensing conserved pathogen-associated molecular patterns (PAMPs). Their recognition activates several signaling pathways that lead the transcription of inflammatory mediators, contributing to trigger a very rapid inflammatory cascade aiming to contain the local infection as well as activating and instructing the adaptive immunity in a specific and synchronized immune response according to the microorganism. Inflammation is a coordinated process involving the secretion of cytokines and chemokines by macrophages and neutrophils leading to the migration of other leukocytes along the endothelium into the injured tissue. Sustained inflammatory responses can cause deleterious effects by promoting the development of autoimmune disorders, allergies, cancer, and other immune pathologies, while weak signals could exacerbate the severity of the disease. Therefore, PRR-mediated signal transduction must be tightly regulated to maintain host immune homeostasis. Innate immunity deficiencies and strategies deployed by microbes to avoid inflammatory responses lead to an altered immune response that allows the pathogen to proliferate causing death or uncontrolled inflammation. This review analyzes the complexity of the immune response at the beginning of the disease focusing on COVID-19 disease and the importance of unraveling its mechanisms to be considered when treating diseases and designing vaccines.
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25
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Wildner NH, Walker A, Brauneck F, Ditt V, Peine S, Huber S, Haag F, Beisel C, Timm J, Schulze zur Wiesch J. Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition. Front Immunol 2022; 13:886646. [PMID: 35734162 PMCID: PMC9207347 DOI: 10.3389/fimmu.2022.886646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/13/2022] [Indexed: 12/26/2022] Open
Abstract
Thymocyte selection-associated high mobility group box (TOX) has been described to be a key regulator in the formation of CD8+ T cell exhaustion. Hepatitis C virus (HCV) infection with different lengths of antigen exposure in acute, chronic, and after resolution of HCV infection is the ideal immunological model to study the expression of TOX in HCV-specific CD8+ T cells with different exposure to antigen. HCV-specific CD8+ T cells from 35 HLA-A*01:01, HLA-A*02:01, and HLA-A*24:02 positive patients were analyzed with a 16-color FACS-panel evaluating the surface expression of lineage markers (CD3, CD8), ectoenzymes (CD39, CD73), markers of differentiation (CD45RO, CCR7, CD127), and markers of exhaustion and activation (TIGIT, PD-1, KLRG1, CD226) and transcription factors (TOX, Eomesodermin, T-bet). Here, we defined on-target T cells as T cells against epitopes without escape mutations and off-target T cells as those against a "historical" antigen mutated in the autologous sequence. TOX+HCV-specific CD8+ T cells from patients with chronic HCV and on-target T cells displayed co-expression of Eomesodermin and were associated with the formation of terminally exhausted CD127-PD1hi, CD39hi, CD73low CD8+ T cells. In contrast, TOX+HCV-specific CD8+ T cells in patients with off-target T cells represented a progenitor memory Tex phenotype characterized by CD127hi expression and a CD39low and CD73hi phenotype. TOX+HCV-specified CD8+ T cells in patients with a sustained virologic response were characterized by a memory phenotype (CD127+, CD73hi) and co-expression of immune checkpoints and Eomesodermin, indicating a key structure in priming of HCV-specific CD8+ T cells in the chronic stage, which persisted as a residual after therapy. Overall, the occurrence of TOX+HCV-specific CD8+ T cells was revealed at each disease stage, which impacted the development of progenitor Tex, intermediate Tex, and terminally exhausted T cell through an individual molecular footprint. In sum, TOX is induced early during acute infection but is modulated by changes in viral sequence and antigen recognition. In the case of antigen persistence, the interaction with Eomesodermin leads to the formation of terminally exhausted virus-specific CD8+ T cells, and there was a direct correlation of the co-expression of TOX and Eomes and terminally exhausted phenotype of virus-specific CD8+ T cells.
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Affiliation(s)
- Nils H. Wildner
- I. Department of Medicine, Section of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Walker
- Institute of Virology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Franziska Brauneck
- II. Department of Medicine, Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Vanessa Ditt
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Peine
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, Section of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Friedrich Haag
- Institute of Immunology, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Beisel
- I. Department of Medicine, Section of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Joerg Timm
- Institute of Virology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany
| | - Julian Schulze zur Wiesch
- I. Department of Medicine, Section of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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26
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Wang R, Suzuki S, Guest JD, Heller B, Almeda M, Andrianov AK, Marin A, Mariuzza RA, Keck ZY, Foung SKH, Yunus AS, Pierce BG, Toth EA, Ploss A, Fuerst TR. Induction of broadly neutralizing antibodies using a secreted form of the hepatitis C virus E1E2 heterodimer as a vaccine candidate. Proc Natl Acad Sci U S A 2022; 119:e2112008119. [PMID: 35263223 PMCID: PMC8931252 DOI: 10.1073/pnas.2112008119] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 01/19/2022] [Indexed: 11/26/2022] Open
Abstract
SignificanceHepatitis C virus chronically infects approximately 1% of the world's population, making an effective vaccine for hepatitis C virus a major unmet public health need. The membrane-associated E1E2 envelope glycoprotein has been used in clinical studies as a vaccine candidate. However, limited neutralization breadth and difficulty in producing large amounts of homogeneous membrane-associated E1E2 have hampered efforts to develop an E1E2-based vaccine. Our previous work described the design and biochemical validation of a native-like soluble secreted form of E1E2 (sE1E2). Here, we describe the immunogenic characterization of the sE1E2 complex. sE1E2 elicited broadly neutralizing antibodies in immunized mice, with increased neutralization breadth relative to the membrane-associated E1E2, thereby validating this platform as a promising model system for vaccine development.
