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1
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Gu Y, Bi Y, Huang Z, Liao C, Li X, Hu H, Xie H, Huang Y. CD69 Expression is Negatively Associated With T-Cell Immunity and Predicts Antiviral Therapy Response in Chronic Hepatitis B. Ann Lab Med 2025; 45:185-198. [PMID: 39703148 PMCID: PMC11788699 DOI: 10.3343/alm.2024.0178] [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: 04/06/2024] [Revised: 08/04/2024] [Accepted: 10/23/2024] [Indexed: 12/21/2024] Open
Abstract
Background The function of CD69 expressed on T cells in chronic hepatitis B (CHB) remains unclear. We aimed to elucidate the roles of CD69 on T cells in the disease process and in antiviral therapy for CHB. Methods We enrolled 335 treatment-naive patients with CHB and 93 patients with CHB on antiviral therapy. CD69, antiviral cytokine production by T cells, T-helper (Th) cells, and inhibitory molecules of T cells were measured using flow cytometry, and clinical-virological characteristics were examined dynamically during antiviral therapy. Results CD69 expression on CD3+, CD4+, and CD8+ T cells was the lowest in the immune-active phase and was negatively correlated with liver transaminase activity, fibrosis features, inflammatory cytokine production by T cells, and Th-cell frequencies but positively with inhibitory molecules on T cells. CD69 expression on CD3+, CD4+, and CD8+ T cells decreased after 48 weeks of antiviral therapy, and patients with hepatitis B e antigen (HBeAg) seroconversion in week 48 showed lower CD69 expression on T cells at baseline and week 48. The area under the ROC curve of CD69 expression on T cells at baseline for predicting HBeAg seroconversion in week 48 was 0.870, the sensitivity was 0.909, and the specificity was 0.714 (P =0.002). Conclusions CD69 negatively regulates T-cell immunity during CHB, and its expression decreases with antiviral therapy. CD69 expression predicts HBeAg seroconversion in week 48. CD69 may play an important negative role in regulating T cells and affect the efficacy of antiviral therapy.
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Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunhong Liao
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Li
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hao Hu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huaping Xie
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuehua Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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2
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Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024; 31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV-host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.
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Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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3
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Zhang W, Yu Q, Gao X, Chen H, Su J, Chen Y, Li Y, Zhang N, Fu Z, Cui M. Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8 + T Cells during JEV Infection. Int J Biol Sci 2024; 20:5959-5978. [PMID: 39664572 PMCID: PMC11628328 DOI: 10.7150/ijbs.102372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/18/2024] [Indexed: 12/13/2024] Open
Abstract
Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), is a mosquito-borne zoonotic disease and a leading cause of viral encephalitis worldwide. While JEV has the ability to traverse the blood-brain barrier (BBB), the precise mechanisms by which it inhibits the immune response prior to penetrating the BBB remain unclear, presenting obstacles in the development of efficacious therapeutic interventions. This study investigated the impact of JEV on CD8+ T cell responses, with a particular focus on the dysfunction of CD8+ T cells during JEV infection. Our results demonstrated that JEV infection significantly elevated the expression of PD-1 and TIM-3 on CD8+ T cells, which are markers of T cell exhaustion, leading to inhibited function and impaired differentiation, resulting in a poorer prognosis in mice. Compared with nondiseased mice, symptomatic mice presented a greater proportion of exhaustion-like CD8+ T cells. In vitro experiments further demonstrated that MDSCs induced an exhaustion-like state in CD8+ T cells, characterized by significant upregulation of PD-1 and TIM-3 expression. Notably, blocking TIM-3 or depleting MDSCs restored CD8+ T cell functionality by rescuing the expression of IFN-γ and TNF-α. Furthermore, the depletion of MDSCs not only alleviated T cell exhaustion-like phenotypes but also improved survival rates in JEV-infected mice. These findings suggest that JEV promotes immune evasion through MDSC-induced CD8+ T cell exhaustion-like states and identify TIM-3 as a promising therapeutic target for JE treatment.
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Affiliation(s)
- Weijia Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Qing Yu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Xiaochen Gao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Haowei Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Jie Su
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanru Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanling Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Nan Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Zhenfang Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Min Cui
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
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Gu Q, Yin S, Tong X, Rui F, Zhu Y, Ma X, Huang R, Wu C, Li J. Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection. J Viral Hepat 2024; 31:557-564. [PMID: 38771314 DOI: 10.1111/jvh.13958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/29/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Qi Gu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Fajuan Rui
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yixuan Zhu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyan Ma
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
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5
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Heim K, Sagar, Sogukpinar Ö, Llewellyn-Lacey S, Price DA, Emmerich F, Kraft ARM, Cornberg M, Kielbassa S, Knolle P, Wohlleber D, Bengsch B, Boettler T, Neumann-Haefelin C, Thimme R, Hofmann M. Attenuated effector T cells are linked to control of chronic HBV infection. Nat Immunol 2024; 25:1650-1662. [PMID: 39198634 PMCID: PMC11362014 DOI: 10.1038/s41590-024-01928-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/12/2024] [Indexed: 09/01/2024]
Abstract
Hepatitis B virus (HBV)-specific CD8+ T cells play a dominant role during acute-resolving HBV infection but are functionally impaired during chronic HBV infection in humans. These functional deficits have been linked with metabolic and phenotypic heterogeneity, but it has remained unclear to what extent different subsets of HBV-specific CD8+ T cells still suppress viral replication. We addressed this issue by deep profiling, functional testing and perturbation of HBV-specific CD8+ T cells during different phases of chronic HBV infection. Our data revealed a mechanism of effector CD8+ T cell attenuation that emerges alongside classical CD8+ T cell exhaustion. Attenuated HBV-specific CD8+ T cells were characterized by cytotoxic properties and a dampened effector differentiation program, determined by antigen recognition and TGFβ signaling, and were associated with viral control during chronic HBV infection. These observations identify a distinct subset of CD8+ T cells linked with immune efficacy in the context of a chronic human viral infection with immunotherapeutic potential.