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Affiliation(s)
- Ruixue Wang
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Saori Suzuki
- Department of Molecular Biology, Princeton University, Princeton, NJ 08540
| | - Johnathan D. Guest
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Brigitte Heller
- Department of Molecular Biology, Princeton University, Princeton, NJ 08540
| | - Maricar Almeda
- Department of Molecular Biology, Princeton University, Princeton, NJ 08540
| | - Alexander K. Andrianov
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Alexander Marin
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Roy A. Mariuzza
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Zhen-Yong Keck
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
| | - Steven K. H. Foung
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
| | - Abdul S. Yunus
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Brian G. Pierce
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Eric A. Toth
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08540
| | - Thomas R. Fuerst
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
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27
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Di Marco L, La Mantia C, Di Marco V. Hepatitis C: Standard of Treatment and What to Do for Global Elimination. Viruses 2022; 14:505. [PMID: 35336911 PMCID: PMC8954407 DOI: 10.3390/v14030505] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/09/2022] [Accepted: 02/21/2022] [Indexed: 12/04/2022] Open
Abstract
Hepatitis C virus infection has a substantial effect on morbidity and mortality worldwide because it is a cause of cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related death. Direct acting antiviral drugs available today have high efficacy and excellent safety and can be used in all patients with clinically evident chronic liver disease and in groups that demonstrate risk behaviors to reduce the spread of infection. The Global Health Strategy of WHO to eliminate hepatitis infection by 2030 assumes "a 90% reduction in new cases of chronic hepatitis C, a 65% reduction in hepatitis C deaths, and treatment of 80% of eligible people with HCV infections". In this review effective models and strategies for achieving the global elimination of HCV infection are analyzed. The screening strategies must be simple and equally effective in high-risk groups and in the general population; fast and effective models for appropriate diagnosis of liver disease are needed; strategies for direct acting antiviral drug selection must be cost-effective; linkage to care models in populations at risk and in marginalized social classes must be specifically designed and applied; strategies for obtaining an effective vaccine against HCV infection have yet to be developed.
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Affiliation(s)
- Lorenza Di Marco
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena & Reggio Emilia, 41100 Modena, Italy
| | - Claudia La Mantia
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy;
| | - Vito Di Marco
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy;
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28
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Nguyen LN, Nguyen LNT, Zhao J, Schank M, Dang X, Cao D, Khanal S, Thakuri BKC, Zhang J, Lu Z, Wu XY, El Gazzar M, Ning S, Wang L, Moorman JP, Yao ZQ. Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection. Hepatology 2021; 74:2380-2394. [PMID: 34110660 PMCID: PMC8542603 DOI: 10.1002/hep.32008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/10/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. APPROACH AND RESULTS Here, we demonstrated that circulating CD4+ T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127- killer cell lectin-like receptor G1+ . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4+ T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. CONCLUSIONS These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
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Affiliation(s)
- Lam Nhat Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Lam Ngoc Thao Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Juan Zhao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Madison Schank
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Xindi Dang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Dechao Cao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Sushant Khanal
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Bal Krishna Chand Thakuri
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Jinyu Zhang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Zeyuan Lu
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Xiao Y Wu
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Mohamed El Gazzar
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Shunbin Ning
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Ling Wang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN
| | - Jonathan P Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN.,Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN
| | - Zhi Q Yao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.,Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN.,Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN
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29
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Borgia M, Dal Bo M, Toffoli G. Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13174387. [PMID: 34503196 PMCID: PMC8431318 DOI: 10.3390/cancers13174387] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma pathogenesis is dependent on a chronic inflammation caused by several factors, including hepatotropic viruses, such as HCV and HBV. This chronic inflammation is established in the context of the immunotolerogenic environment peculiar of the liver, in which the immune system can be stimulated by HCV and HBV viral antigens. This complex interaction can be influenced by direct-acting antiviral drug treatments, capable of (almost totally) rapidly eradicating HCV infection. The influence of anti-viral treatments on HCC pathogenesis and progression remains to be fully clarified. Abstract Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.
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Hartlage AS, Kapoor A. Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up. Viruses 2021; 13:1596. [PMID: 34452460 PMCID: PMC8402855 DOI: 10.3390/v13081596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/27/2021] [Accepted: 07/31/2021] [Indexed: 12/16/2022] Open
Abstract
Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development.
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Affiliation(s)
- Alex S. Hartlage
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Medical Scientist Training Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
| | - Amit Kapoor
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
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31
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Colucci G, Invernizzi F, Uceda Renteria S, Perbellini R, Degasperi E, D'Ambrosio R, Galmozzi E, Lunghi G, Sguazzini E, Lampertico P, Donato MF. The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles. Viral Immunol 2021; 34:542-551. [PMID: 34252334 DOI: 10.1089/vim.2021.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R (p > 0.01) and CHC (p > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC (p > 0.05 and p = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R (p < 0.01) and in CHC, but only at FU (p < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R (p < 0.03) and CHC (p < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.
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Affiliation(s)
- Giuseppe Colucci
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Federica Invernizzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Sara Uceda Renteria
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Riccardo Perbellini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Elisabetta Degasperi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Roberta D'Ambrosio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Enrico Galmozzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Giovanna Lunghi
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Enrico Sguazzini
- Department of Medical Biotechnology, Università Degli Studi di Milano, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy.,Department of Medical Surgical Physiopatology and Transplantation, University of Milan, Milan, Italy
| | - Maria Francesca Donato
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
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Llorens-Revull M, Costafreda MI, Rico A, Guerrero-Murillo M, Soria ME, Píriz-Ruzo S, Vargas-Accarino E, Gabriel-Medina P, Rodríguez-Frías F, Riveiro-Barciela M, Perales C, Quer J, Sauleda S, Esteban JI, Bes M. Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy. PLoS One 2021; 16:e0254243. [PMID: 34242330 PMCID: PMC8270431 DOI: 10.1371/journal.pone.0254243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND & AIMS HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. METHODS We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. RESULTS We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. CONCLUSIONS Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA's therapies.
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Affiliation(s)
- Meritxell Llorens-Revull
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Maria Isabel Costafreda
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Angie Rico
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Mercedes Guerrero-Murillo
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Maria Eugenia Soria
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Sofía Píriz-Ruzo
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Elena Vargas-Accarino
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Pablo Gabriel-Medina
- Liver Pathology Laboratory, Biochemistry and Microbiology Unit, Vall d’Hebron Hospital Universitari (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Liver Pathology Laboratory, Biochemistry and Microbiology Unit, Vall d’Hebron Hospital Universitari (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Clinical Biochemistry Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Celia Perales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Josep Quer
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Silvia Sauleda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Juan Ignacio Esteban
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
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Hastings KL, Green MD, Gao B, Ganey PE, Roth RA, Burleson GR. Beyond Metabolism: Role of the Immune System in Hepatic Toxicity. Int J Toxicol 2021; 39:151-164. [PMID: 32174281 DOI: 10.1177/1091581819898399] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The liver is primarily thought of as a metabolic organ; however, the liver is also an important mediator of immunological functions. Key perspectives on this emerging topic were presented in a symposium at the 2018 annual meeting of the American College of Toxicology entitled "Beyond metabolism: Role of the immune system in hepatic toxicity." Viral hepatitis is an important disease of the liver for which insufficient preventive vaccines exist. Host immune responses inadequately clear these viruses and often potentiate immunological inflammation that damages the liver. In addition, the liver is a key innate immune organ against bacterial infection. Hepatocytes and immune cells cooperatively control systemic and local bacterial infections. Conversely, bacterial infection can activate multiple types of immune cells and pathways to cause hepatocyte damage and liver injury. Finally, the immune system and specifically cytokines and drugs can interact in idiosyncratic drug-induced liver injury. This rare disease can result in a disease spectrum that ranges from mild to acute liver failure. The immune system plays a role in this disease spectrum.
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Affiliation(s)
| | | | - Bin Gao
- Laboratory of Liver Diseases, NIH, Bethesda, MD, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Gary R Burleson
- BRT-Burleson Research Technologies, Inc, Morrisville, NC, USA
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Icer Baykal PB, Lara J, Khudyakov Y, Zelikovsky A, Skums P. Quantitative differences between intra-host HCV populations from persons with recently established and persistent infections. Virus Evol 2020; 7:veaa103. [PMID: 33505710 PMCID: PMC7816669 DOI: 10.1093/ve/veaa103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Detection of incident hepatitis C virus (HCV) infections is crucial for identification of outbreaks and development of public health interventions. However, there is no single diagnostic assay for distinguishing recent and persistent HCV infections. HCV exists in each infected host as a heterogeneous population of genomic variants, whose evolutionary dynamics remain incompletely understood. Genetic analysis of such viral populations can be applied to the detection of incident HCV infections and used to understand intra-host viral evolution. We studied intra-host HCV populations sampled using next-generation sequencing from 98 recently and 256 persistently infected individuals. Genetic structure of the populations was evaluated using 245,878 viral sequences from these individuals and a set of selected features measuring their diversity, topological structure, complexity, strength of selection, epistasis, evolutionary dynamics, and physico-chemical properties. Distributions of the viral population features differ significantly between recent and persistent infections. A general increase in viral genetic diversity from recent to persistent infections is frequently accompanied by decline in genomic complexity and increase in structuredness of the HCV population, likely reflecting a high level of intra-host adaptation at later stages of infection. Using these findings, we developed a machine learning classifier for the infection staging, which yielded a detection accuracy of 95.22 per cent, thus providing a higher accuracy than other genomic-based models. The detection of a strong association between several HCV genetic factors and stages of infection suggests that intra-host HCV population develops in a complex but regular and predictable manner in the course of infection. The proposed models may serve as a foundation of cyber-molecular assays for staging infection, which could potentially complement and/or substitute standard laboratory assays.
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Affiliation(s)
- Pelin B Icer Baykal
- Department of Computer Science, Georgia State University, 25 Park Place, Atlanta, GA 30302, USA
| | - James Lara
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30329, USA
| | - Yury Khudyakov
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30329, USA
| | - Alex Zelikovsky
- Department of Computer Science, Georgia State University, 25 Park Place, Atlanta, GA 30302, USA
| | - Pavel Skums
- Department of Computer Science, Georgia State University, 25 Park Place, Atlanta, GA 30302, USA
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Mohamed AA, Hemeda AA, Aziz RK, Abdel-Hakeem MS, Ali-Tammam M. Body mass index (BMI) and alpha-fetoprotein (AFP) level correlate with the severity of HCV-induced fibrosis in a cohort of Egyptian patients with chronic HCV. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00085-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
Viral hepatitis is the seventh leading cause of mortality globally, and half of this mortality is attributed to hepatitis C virus (HCV). Egypt has the highest HCV prevalence worldwide, with an estimated 14.7% of the population being HCV-positive. HCV infection is the primary cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis varies in severity during chronic HCV infection, and 10–20% of chronic hepatitis C (CHC) patients with severe fibrosis develop cirrhosis. The goal of this work was to assess the clinico-demographic predictors of severity of HCV-induced fibrosis in a cohort of Egyptian patients.
Results
A cohort of Egyptian patients with chronic HCV genotype 4a infection showed significant association between severe fibrosis stages and obesity, represented by a higher body mass index (BMI), low albumin level, high alpha-fetoprotein (AFP) level, low thyroid-stimulating hormone (TSH) level, and high alkaline phosphatase (ALP) level. Multivariate analysis delineated BMI, TSH, and ALP as independent significant variables that could predict the risk of fibrosis severity in HCV infections.
Conclusion
This study argues in favor of using the biomarker profile of CHC patients infected with HCV genotype 4a to identify patients at higher risk of developing severe fibrosis, which is a necessary first step towards precision medicine via patient stratification.