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Affiliation(s)
- Kathrin Heim
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sagar
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Özlem Sogukpinar
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sian Llewellyn-Lacey
- Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
| | - Florian Emmerich
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Institute for Transfusion Medicine and Gene Therapy, University Medical Center, University of Freiburg, Freiburg, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
- Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
- Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC), Hannover Medical School, Hannover, Germany
| | - Sophie Kielbassa
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Percy Knolle
- Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
- German Center for Infection Research, Munich, Germany
- Institute of Molecular Immunology, School of Life Science, TUM, Munich, Germany
| | - Dirk Wohlleber
- Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Bertram Bengsch
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signaling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany.
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Maike Hofmann
- Department of Medicine II, Medical Center - University of Freiburg, Freiburg, Germany.
- Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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6
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Sun B, da Costa KA, Alrubayyi A, Kokici J, Fisher-Pearson N, Hussain N, D’Anna S, Piermatteo L, Salpini R, Svicher V, Kucykowicz S, Ghosh I, Burns F, Kinloch S, Simoes P, Bhagani S, Kennedy PTF, Maini MK, Bashford-Rogers R, Gill US, Peppa D. HIV/HBV coinfection remodels the immune landscape and natural killer cell ADCC functional responses. Hepatology 2024; 80:649-663. [PMID: 38687604 PMCID: PMC11782918 DOI: 10.1097/hep.0000000000000877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/23/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIMS HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed. APPROACH AND RESULTS Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of "exhaustion" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased "adaptiveness" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort. CONCLUSIONS This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.
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Affiliation(s)
- Bo Sun
- Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom
| | - Kelly A.S. da Costa
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Jonida Kokici
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Noshin Hussain
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Stefano D’Anna
- University of Rome Tor Vergata, Department of Experimental Medicine, Rome, Italy
| | | | - Romina Salpini
- University of Rome Tor Vergata, Department of Experimental Medicine, Rome, Italy
| | | | - Stephanie Kucykowicz
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Indrajit Ghosh
- Mortimer Market Centre, Department of HIV, CNWL NHS Trust, London, United Kingdom
| | - Fiona Burns
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
- Institute for Global Health, University College London, UK
| | - Sabine Kinloch
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
| | - Pedro Simoes
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
| | - Sanjay Bhagani
- Division of Infection and Immunity, University College London, London, United Kingdom
- Department of HIV Medicine, Royal Free Hospital NHS Foundation Trust, UK
| | | | - Mala K Maini
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Upkar S Gill
- Barts Liver Centre, Barts & The London School of Medicine & Dentistry, QMUL
| | - Dimitra Peppa
- Division of Infection and Immunity, University College London, London, United Kingdom
- Mortimer Market Centre, Department of HIV, CNWL NHS Trust, London, United Kingdom
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
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7
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Tu T, Wettengel J, Xia Y, Testoni B, Littlejohn M, Le Bert N, Ebert G, Verrier ER, Tavis JE, Cohen C. Major open questions in the hepatitis B and D field - Proceedings of the inaugural International emerging hepatitis B and hepatitis D researchers workshop. Virology 2024; 595:110089. [PMID: 38640789 PMCID: PMC11517827 DOI: 10.1016/j.virol.2024.110089] [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: 02/29/2024] [Revised: 04/01/2024] [Accepted: 04/12/2024] [Indexed: 04/21/2024]
Abstract
The early and mid-career researchers (EMCRs) of scientific communities represent the forefront of research and the future direction in which a field takes. The opinions of this key demographic are not commonly aggregated to audit fields and precisely demonstrate where challenges lie for the future. To address this, we initiated the inaugural International Emerging Researchers Workshop for the global Hepatitis B and Hepatitis D scientific community (75 individuals). The cohort was split into small discussion groups and the significant problems, challenges, and future directions were assessed. Here, we summarise the outcome of these discussions and outline the future directions suggested by the EMCR community. We show an effective approach to gauging and accumulating the ideas of EMCRs and provide a succinct summary of the significant gaps remaining in the Hepatitis B and Hepatitis D field.
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Affiliation(s)
- Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney at Westmead Hospital, Westmead, NSW, Australia; Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
| | - Jochen Wettengel
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA; Institute of Virology, Technical University of Munich /Helmholtz Munich, Munich, Germany; German Center for Infection Research, Munich Partner Site, 81675, Munich, Germany
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China; Hubei Jiangxia Laboratory, Wuhan, China; Pingyuan Laboratory, Henan, China
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon, Lyon, France; University of Lyon, Université Claude-Bernard, Lyon, France; Hepatology Institute of Lyon, France
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital and Department of Infectious Disease, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Nina Le Bert
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Gregor Ebert
- Institute of Virology, Technical University of Munich /Helmholtz Munich, Munich, Germany
| | - Eloi R Verrier
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease, UMR_S1110, Strasbourg, France
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine and the Saint Louis University Institute for Drug and Biotherapeutic Innovation, Saint Louis, MO, USA
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8
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Xie H, Deng H, Yang X, Gao X, Yang S, Chen W, Wang Y, Yang N, Yong L, Hou X. Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance. Cell Mol Gastroenterol Hepatol 2024; 18:101360. [PMID: 38759839 PMCID: PMC11255368 DOI: 10.1016/j.jcmgh.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 05/10/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND & AIMS The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV. METHODS We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA. RESULTS Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice. CONCLUSION The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.
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Affiliation(s)
- Huiyuan Xie
- Department of Laboratory Medicine, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Haiyan Deng
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xiaoping Yang
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xianxian Gao
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Shanru Yang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Weiyi Chen
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Yixuan Wang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Naibin Yang
- Department of Infection, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Liang Yong
- Laboratory of Stem Cell, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xin Hou
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China.
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9
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Hu JL, Huang AL. Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics. Virol Sin 2024; 39:9-23. [PMID: 38110037 PMCID: PMC10877440 DOI: 10.1016/j.virs.2023.12.005] [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: 01/29/2023] [Accepted: 12/13/2023] [Indexed: 12/20/2023] Open
Abstract
The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.
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Affiliation(s)
- Jie-Li Hu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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10
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Razafimahatratra SL, Andriatefy OH, Mioramalala DJN, Tsatoromila FAM, Randrianarisaona F, Dussart P, Schoenhals M. Multiple SARS-CoV-2 immunizations of an unvaccinated population lead to complex immunity. A T cell reactivity study of blood donors in Antananarivo. J Infect Public Health 2024; 17:175-181. [PMID: 38039861 DOI: 10.1016/j.jiph.2023.11.020] [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: 07/24/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Madagascar has undergone multiple and robust COVID-19 waves. The resulting immune background developed by its poorly vaccinated population has however not been described. METHODS In this study, serological analysis and specific T cell response descriptions were used to describe the history of exposures of the capital's blood donors to SARS-CoV-2 and its VOCs. Samples were collected early 2022, and pools of multiple immunogenic peptides of SARS-CoV-2 were used in an IFN-γ secretion ELISPOT assay to characterize the specific T-cell immunity developed against these potential epitopes. RESULTS Multiple epidemic waves have led to 92.1% of donors having detectable antibodies, and 94.8% having developed T-cells against SARS-CoV-2. Heterogeneous reactivities to different strain-derived peptides suggested multiple immunological backgrounds in the population including 16.1% of individuals exposed at least once to a unique strain, 27.1% to two strains, 28.5% to three strains, and 23.1% to four distinct strains. CONCLUSIONS Cross-reactivity increased with multiple exposures but did not decrease the risk of re-infection. These results describe the extremely complex immunological background developed following multiple natural immunizations.
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Affiliation(s)
| | | | | | | | | | - Philippe Dussart
- Direction, Institut Pasteur of Madagascar, 101 Antananarivo, Madagascar
| | - Matthieu Schoenhals
- Immunology of Infectious Diseases Unit, Institut Pasteur of Madagascar, 101 Antananarivo, Madagascar.
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11
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Boni C, Rossi M, Montali I, Tiezzi C, Vecchi A, Penna A, Doselli S, Reverberi V, Ceccatelli Berti C, Montali A, Schivazappa S, Laccabue D, Missale G, Fisicaro P. What Is the Current Status of Hepatitis B Virus Viro-Immunology? Clin Liver Dis 2023; 27:819-836. [PMID: 37778772 DOI: 10.1016/j.cld.2023.05.001] [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] [Indexed: 10/03/2023]
Abstract
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
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Affiliation(s)
- Carolina Boni
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Sara Doselli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valentina Reverberi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | - Anna Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Simona Schivazappa
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Gabriele Missale
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
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12
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Kotsari M, Dimopoulou V, Koskinas J, Armakolas A. Immune System and Hepatocellular Carcinoma (HCC): New Insights into HCC Progression. Int J Mol Sci 2023; 24:11471. [PMID: 37511228 PMCID: PMC10380581 DOI: 10.3390/ijms241411471] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.
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Affiliation(s)
- Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Vassiliki Dimopoulou
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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13
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Laupèze B, Vassilev V, Badur S. A role for immune modulation in achieving functional cure for chronic hepatitis B among current changes in the landscape of new treatments. Expert Rev Gastroenterol Hepatol 2023; 17:1135-1147. [PMID: 37847193 DOI: 10.1080/17474124.2023.2268503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/05/2023] [Indexed: 10/18/2023]
Abstract
INTRODUCTION Chronic hepatitis B (CHB) is rarely cured using available treatments. Barriers to cure are: 1) persistence of reservoirs of hepatitis B virus (HBV) replication and antigen production (HBV DNA); 2) high burden of viral antigens that promote T cell exhaustion with T cell dysfunction; 3) CHB-induced impairment of immune responses. AREAS COVERED We discuss options for new therapies that could address one or more of the barriers to functional cure, with particular emphasis on the potential role of immunotherapy. EXPERT OPINION/COMMENTARY Ideally, a sterilizing cure for CHB would translate into finite therapies that result in loss of HBV surface antigen and eradication of HBV DNA. Restoration of a functional adaptive immune response, a key facet of successful CHB treatment, remains elusive. Numerous strategies targeting the high viral DNA and antigen burden and aiming to restore the host immune responses will enter clinical development in coming years. Most patients are likely to require combinations of several drugs, personalized according to virologic and disease characteristics, patient preference, accessibility, and affordability. The management of CHB is a global health priority. Expedited drug development requires collaborations between regulatory agencies, scientists, clinicians, and within the industry to facilitate testing of the best drug combinations.
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14
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Li S, Hao L, Zhang J, Deng J, Hu X. Focus on T cell exhaustion: new advances in traditional Chinese medicine in infection and cancer. Chin Med 2023; 18:76. [PMID: 37355637 DOI: 10.1186/s13020-023-00785-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/16/2023] [Indexed: 06/26/2023] Open
Abstract
In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called "exhaustion". T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.