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Mekonnen ZA, Masavuli MG, Yu W, Gummow J, Whelan DM, Al-Delfi Z, Torresi J, Gowans EJ, Grubor-Bauk B. Enhanced T Cell Responses Induced by a Necrotic Dendritic Cell Vaccine, Expressing HCV NS3. Front Microbiol 2020; 11:559105. [PMID: 33343515 PMCID: PMC7739890 DOI: 10.3389/fmicb.2020.559105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/28/2020] [Indexed: 12/21/2022] Open
Abstract
A vaccine that induces potent, broad and sustained cell-mediated immunity, resulting in effective memory has the potential to restrict hepatitis C (HCV) virus infection. Early, multi-functional CD4+ and CD8+ T cell responses against non-structural protein 3 (NS3) have been associated with HCV clearance. Necrotic cells generate strong immune responses and represent a major antigenic source used by dendritic cells (DC) for processing and presentation, but there is conflicting evidence as to their immunogenicity in vaccination. Immunization with DC loaded with viral antigens has been done in the past, but to date the immunogenicity of live vs. necrotic DC vaccines has not been investigated. We developed a DC2.4 cell line stably expressing HCV NS3, and compared the NS3-specific responses of live vs. necrotic NS3 DC. Vaccination of mice with necrotic NS3 DC increased the breadth of T-cell responses and enhanced the production of IL-2, TNF-α, and IFN-γ by effector memory CD4+ and CD8+T cells, compared to mice vaccinated with live NS3 DC. A single dose of necrotic NS3 DC vaccine induced a greater influx and activation of cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A+ DC in the draining lymph nodes. Furthermore, using a hydrodynamic challenge model necrotic NS3 DC vaccination resulted in enhanced clearance of NS3-positive hepatocytes from the livers of vaccinated mice. Taken together, the data demonstrate that necrotic DC represent a novel and exciting vaccination strategy capable of inducing broad and multifunctional T cell memory.
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Affiliation(s)
- Zelalem A Mekonnen
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Makutiro G Masavuli
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Wenbo Yu
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia.,Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Jason Gummow
- Gene Silencing and Expression Laboratory, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Dawn M Whelan
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Zahraa Al-Delfi
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Eric J Gowans
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Branka Grubor-Bauk
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
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Hartnell F, Esposito I, Swadling L, Brown A, Phetsouphanh C, de Lara C, Gentile C, Turner B, Dorrell L, Capone S, Folgori A, Barnes E, Klenerman P. Characterizing Hepatitis C Virus-Specific CD4 + T Cells Following Viral-Vectored Vaccination, Directly Acting Antivirals, and Spontaneous Viral Cure. Hepatology 2020; 72:1541-1555. [PMID: 32012325 PMCID: PMC7610807 DOI: 10.1002/hep.31160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 01/07/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Induction of functional helper CD4+ T cells is the hallmark of a protective immune response against hepatitis C virus (HCV), associated with spontaneous viral clearance. Heterologous prime/boost viral vectored vaccination has demonstrated induction of broad and polyfunctional HCV-specific CD8+ T cells in healthy volunteers; however, much less is known about CD4+ T-cell subsets following vaccination. APPROACH AND RESULTS We analyzed HCV-specific CD4+ T-cell populations using major histocompatibility complex class II tetramers in volunteers undergoing HCV vaccination with recombinant HCV adenoviral/modified vaccinia Ankara viral vectors. Peptide-specific T-cell responses were tracked over time, and functional (proliferation and cytokine secretion) and phenotypic (cell surface and intranuclear) markers were assessed using flow cytometry. These were compared to CD4+ responses in 10 human leukocyte antigen-matched persons with HCV spontaneous resolution and 21 chronically infected patients treated with directly acting antiviral (DAA) therapy. Vaccination induced tetramer-positive CD4+ T cells that were highest 1-4 weeks after boosting (mean, 0.06%). Similar frequencies were obtained for those tracked following spontaneous resolution of disease (mean, 0.04%). In addition, the cell-surface phenotype (CD28, CD127) memory subset markers and intranuclear transcription factors, as well as functional capacity of peptide-specific CD4+ T-cell responses characterized after vaccination, are comparable to those following spontaneous viral resolution. In contrast, helper responses in chronic infection were infrequently detected and poorly functional and did not consistently recover following HCV cure. CONCLUSIONS Helper CD4+ T-cell phenotype and function following HCV viral vectored vaccination resembles "protective memory" that is observed following spontaneous clearance of HCV. DAA cure does not promote resurrection of exhausted CD4+ T-cell memory in chronic infection.