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Affiliation(s)
- Shenghao Li
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
| | - Liyuan Hao
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
| | - Junli Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
| | - Jiali Deng
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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15
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Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology 2023; 77:1773-1796. [PMID: 35989535 PMCID: PMC9941399 DOI: 10.1002/hep.32740] [Citation(s) in RCA: 268] [Impact Index Per Article: 134.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 12/19/2022]
Abstract
The liver is the sixth most common site of primary cancer in humans and the fourth leading cause of cancer-related death in the world. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers. HCC is a prevalent disease with a progression that is modulated by the immune system. Half of the patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib, as a first-line therapy. In the last few years, immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy and have gained an increased interest in the treatment of HCC. In 2020, the combination of atezolizumab (anti-programmed death-ligand 1) and bevacizumab (anti-vascular endothelial growth factor) improved overall survival over sorafenib, resulting in Food and Drug Administration (FDA) approval as a first-line treatment for patients with advanced HCC. Despite these major advances, a better molecular and cellular characterization of the tumor microenvironment is still needed because it has a crucial role in the development and progression of HCC. Inflamed (hot) and noninflamed (cold) HCC tumors and genomic signatures have been associated with response to ICIs. However, there are no additional biomarkers to guide clinical decision-making. Other immune-targeting strategies, such as adoptive T-cell transfer, vaccination, and virotherapy, are currently under development. This review provides an overview on the HCC immune microenvironment, different cellular players, current available immunotherapies, and potential immunotherapy modalities.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
| | - Amaia Lujambio
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
- Graduate School of Biomedical Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
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16
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Khanam A, Ghosh A, Chua JV, Kottilil S. Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways. J Transl Med 2023; 21:271. [PMID: 37081509 PMCID: PMC10120209 DOI: 10.1186/s12967-023-04104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/04/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. METHODS We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. RESULTS CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. CONCLUSIONS CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Alip Ghosh
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joel V Chua
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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17
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Starikova EA, Rubinstein AA, Mammedova JT, Isakov DV, Kudryavtsev IV. Regulated Arginine Metabolism in Immunopathogenesis of a Wide Range of Diseases: Is There a Way to Pass between Scylla and Charybdis? Curr Issues Mol Biol 2023; 45:3525-3551. [PMID: 37185755 PMCID: PMC10137093 DOI: 10.3390/cimb45040231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
More than a century has passed since arginine was discovered, but the metabolism of the amino acid never ceases to amaze researchers. Being a conditionally essential amino acid, arginine performs many important homeostatic functions in the body; it is involved in the regulation of the cardiovascular system and regeneration processes. In recent years, more and more facts have been accumulating that demonstrate a close relationship between arginine metabolic pathways and immune responses. This opens new opportunities for the development of original ways to treat diseases associated with suppressed or increased activity of the immune system. In this review, we analyze the literature describing the role of arginine metabolism in the immunopathogenesis of a wide range of diseases, and discuss arginine-dependent processes as a possible target for therapeutic approaches.
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Affiliation(s)
- Eleonora A Starikova
- Laboratory of Cellular Immunology, Department of Immunology, Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L'va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Artem A Rubinstein
- Laboratory of Cellular Immunology, Department of Immunology, Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
| | - Jennet T Mammedova
- Laboratory of General Immunology, Department of Immunology, Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
| | - Dmitry V Isakov
- Medical Faculty, First Saint Petersburg State I. Pavlov Medical University, L'va Tolstogo St. 6-8, 197022 Saint Petersburg, Russia
| | - Igor V Kudryavtsev
- Laboratory of Cellular Immunology, Department of Immunology, Institute of Experimental Medicine, Akademika Pavlova 12, 197376 Saint Petersburg, Russia
- School of Biomedicine, Far Eastern Federal University, FEFU Campus, 10 Ajax Bay, Russky Island, 690922 Vladivostok, Russia
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18
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Stephan AS, Kosinska AD, Mück-Häusl M, Muschaweckh A, Jäger C, Röder N, Heikenwälder M, Dembek C, Protzer U. Evaluation of the Effect of CD70 Co-Expression on CD8 T Cell Response in Protein-Prime MVA-Boost Vaccination in Mice. Vaccines (Basel) 2023; 11:vaccines11020245. [PMID: 36851121 PMCID: PMC9966001 DOI: 10.3390/vaccines11020245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Here, we investigate the potential of CD70 co-expression during viral vector boost vaccination to improve an antigen-specific T cell response. To determine the chance of activating antigen-specific T cells by CD70, we used the HBV core antigen as a model antigen in a heterologous protein-prime, Modified Vaccinia virus Ankara (MVA) boost vaccination scheme. Both the HBV core and a CD70 expression cassette were co-expressed upon delivery by an MVA vector under the same promoter linked by a P2A site. To compare immunogenicity with and without CD70 co-expression, HBV-naïve, C57BL/6 (wt) mice and HBV-transgenic mice were prime-vaccinated using recombinant HBV core antigen followed by the MVA vector boost. Co-expression of CD70 increased the number of vaccine-induced HBV core-specific CD8 T cells by >2-fold and improved their effector functions in HBV-naïve mice. In vaccinated HBV1.3tg mice, the number and functionality of HBV core-specific CD8 T cells was slightly increased upon CD70 co-expression in low-viremic, but not in high-viremic animals. CD70 co-expression did not impact liver damage as indicated by ALT levels in the serum, but increased the number of vaccine-induced, proliferative T cell clusters in the liver. Overall, this study indicates that orchestrated co-expression of CD70 and a vaccine antigen may be an interesting and safe means of enhancing antigen-specific CD8 T cell responses using vector-based vaccines, although in our study it was not sufficient to break immune tolerance.
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Affiliation(s)
- Ann-Sophie Stephan
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Anna D. Kosinska
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
| | - Martin Mück-Häusl
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Andreas Muschaweckh
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, 81675 Munich, Germany
| | - Clemens Jäger
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Natalie Röder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Mathias Heikenwälder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany
| | - Claudia Dembek
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
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19
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Darmadi D, Lindarto D, Siregar J, Widyawati T, Rusda M, Amin MM, Yusuf F, Eyanoer PC, Lubis M, Rey I. Study of the Molecular Dynamics Stability in the Inhibitory Interaction of Tenofovir Disoproxil Fumarate against CTLA-4 in Chronic Hepatitis B Patients. Med Arch 2023; 77:227-230. [PMID: 37700917 PMCID: PMC10495148 DOI: 10.5455/medarh.2023.77.227-230] [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: 04/26/2023] [Accepted: 05/24/2023] [Indexed: 09/14/2023] Open
Abstract
Background Tenofovir disoproxil fumarate (TDF) is a first-line nucleotide analog (NA) drug for hepatitis B therapy. Long-term NA therapy increases peripheral T cell levels to enhance antiviral response, while CTLA-4 inhibits the activation. Objective This study analyzed the interaction between TDF and CTLA-4 through molecular docking. Methods Target protein and ligand data mining were performed, and proteins were prepared by removing water molecules in the Discovery Studio 2019 software. The energy minimization was performed on ligands using Pyrx v.0.9.8 software. Protein-ligand docking was performed using Autodock Vina integrated with Pyrx v.09.8. Meanwhile, the docking of proteins was accomplished using the Haddock server. The BioVia Discovery Studio 2019 software visualized the interaction between the compound and the docked protein. Molecular dynamics simulations were carried out using the YASARA Dynamic program developed by Biosciences GmbH. Results TDF ligand has good and stable inhibitory activity against the CTLA-4/B7-1 and CTLA4/B7-2 complexes. TDF docking has been shown to initiate conformational changes, indicating the ligand's inhibitory activity. The significant conformational changes based on superimposition results were shown by the CTLA-4/TDF/B7-2 and CTLA-4/B7-1/TDF complexes. TDF in all ligands undergoes bonding and displacement of binding sites. Conclusion Treatment with TDF was predicted to have inhibitory activity against CTLA-4, especially in its complex form with B7-1 and B7-2.