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Affiliation(s)
- Felicity Hartnell
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Ilaria Esposito
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Leo Swadling
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Anthony Brown
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | | | - Catherine de Lara
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | | | - Bethany Turner
- Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Lucy Dorrell
- Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | | | | | - Eleanor Barnes
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom,Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom,NIHR Biomedical Research Centre OxfordJohn Radcliffe HospitalOxfordUnited Kingdom,Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
| | - Paul Klenerman
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom,Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom,NIHR Biomedical Research Centre OxfordJohn Radcliffe HospitalOxfordUnited Kingdom,Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
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Donnison T, von Delft A, Brown A, Swadling L, Hutchings C, Hanke T, Chinnakannan S, Barnes E. Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes. Vaccine 2020; 38:5036-5048. [PMID: 32532545 DOI: 10.1016/j.vaccine.2020.05.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/11/2020] [Accepted: 05/15/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Viral genetic variability presents a major challenge to the development of a prophylactic hepatitis C virus (HCV) vaccine. A promising HCV vaccine using chimpanzee adenoviral vectors (ChAd) encoding a genotype (gt) 1b non-structural protein (ChAd-Gt1b-NS) generated high magnitude T cell responses. However, these T cells showed reduced cross-recognition of dominant epitope variants and the vaccine has recently been shown to be ineffective at preventing chronic HCV. To address the challenge of viral diversity, we developed ChAd vaccines encoding HCV genomic sequences that are conserved between all major HCV genotypes and adjuvanted by truncated shark invariant chain (sIitr). METHODS Age-matched female mice were immunised intramuscularly with ChAd (108 infectious units) encoding gt-1 and -3 (ChAd-Gt1/3) or gt-1 to -6 (ChAd-Gt1-6) conserved segments spanning the HCV proteome, or gt-1b (ChAd-Gt1b-NS control), with immunogenicity assessed 14-days post-vaccination. RESULTS Conserved segment vaccines, ChAd-Gt1/3 and ChAd-Gt1-6, generated high-magnitude, broad, and functional CD4+ and CD8+ T cell responses. Compared to the ChAd-Gt1b-NS vaccine, these vaccines generated significantly greater responses against conserved non-gt-1 antigens, including conserved subdominant epitopes that were not targeted by ChAd-Gt1b-NS. Epitopes targeted by the conserved segment HCV vaccine induced T cells, displayed 96.6% mean sequence homology between all HCV subtypes (100% sequence homology for the majority of genotype-1, -2, -4 sequences and 94% sequence homology for gt-3, -6, -7, and -8) in contrast to 85.1% mean sequence homology for epitopes targeted by ChAd-Gt1b-NS induced T cells. The addition of truncated shark invariant chain (sIitr) increased the magnitude, breadth, and cross-reactivity of the T cell response. CONCLUSIONS We have demonstrated that genetically adjuvanted ChAd vectored HCV T cell vaccines encoding genetic sequences conserved between genotypes are immunogenic, activating T cells that target subdominant conserved HCV epitopes. These pre-clinical studies support the use of conserved segment HCV T cell vaccines in human clinical trials.
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Affiliation(s)
- Timothy Donnison
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Annette von Delft
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Anthony Brown
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Leo Swadling
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Claire Hutchings
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Tomáš Hanke
- Jenner Institute, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom; Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Senthil Chinnakannan
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom; Jenner Institute, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom.
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Beaurepaire A, Piot N, Doublet V, Antunez K, Campbell E, Chantawannakul P, Chejanovsky N, Gajda A, Heerman M, Panziera D, Smagghe G, Yañez O, de Miranda JR, Dalmon A. Diversity and Global Distribution of Viruses of the Western Honey Bee, Apis mellifera. INSECTS 2020; 11:E239. [PMID: 32290327 PMCID: PMC7240362 DOI: 10.3390/insects11040239] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/31/2022]
Abstract
In the past centuries, viruses have benefited from globalization to spread across the globe, infecting new host species and populations. A growing number of viruses have been documented in the western honey bee, Apis mellifera. Several of these contribute significantly to honey bee colony losses. This review synthetizes the knowledge of the diversity and distribution of honey-bee-infecting viruses, including recent data from high-throughput sequencing (HTS). After presenting the diversity of viruses and their corresponding symptoms, we surveyed the scientific literature for the prevalence of these pathogens across the globe. The geographical distribution shows that the most prevalent viruses (deformed wing virus, sacbrood virus, black queen cell virus and acute paralysis complex) are also the most widely distributed. We discuss the ecological drivers that influence the distribution of these pathogens in worldwide honey bee populations. Besides the natural transmission routes and the resulting temporal dynamics, global trade contributes to their dissemination. As recent evidence shows that these viruses are often multihost pathogens, their spread is a risk for both the beekeeping industry and the pollination services provided by managed and wild pollinators.
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Affiliation(s)
- Alexis Beaurepaire
- Institute of Bee Health, Vetsuisse Faculty, University of Bern, 3003 Bern, Switzerland;
- Agroscope, Swiss Bee Research Center, 3003 Bern, Switzerland
- UR Abeilles et Environnement, INRAE, 84914 Avignon, France;
| | - Niels Piot
- Laboratory of Agrozoology, Department of Plants and Crops, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium; (N.P.); (G.S.)
| | - Vincent Doublet
- Institute of Evolutionary Ecology and Conservation Genomics, University of Ulm, 86069 Ulm, Germany;
| | - Karina Antunez
- Department of Microbiology, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay;
| | - Ewan Campbell
- Centre for Genome Enabled Biology and Medicine, University of Aberdeen, Aberdeen AB24 3FX, UK;
| | - Panuwan Chantawannakul
- Environmental Science Research Center (ESRC), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Bee Protection Laboratory (BeeP), Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nor Chejanovsky
- Entomology Department, Institute of Plant Protection, The Volcani Center, Rishon Lezion, Tel Aviv 5025001, Israel;
| | - Anna Gajda
- Laboratory of Bee Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | | | - Delphine Panziera
- Institute of Biology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, 04103 Leipzig, Germany
| | - Guy Smagghe
- Laboratory of Agrozoology, Department of Plants and Crops, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium; (N.P.); (G.S.)
| | - Orlando Yañez
- Institute of Bee Health, Vetsuisse Faculty, University of Bern, 3003 Bern, Switzerland;
- Agroscope, Swiss Bee Research Center, 3003 Bern, Switzerland
| | - Joachim R. de Miranda
- Department of Ecology, Swedish University of Agricultural Sciences, 750-07 Uppsala, Sweden;
| | - Anne Dalmon
- UR Abeilles et Environnement, INRAE, 84914 Avignon, France;
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40
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Schnell A, Bod L, Madi A, Kuchroo VK. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res 2020; 30:285-299. [PMID: 31974523 PMCID: PMC7118128 DOI: 10.1038/s41422-020-0277-x] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/06/2020] [Indexed: 12/31/2022] Open
Abstract
Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.