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Affiliation(s)
- Darmadi Darmadi
- Philosophy Doctor in Medicine Program, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Dharma Lindarto
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Jelita Siregar
- Department of Clinical Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Tri Widyawati
- Department of Pharmacology and Therapeutic, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Master Program in Tropical Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Muhammad Rusda
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Mustafa Mahmud Amin
- Department of Psychiatry, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Fauzi Yusuf
- Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
| | - Putri Chairani Eyanoer
- Department of Public Health, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Imelda Rey
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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20
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Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, Janssen HLA, Lau DTY, Penicaud C, Pollicino T, Testoni B, Van Bömmel F, Andrisani O, Beumont-Mauviel M, Block TM, Chan HLY, Cloherty GA, Delaney WE, Geretti AM, Gehring A, Jackson K, Lenz O, Maini MK, Miller V, Protzer U, Yang JC, Yuen MF, Zoulim F, Revill PA. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19:727-745. [PMID: 35859026 PMCID: PMC9298709 DOI: 10.1038/s41575-022-00649-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Daryl T Y Lau
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Capucine Penicaud
- Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Teresa Pollicino
- Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Florian Van Bömmel
- Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | | | | | - Henry L Y Chan
- Chinese University of Hong Kong, Shatin, Hong Kong
- Union Hospital, Shatin, Hong Kong
| | | | | | - Anna Maria Geretti
- Roche Pharma Research & Early Development, Basel, Switzerland
- Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | | | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
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21
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Aliabadi E, Urbanek-Quaing M, Maasoumy B, Bremer B, Grasshoff M, Li Y, Niehaus CE, Wedemeyer H, Kraft ARM, Cornberg M. Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection. Gut 2022; 71:2300-2312. [PMID: 34702717 PMCID: PMC9554084 DOI: 10.1136/gutjnl-2021-324646] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure. DESIGN We analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core18-specific and polymerase (pol)455-specific CD8+ T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated. RESULTS HBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4+ T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core18-specific and pol455-specific CD8+ T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg. CONCLUSION Our data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition.
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Affiliation(s)
- Elmira Aliabadi
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Melanie Urbanek-Quaing
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Martin Grasshoff
- Computational Biology for Individualised Medicine, Helmholtz Centre for Infection Research (HZI), c/o CRC, Hannover, Germany
| | - Yang Li
- TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany,Computational Biology for Individualised Medicine, Helmholtz Centre for Infection Research (HZI), c/o CRC, Hannover, Germany,Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany
| | - Christian E Niehaus
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany .,TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany.,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.,Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany.,Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Hannover, Germany
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22
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Wong GLH, Gane E, Lok ASF. How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development? J Hepatol 2022; 76:1249-1262. [PMID: 35589248 DOI: 10.1016/j.jhep.2021.11.024] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/20/2022]
Abstract
Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.
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Affiliation(s)
- Grace L H Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, University of Auckland, New Zealand
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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23
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Middlebrook EA, Romero AT, Bett B, Nthiwa D, Oyola SO, Fair JM, Bartlow AW. Identification and distribution of pathogens coinfecting with Brucella spp., Coxiella burnetii and Rift Valley fever virus in humans, livestock and wildlife. Zoonoses Public Health 2022; 69:175-194. [PMID: 35034427 PMCID: PMC9303618 DOI: 10.1111/zph.12905] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Indexed: 01/20/2023]
Abstract
Zoonotic diseases, such as brucellosis, Q fever and Rift Valley fever (RVF) caused by Brucella spp., Coxiella burnetii and RVF virus, respectively, can have devastating effects on human, livestock, and wildlife health and cause economic hardship due to morbidity and mortality in livestock. Coinfection with multiple pathogens can lead to more severe disease outcomes and altered transmission dynamics. These three pathogens can alter host immune responses likely leading to increased morbidity, mortality and pathogen transmission during coinfection. Developing countries, such as those commonly afflicted by outbreaks of brucellosis, Q fever and RVF, have high disease burden and thus common coinfections. A literature survey provided information on case reports and studies investigating coinfections involving the three focal diseases. Fifty five studies were collected demonstrating coinfections of Brucella spp., C. burnetii or RVFV with 50 different pathogens, of which 64% were zoonotic. While the literature search criteria involved ‘coinfection’, only 24/55 studies showed coinfections with direct pathogen detection methods (microbiology, PCR and antigen test), while the rest only reported detection of antibodies against multiple pathogens, which only indicate a history of co‐exposure, not concurrent infection. These studies lack the ability to test whether coinfection leads to changes in morbidity, mortality or transmission dynamics. We describe considerations and methods for identifying ongoing coinfections to address this critical blind spot in disease risk management.
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Affiliation(s)
- Earl A Middlebrook
- Biosecurity and Public Health, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Alicia T Romero
- Biosecurity and Public Health, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Bernard Bett
- International Livestock Research Institute, Nairobi, Kenya
| | - Daniel Nthiwa
- International Livestock Research Institute, Nairobi, Kenya.,Department of Biological Sciences, University of Embu, Embu, Kenya
| | - Samuel O Oyola
- International Livestock Research Institute, Nairobi, Kenya
| | - Jeanne M Fair
- Biosecurity and Public Health, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Andrew W Bartlow
- Biosecurity and Public Health, Los Alamos National Laboratory, Los Alamos, NM, USA
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24
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Wang X, Wang X, Li J. Overcoming T-cell exhaustion in glioblastoma: A narrative review. GLIOMA 2022. [DOI: 10.4103/glioma.glioma_16_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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25
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Argemi J, Ponz-Sarvise M, Sangro B. Immunotherapies for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Current and developing strategies. Adv Cancer Res 2022; 156:367-413. [PMID: 35961706 DOI: 10.1016/bs.acr.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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26
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Jin J, Liu Y, Xu X, Wang Z, Niu J. The association between Fc gamma RIIb expression levels and chronic hepatitis B virus infection progression. BMC Infect Dis 2021; 21:1235. [PMID: 34879827 PMCID: PMC8653572 DOI: 10.1186/s12879-021-06918-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/17/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Fc gamma receptor IIb (FcγRIIb) is an important inhibitory receptor that plays vital roles in regulating various immune response processes and the pathogenesis of many infectious diseases. The purpose of our research was to evaluate FcγRIIb expression in serum and liver biopsy specimens from hepatitis B virus (HBV)-infected patients and to explore the association of FcγRIIb with chronic HBV infection. METHODS Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the serum FcγRIIb levels in 119 HBV-infected patients and 24 healthy controls. An immunohistochemical method was then employed to identify FcγRIIb expression in biopsy specimens from patients with chronic hepatitis B (CHB). The integrated optical density (IOD) value was measured to represent FcγRIIb expression levels. RESULTS Serum FcγRIIb levels were decreased in CHB patients compared to controls (P < 0.001). The FcγRIIb levels in the CHB patient group were remarkably lower than those in the HBV carrier group (P < 0.001). In addition, FcγRIIb levels were negatively associated with AST and ALT (r = -0.3936, P = 0.0063; r = -0.3459, P = 0.0097, respectively). The IOD values of FcγRIIb expression in the moderate and severe CHB groups were significantly lower than those in the control group (P = 0.006 and P < 0.001, respectively). The FcγRIIb level tended to be lower with pathological changes related to hepatitis. Furthermore, correlation analysis revealed that FcγRIIb had negative correlations with AST and ALT (r = -0.688, P = 0.0016; r = -0.686, P = 0.0017, respectively) but a positive association with the platelet count (r = 0.6464, P = 0.0038). CONCLUSIONS FcγRIIb levels are significantly related to chronic HBV infection and the progression of CHB. Changes in FcγRIIb may affect the progression of liver inflammation and fibrosis in CHB patients.
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Affiliation(s)
- Jinglan Jin
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Yuwei Liu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Xiaotong Xu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Zhongfeng Wang
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Junqi Niu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China.
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27
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van Bömmel F, Berg T. Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatol Commun 2021; 5:1632-1648. [PMID: 34558833 PMCID: PMC8485892 DOI: 10.1002/hep4.1708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.
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Affiliation(s)
- Florian van Bömmel
- Division of HepatologyDepartment of Medicine IILeipzig University Medical CenterLeipzigGermany
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28
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Abstract
Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
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29
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Shared immunotherapeutic approaches in HIV and hepatitis B virus: combine and conquer. Curr Opin HIV AIDS 2021; 15:157-164. [PMID: 32167944 DOI: 10.1097/coh.0000000000000621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The aim of this study was to identify similarities, differences and lessons to be shared from recent progress in HIV and hepatitis B virus (HBV) immunotherapeutic approaches. RECENT FINDINGS Immune dysregulation is a hallmark of both HIV and HBV infection, which have shared routes of transmission, with approximately 10% of HIV-positive patients worldwide being coinfected with HBV. Immune modulation therapies to orchestrate effective innate and adaptive immune responses are currently being sought as potential strategies towards a functional cure in both HIV and HBV infection. These are based on activating immunological mechanisms that would allow durable control by triggering innate immunity, reviving exhausted endogenous responses and/or generating new immune responses. Recent technological advances and increased appreciation of humoral responses in the control of HIV have generated renewed enthusiasm in the cure field. SUMMARY For both HIV and HBV infection, a primary consideration with immunomodulatory therapies continues to be a balance between generating highly effective immune responses and mitigating any significant toxicity. A large arsenal of new approaches and ongoing research offer the opportunity to define the pathways that underpin chronic infection and move closer to a functional cure.
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30
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Yang S, Zeng W, Zhang J, Lu F, Chang J, Guo JT. Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary? Emerg Microbes Infect 2021; 10:1545-1554. [PMID: 34227927 PMCID: PMC8354158 DOI: 10.1080/22221751.2021.1952851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The prolonged viral antigen stimulation is the driving force for the development of immune tolerance to chronic hepatitis B virus (HBV) infection. The sustained reduction of viral proteins may allow for the recovery and efficient activation of HBV-specific T and B cells by immune-stimulating agents, checkpoint blockades and/or therapeutic vaccinations. Recently, several therapeutic approaches have been shown to significantly reduce intrahepatic viral proteins and/or circulating HBV surface antigen (HBsAg) with variable impacts on the host antiviral immune responses in animal models or human clinical trials. It remains to be further investigated whether reduction of viral protein expression or induction of intrahepatic viral protein degradation is more efficacious to break the immune tolerance to chronic HBV infection. It is also of great interest to know if the accelerated clearance of circulating HBsAg by antibodies has a long-term immunological impact on HBV infection and disease progression. Although it is clear that removal of antigen stimulation alone is not sufficient to induce the functional recovery of exhausted T and B cells, accumulating evidence suggests that the reduction of viral antigen load appears to facilitate the therapeutic activation of functional antiviral immunity in chronic HBV carriers. Based on a systematic review of the findings in animal models and clinical studies, the research directions toward discovery and development of more efficacious therapeutic approaches to reinvigorate HBV-specific adaptive immune function and achieve the durable control of chronic HBV infection, i.e. a functional cure, in the vast majority of treated patients are discussed.