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Affiliation(s)
- Alexandra Schnell
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Lloyd Bod
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Asaf Madi
- Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
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41
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Cardozo EF, Ji D, Lau G, Schinazi RF, Chen GF, Ribeiro RM, Perelson AS. Disentangling the lifespans of hepatitis C virus-infected cells and intracellular vRNA replication-complexes during direct-acting anti-viral therapy. J Viral Hepat 2020; 27:261-269. [PMID: 31670859 PMCID: PMC7031045 DOI: 10.1111/jvh.13229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/06/2019] [Accepted: 10/16/2019] [Indexed: 01/25/2023]
Abstract
The decay rate of hepatitis C virus (HCV)-infected cells during therapy has been used to determine the duration of treatment needed to attain a sustained virologic response, but with direct-acting anti-virals (DAA), this rate has been difficult to estimate. Here, we show that it is possible to estimate it, by simultaneously analysing the viral load and alanine aminotransferase (ALT) kinetics during combination DAA therapy. We modelled the HCV RNA and ALT serum kinetics in 26 patients with chronic HCV genotype 1b infection, under four different sofosbuvir-based combination treatments. In all patients, ALT decayed exponentially to a set point in the normal range by 1-3 weeks after initiation of therapy. The model indicates that the ALT decay rate during the first few weeks after initiation of therapy reflects the death rate of infected cells, with an estimated median half-life of 2.5 days in this patient population. This information allows independent estimation of the rate of loss of intracellular replication complexes during therapy. Our model also predicts that the final ALT set point is not related to the release of ALT by dying HCV-infected cells. Using ALT data, one can separately obtain information about the rate of 'cure' of HCV-infected cells versus their rate of death, something not possible when analysing only HCV RNA data. This information can be used to compare the effects of different DAA combinations and to rationally evaluate their anti-viral effects.
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Affiliation(s)
- E. Fabian Cardozo
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Dong Ji
- The Fifth Medical Center of Chinese PLA General Hospital (302 Hospital)-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, Beijing, China
| | - George Lau
- The Fifth Medical Center of Chinese PLA General Hospital (302 Hospital)-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, Beijing, China;,Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China
| | - Raymond F. Schinazi
- Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Guo-feng Chen
- The Fifth Medical Center of Chinese PLA General Hospital (302 Hospital)-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, Beijing, China
| | - Ruy M. Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA;,Laboratório de Biomatemática, Faculdade de Medicina da Universidade de Lisboa, Portugal
| | - Alan S. Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA
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42
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Barili V, Fisicaro P, Montanini B, Acerbi G, Filippi A, Forleo G, Romualdi C, Ferracin M, Guerrieri F, Pedrazzi G, Boni C, Rossi M, Vecchi A, Penna A, Zecca A, Mori C, Orlandini A, Negri E, Pesci M, Massari M, Missale G, Levrero M, Ottonello S, Ferrari C. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat Commun 2020; 11:604. [PMID: 32001678 PMCID: PMC6992697 DOI: 10.1038/s41467-019-14137-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 12/11/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
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Affiliation(s)
- Valeria Barili
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Barbara Montanini
- Biomolecular, Genomic and Biocomputational Sciences Unit, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.,Biopharmanet-Tec, University of Parma, Parma, Italy
| | - Greta Acerbi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Anita Filippi
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Giovanna Forleo
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | | | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy
| | | | - Giuseppe Pedrazzi
- Unit of Neuroscience, Department of Medicine and Surgery, Robust Statistics Academy (Ro.S.A.), University of Parma, Parma, Italy
| | - Carolina Boni
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Andrea Vecchi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Alessandra Zecca
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Cristina Mori
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Alessandra Orlandini
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Elisa Negri
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marco Pesci
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marco Massari
- Unit of Infectious Diseases, IRCCS-Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL)-INSERM U1052, Lyon, France.,Université Claude Bernard Lyon 1, Service d'Hepatologie et Gastroenterologie Hopital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.,Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Simone Ottonello
- Biomolecular, Genomic and Biocomputational Sciences Unit, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.,Biopharmanet-Tec, University of Parma, Parma, Italy
| | - Carlo Ferrari
- Department of Medicine and Surgery, University of Parma, Parma, Italy. .,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
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Safety Profile of a Multi-Antigenic DNA Vaccine Against Hepatitis C Virus. Vaccines (Basel) 2020; 8:vaccines8010053. [PMID: 32013228 PMCID: PMC7158683 DOI: 10.3390/vaccines8010053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 01/21/2020] [Indexed: 12/17/2022] Open
Abstract
Despite direct acting antivirals (DAAs) curing >95% of individuals infected with hepatitis C (HCV), in order to achieve the World Health Organization HCV Global Elimination Goals by 2030 there are still major challenges that need to be overcome. DAAs alone are unlikely to eliminate HCV in the absence of a vaccine that can limit viral transmission. Consequently, a prophylactic HCV vaccine is necessary to relieve the worldwide burden of HCV disease. DNA vaccines are a promising vaccine platform due to their commercial viability and ability to elicit robust T-cell-mediated immunity (CMI). We have developed a novel cytolytic DNA vaccine that encodes non-structural HCV proteins and a truncated mouse perforin (PRF), which is more immunogenic than the respective canonical DNA vaccine lacking PRF. Initially we assessed the ability of the HCV pNS3-PRF and pNS4/5-PRF DNA vaccines to elicit robust long-term CMI without any adverse side-effects in mice. Interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay was used to evaluate CMI against NS3, NS4 and NS5B in a dose-dependent manner. This analysis showed a dose-dependent bell-curve of HCV-specific responses in vaccinated animals. We then thoroughly examined the effects associated with reactogenicity of cytolytic DNA vaccination with the multi-antigenic HCV DNA vaccine (pNS3/4/5B). Hematological, biochemical and histological studies were performed in male Sprague Dawley rats with a relative vaccine dose 10–20-fold higher than the proposed dose in Phase I clinical studies. The vaccine was well tolerated, and no toxicity was observed. Thus, the cytolytic multi-antigenic DNA vaccine is safe and elicits broad memory CMI.