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Affiliation(s)
- Sisi Yang
- Baruch S. Blumberg Institute, Doylestown, PA, USA.,Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wanjia Zeng
- Peking University Health Science Center, Beijing, People's Republic of China
| | - Jiming Zhang
- Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Fengmin Lu
- Peking University Health Science Center, Beijing, People's Republic of China
| | | | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, USA
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31
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Baudi I, Kawashima K, Isogawa M. HBV-Specific CD8+ T-Cell Tolerance in the Liver. Front Immunol 2021; 12:721975. [PMID: 34421926 PMCID: PMC8378532 DOI: 10.3389/fimmu.2021.721975] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/13/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.
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Affiliation(s)
- Ian Baudi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masanori Isogawa
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
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Cargill T, Barnes E. Therapeutic vaccination for treatment of chronic hepatitis B. Clin Exp Immunol 2021; 205:106-118. [PMID: 33969474 PMCID: PMC8274149 DOI: 10.1111/cei.13614] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B infection remains a serious global health threat, contributing to a large number of deaths through liver cirrhosis and hepatocellular carcinoma. Current treatment does not eradicate disease, and therefore new treatments are urgently needed. In acute hepatitis B virus (HBV) a strong immune response is necessary to clear the virus, but in chronic infection the immune response is weakened and dysfunctional. Therapeutic vaccination describes the process of inoculating individuals with a non‐infective form of viral antigen with the aim of inducing or boosting existing HBV‐specific immune responses, resulting in sustained control of HBV infection. In this review we outline the rationale for therapeutic vaccination in chronic HBV infection, discuss previous and ongoing trials of novel HBV therapeutic vaccine candidates and outline strategies to improve vaccine efficacy going forward.
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Affiliation(s)
- Tamsin Cargill
- Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom.,Translational Gastroenterology Unit, Oxford University, Oxford, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom.,Translational Gastroenterology Unit, Oxford University, Oxford, United Kingdom.,Oxford NIHR Biomedical Research Centre and Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom
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Gogoi D, Borkakoty B, Biswas D, Yadav K, Patel V. Characteristics of Circulatory γδ T cells in Patients with Symptomatic Chronic Hepatitis B Infection. Viral Immunol 2021; 34:483-490. [PMID: 34096794 DOI: 10.1089/vim.2020.0314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B is a viral infection that can cause serious liver disease. Chronic hepatitis B (CHB) infection places individuals at higher risk of developing cirrhosis of the liver and hepatocellular cancer. Immune dysfunction, including altered distribution and functional status of T cell immunity, is a contributor to hepatitis B virus (HBV) pathogenesis. In this study, we examined the distribution of circulating γδ T cell subpopulations and levels of cell surface expression of suppressive markers on γδ T cells in individuals with CHB infection and clinical liver disease. A significantly higher proportion of terminally differentiated (TEMRA) (CD27-CD45RA+) γδ T cells along with significantly lower percentages of central memory (CD27+CD45RA-) and effector memory (CD27-CD45RA-) γδ T cells were observed in peripheral blood of these individuals. The expression of exhaustion markers-Tim-3 and Lag-3 was elevated in γδ T cells from CHB-infected individuals compared with healthy controls (HC) and blockade of these exhaustion markers resulted in restoration of interferon gamma (IFN-γ) secretion by γδ T cells. In addition, γδ T cells from CHB patients expressed increased levels of CD69, another important regulator of immune responses. Together, these results suggest that CHB patients with clinical sign of liver disease have TEMRA γδ T cells with a potentially exhausted phenotype that may in turn impair their immunoregulatory role and facilitate pathogenesis of CHB disease.
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Affiliation(s)
- Dimpu Gogoi
- Department of Biochemistry and Virology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Mumbai, India.,Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Biswajyoti Borkakoty
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Dipankar Biswas
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Kaushal Yadav
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Vainav Patel
- Department of Biochemistry and Virology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Mumbai, India
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Jiang L, Niu W, Zheng Q, Meng G, Chen X, Zhang M, Deng G, Mao Q, Wang L. Identification of an Autoantibody Against ErbB-3-Binding Protein-1 in the Sera of Patients With Chronic Hepatitis B Virus Infection. Front Immunol 2021; 12:640335. [PMID: 34113340 PMCID: PMC8185336 DOI: 10.3389/fimmu.2021.640335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 05/11/2021] [Indexed: 01/12/2023] Open
Abstract
Background Studies have shown that autoimmune response contributes to chronic hepatitis B (CHB) development. Aim This study aimed to identify autoantibodies in the sera of patients with CHB and to investigate the association of autoimmune response with disease severity in CHB. Methods Proteins from human liver carcinoma cell line HepG2 were separated by two-dimensional electrophoresis. The candidate autoantigens were recognized by serum autoantibodies from Chinese CHB patients. Immunohistochemical staining was performed to determine the hepatic expression of the autoantigen in CHB patients with different inflammatory grades. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure the prevalence and the levels of serum autoantibody in CHB patients with different disease severity. Flow cytometry analysis was carried out to assess the autoreactive T cell response in the peripheral circulation of CHB patients. Results ErbB-3-binding protein-1 (EBP-1) was identified as an autoantigen of serum autoantibodies in CBP patients. EBP-1 protein expression was upregulated in the liver of CHB patients with high-grade hepatic inflammation. The prevalence and levels of serum anti-EBP1 IgG were significantly increased in CHB patients with severe diseases compared with those with mild or moderate diseases, but none was detectable in the healthy controls. EBP-1 peptides induced proinflammatory cytokine expression in CD4+ T cells from CHB patients. Conclusion Our results demonstrate the presence of an autoantibody against EBP-1 in the sera as well as EBP-1-reactive T cells in the peripheral blood of CHB patient. EBP-1-induced autoimmune response is positively associated with the disease severity, suggesting that EBP-1-induced autoimmune response possibly contributes to progressive liver failure.