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Rutledge B, Jan J, Benjaram S, Sahni N, Naylor P, Philip P, Ehrinpreis M, Mutchnick M. Racial Diversity in Hepatocellular Carcinoma in a Predominately African-American Population at an Urban Medical Center. J Gastrointest Cancer 2019; 51:972-979. [PMID: 31792736 DOI: 10.1007/s12029-019-00342-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE Surveillance, treatment, and outcomes for African-American (AA) populations with hepatocellular carcinoma (HCC) remain under evaluated. This study evaluated demographics, surveillance, therapy, and outcomes for a predominately AA population. METHODS The electronic medical records of a large health-care provider were used to identify 274 patients with visits for HCC between 2010 and 2017. Tumor size at diagnosis was defined by imaging with ≤ 5 cm being defined as "small." Surveillance for HCC was defined based on ultrasound (US) assessments. RESULTS Patients were primarily AA (78%) and male (76%) with an average age at diagnosis of 62 years. Hepatitis C virus (HCV) was more likely to be a risk factor for the development of HCC in AA as compared to non-AA (92% vs 67%; p < 0.005). Surveillance rates were low (16% for AA vs 7% for non-AA). An aspartate aminotransferase platelet ratio index (APRI) value > 0.7 within 2 years of tumor diagnosis was a strong predictor for the risk of the development of HCC (86% AA vs 79 % non-AA). In this study, race was not a factor in treatment or outcomes, and most patients received tumor ablative treatment. CONCLUSION Given the low surveillance rates and the demonstrated increased survival for patients with small tumors, ways to increase surveillance must be initiated. The results of this study demonstrate the need for physician/patient education on the importance of surveillance US. Further, this study supports routine assessment of APRI in AA patients in an effort to identify patients in whom intensive surveillance will significantly improve earlier detection of tumors.
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Affiliation(s)
- Brian Rutledge
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA.
| | - Jenny Jan
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
| | - Sindhuri Benjaram
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
| | - Neha Sahni
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
| | - Paul Naylor
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
| | - Philip Philip
- Department of Oncology, Karmanos Cancer Institute/Wayne State University School of Medicine, Detroit, MI, USA
| | - Murray Ehrinpreis
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
| | - Milton Mutchnick
- Department of Gastroenterology, Wayne State University School of Medicine, 3990 John R St 6 Hudson Room 6938, Detroit, MI, 48201, USA
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Fellay J, Pedergnana V. Exploring the interactions between the human and viral genomes. Hum Genet 2019; 139:777-781. [PMID: 31729546 DOI: 10.1007/s00439-019-02089-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 10/31/2019] [Indexed: 12/20/2022]
Abstract
Over the last decade, genome-wide association studies led to major advances in identifying human genetic variants associated with infectious disease susceptibility. On the pathogen side, comparable methods are now applied to identify disease-modulating pathogen variants. As host and pathogen variants jointly determine disease outcomes, the most recent development has been to explore simultaneously host and pathogen genomes, through so-called genome-to-genome studies. In this review, we provide some background on the development of genome-to-genome analysis and we detail the first wave of studies in this emerging field, which focused on patients chronically infected with HIV and hepatitis C virus. We also discuss the need for novel statistical methods to better tackle the issues of population stratification and multiple testing. Finally, we speculate on future research areas where genome-to-genome analysis may prove to be particularly effective.
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Affiliation(s)
- Jacques Fellay
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. .,Precision Medicine Unit, University Hospital and University of Lausanne, Lausanne, Switzerland. .,Swiss Institute of Bioinformatics, Lausanne, Switzerland.
| | - Vincent Pedergnana
- French National Center for Scientific Research (CNRS), Laboratory MIVEGEC (CNRS, IRD, UM), Montpellier, France
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Palmer DS, Turner I, Fidler S, Frater J, Goedhals D, Goulder P, Huang KHG, Oxenius A, Phillips R, Shapiro R, Vuuren CV, McLean AR, McVean G. Mapping the drivers of within-host pathogen evolution using massive data sets. Nat Commun 2019; 10:3017. [PMID: 31289267 PMCID: PMC6616926 DOI: 10.1038/s41467-019-10724-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 05/20/2019] [Indexed: 11/09/2022] Open
Abstract
Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.
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Affiliation(s)
- Duncan S Palmer
- Department of Statistics, University of Oxford, 24-29 St Giles', Oxford, OX1 3LB, UK.
- Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK.
- Institute for Emerging Infections, The Oxford Martin School, Oxford, OX1 3BD, UK.
| | - Isaac Turner
- Department of Statistics, University of Oxford, 24-29 St Giles', Oxford, OX1 3LB, UK
- Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Sarah Fidler
- Division of Medicine, Wright Fleming Institute, Imperial College, London, W2 1PG, UK
| | - John Frater
- Institute for Emerging Infections, The Oxford Martin School, Oxford, OX1 3BD, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, OX1 3SY, UK
- Oxford NIHR Biomedical Research Centre, Oxford, OX3 7LE, UK
| | - Dominique Goedhals
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, 4013, South Africa
| | - Philip Goulder
- Division of Infectious Diseases, University of the Free State, and 3 Military Hospital, Bloemfontein, 9300, South Africa
- Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, OX1 3SY, UK
| | - Kuan-Hsiang Gary Huang
- Nuffield Department of Clinical Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, OX1 3SY, UK
- Einstein Medical Center Philadelphia, 5501 Old York Road, PA, 19141, USA
| | - Annette Oxenius
- Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093, Zurich, Switzerland
| | - Rodney Phillips
- Institute for Emerging Infections, The Oxford Martin School, Oxford, OX1 3BD, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, OX1 3SY, UK
- Oxford NIHR Biomedical Research Centre, Oxford, OX3 7LE, UK
- Faculty of Medicine, UNSW Sydney, NSW, 2052, Australia
| | - Roger Shapiro
- Botswana Harvard AIDS Institute Partnership, Gaborone, BO 320, Botswana
- Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, 02215, USA
| | - Cloete van Vuuren
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, 4013, South Africa
| | - Angela R McLean
- Institute for Emerging Infections, The Oxford Martin School, Oxford, OX1 3BD, UK
- Zoology Department, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK
| | - Gil McVean
- Department of Statistics, University of Oxford, 24-29 St Giles', Oxford, OX1 3LB, UK
- Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK
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47
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Bakr NM, Awad A, Moustafa EA, El-Gebaly AM. The association between interleukin-21 (rs2055979G/T) gene polymorphism and the risk of hepatocellular carcinoma and metastasis in patients with hepatitis C virus. J Cell Biochem 2019; 120:18524-18532. [PMID: 31237020 DOI: 10.1002/jcb.29174] [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: 01/07/2019] [Revised: 05/19/2019] [Accepted: 05/23/2019] [Indexed: 11/09/2022]
Abstract
Cancer prevalence is critically increasing worldwide; accordingly, improved prediction and therapeutic tools are necessary. Interleukin (IL)-21 is a potent antitumor cytokine, and the relationship between its gene variations and cancer risk is well established. Nevertheless, so far no study has investigated its role in hepatocellular carcinoma (HCC) progression and metastasis in hepatitis C virus (HCV)-infected people. Therefore, the present investigation was led on 267 Egyptian participants, involving 177 patients with HCV of which 90 patients had HCC (HCC group), 87 patients without HCC (non-HCC group), and 90 unrelated healthy controls. The association between rs2221903A/G and rs2055979G/T of the IL-21 gene and the risk of HCC and metastasis, as well as the clinico-pathological features, were analyzed. While rs2221903A/G polymorphism was not polymorphic in our cohort, patients carrying the genotype TT and allele T of the rs2055979G/T polymorphism had a significantly lower risk of HCC when comparing with HCC group and healthy controls. Also, participants carrying the aforementioned genotype and allele had a significantly lower risk of metastasis when comparing metastatic group with both nonmetastatic group and control group. The rs2055979G/T polymorphism was not significantly associated with clinico-pathological features of HCC. This is the first study to report a relationship between an intronic polymorphism in IL-21 gene and HCC and metastasis risk in the Egyptian people, in addition to identifying a potential new marker for the early detection and treatment of HCC.
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Affiliation(s)
- Noha M Bakr
- Biochemistry Department, National Research Centre, Giza, Egypt
| | - Ashraf Awad
- Department of Animal Wealth Development, Zagazig University, Zagazig, Egypt
| | - Emad A Moustafa
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ahmed M El-Gebaly
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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48
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Santiago-Olivares C, Rivera-Toledo E, Gómez B. Nitric oxide production is downregulated during respiratory syncytial virus persistence by constitutive expression of arginase 1. Arch Virol 2019; 164:2231-2241. [DOI: 10.1007/s00705-019-04259-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/24/2019] [Indexed: 12/25/2022]
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Abd Ellah NH, Tawfeek HM, John J, Hetta HF. Nanomedicine as a future therapeutic approach for Hepatitis C virus. Nanomedicine (Lond) 2019; 14:1471-1491. [PMID: 31166139 DOI: 10.2217/nnm-2018-0348] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) is not easily cleared from the human body and in most cases turned into chronic infection. This chronicity is a major cause of liver damage, cirrhosis and hepatocellular carcinoma. Therefore, immediate detection and treatment of HCV guarantees eradication of the virus and prevention of chronicity complications. Since discovery of HCV in 1989, several emerging treatments were developed such as polyethylene glycol(PEG)-ylated interferon/ribavirin, direct acting antivirals and host targeting antivirals. Despite the progress in anti-HCV therapy, there is still a pressing need of new approaches for affordable and effective drug delivery systems using nanomedicine. In this review, the contribution of nanoparticles as a promising delivery system for HCV immunizing, diagnostic and therapeutic agents are discussed.
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Affiliation(s)
- Noura H Abd Ellah
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Medical Sciences Building, University of Cincinnati, Cincinnati, OH 45267, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hesham M Tawfeek
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.,Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmacy, Mutah University, Karak, Jordan
| | - James John
- Central Research Facilities, Sri Ramachandra institute of higher education & research, Sri Ramachandra University, Chennai, India
| | - Helal F Hetta
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Assiut University, Assiut, 71526, Egypt.,Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA
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Agrawal B, Gupta N, Vedi S, Singh S, Li W, Garg S, Li J, Kumar R. Heterologous Immunity between Adenoviruses and Hepatitis C Virus (HCV): Recombinant Adenovirus Vaccine Vectors Containing Antigens from Unrelated Pathogens Induce Cross-Reactive Immunity Against HCV Antigens. Cells 2019; 8:E507. [PMID: 31130710 PMCID: PMC6562520 DOI: 10.3390/cells8050507] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/13/2019] [Accepted: 05/24/2019] [Indexed: 12/15/2022] Open
Abstract
Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive immunity can (a) accommodate the making of dual-pathogen vaccines, (b) play an important role in the natural course of HCV infection and (c) provide a plausible answer to many unexplained questions regarding immunity to HCV.
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Affiliation(s)
- Babita Agrawal
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Nancy Gupta
- Department of Laboratory Medicine & Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Satish Vedi
- Department of Laboratory Medicine & Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Shakti Singh
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Wen Li
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Saurabh Garg
- Department of Laboratory Medicine & Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Jie Li
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
| | - Rakesh Kumar
- Department of Laboratory Medicine & Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2S2, Canada.
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