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Affiliation(s)
- Li Jiang
- Department of Infectious Diseases, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wei Niu
- Department of Immunology & Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qian Zheng
- Function Center, North Sichuan Medical College, Nanchong, China
| | - Gang Meng
- Department of Pathology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaoling Chen
- Department of Immunology & Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mengjun Zhang
- Department of Pharmaceutical Analysis and Analytical Chemistry, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Li Wang
- Department of Immunology & Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
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Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition. Semin Immunopathol 2021; 43:535-548. [PMID: 34019142 PMCID: PMC8443521 DOI: 10.1007/s00281-021-00864-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.
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Jiang Y, Qin S, Wei X, Liu X, Guan J, Zhu H, Chang G, Chen Y, Lu H, Qian J, Wang Z, Shen M, Lin X. Highly activated TRAIL + CD56 bright NK cells are associated with the liver damage in HBV-LC patients. Immunol Lett 2021; 232:9-19. [PMID: 33515618 DOI: 10.1016/j.imlet.2020.12.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic hepatitis B-related liver cirrhosis(HBV-LC)is the most common cirrhosis in China, which is characterized as liver damage and high mortality. We aim to investigate the characteristics of TRAIL+NK cells in patients with HBV-LC and their relationship with liver damage in patients with HBV-LC. METHODS Thirty cases each of chronic hepatitis B (CHB), HBV-related compensated liver cirrhosis (HBV-CLC) and HBV-related decompensated liver cirrhosis (HBV-DLC) patients were recruited in this study. Thirty age-and sex-matched healthy individuals were recruited as healthy controls (HCs). NK cell phenotypes were determined using flow cytometry. Serum chemokine concentrations were ascertained using the CBA Flex set. Cell apoptosis was analyzed using the Annexin V-PE/7-AAD apoptosis Kit. RESULTS CD56bright NK cells increased, but CD56dim NK cells reduced in HBV-LC patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was mainly expressed on CD56bright NK cells. As the degree of liver damage increased, the frequency and activation of total TRAIL+NK cells and TRAIL+NK cell subsets continued to increase, especially in the HBV-LC patients. Furthermore, the difference in frequency and activation of total TRAIL+NK cells between the HBV-CLC and HBV-DLC groups was mainly due to the highly activation and increase of TRAIL+CD56bright NK cells. With the increasing degree of liver damage, CXCR3-associated chemokines (including CXCL9, CXCL10 and CXCL11) were constantly increased, particularly in the HBV-DLC group. The expression of CXCR3 on CD56bright NK cells was almost 100 % in all enrolled cohorts. CXCR3-associated chemokines were negatively correlated with liver function and positively correlated with fibrosis degree. TRAIL+CD56bright NK cells were negatively correlated with liver function, and positively correlated with fibrosis degree and CXCR3-associated chemokines. The apoptosis of K562 cells and hepatocytes was suppressed partially by the TRAIL-neutralizing antibodies. CONCLUSIONS The increase of CXCR3-related chemokines (including CXCL9, CXCL10 and CXCL11) might be related to the migration of TRAIL+ CD56bright NK cells to the liver. Highly activated TRAIL+ CD56bright NK cells were associated with the liver damage in HBV-LC patients. These findings may provide new perspectives and theoretical basis for future immunotherapy of HBV-LC patients.
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Affiliation(s)
- Yujie Jiang
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Shuang Qin
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xin Wei
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xiaoyuan Liu
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jingjing Guan
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Hengyue Zhu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Guolin Chang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yingxiao Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou, Medical University, Wenzhou, 325000, China
| | - Hong Lu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jingjing Qian
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhongyong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Mo Shen
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xiangyang Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Swadling L, Pallett LJ, Diniz MO, Baker JM, Amin OE, Stegmann KA, Burton AR, Schmidt NM, Jeffery-Smith A, Zakeri N, Suveizdyte K, Froghi F, Fusai G, Rosenberg WM, Davidson BR, Schurich A, Simon AK, Maini MK. Human Liver Memory CD8 + T Cells Use Autophagy for Tissue Residence. Cell Rep 2021; 30:687-698.e6. [PMID: 31968246 PMCID: PMC6988113 DOI: 10.1016/j.celrep.2019.12.050] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/04/2019] [Accepted: 12/13/2019] [Indexed: 12/11/2022] Open
Abstract
Tissue-resident memory T cells have critical roles in long-term pathogen and tumor immune surveillance in the liver. We investigate the role of autophagy in equipping human memory T cells to acquire tissue residence and maintain functionality in the immunosuppressive liver environment. By performing ex vivo staining of freshly isolated cells from human liver tissue, we find that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells. CD8+ T cells with increased autophagy are those best able to proliferate and mediate cytotoxicity and cytokine production. Conversely, blocking autophagy induction results in the accumulation of depolarized mitochondria, a feature of exhausted T cells. Primary hepatic stellate cells or the prototypic hepatic cytokine interleukin (IL)-15 induce autophagy in parallel with tissue-homing/retention markers. Inhibition of T cell autophagy abrogates tissue-residence programming. Thus, upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.
An increased rate of basal autophagy is a hallmark of liver-resident CD8+ T cells Enhanced T cell autophagy can be imprinted by IL-15 or hepatic stellate cells Autophagy induction is required for tissue-residence programming in vitro Enhanced autophagy maintains TRM mitochondrial fitness in the liver
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Affiliation(s)
- Leo Swadling
- Division of Infection and Immunity, University College London, London, UK.
| | - Laura J Pallett
- Division of Infection and Immunity, University College London, London, UK
| | - Mariana O Diniz
- Division of Infection and Immunity, University College London, London, UK
| | - Josephine M Baker
- Division of Infection and Immunity, University College London, London, UK
| | - Oliver E Amin
- Division of Infection and Immunity, University College London, London, UK
| | - Kerstin A Stegmann
- Division of Infection and Immunity, University College London, London, UK
| | - Alice R Burton
- Division of Infection and Immunity, University College London, London, UK
| | - Nathalie M Schmidt
- Division of Infection and Immunity, University College London, London, UK
| | - Anna Jeffery-Smith
- Division of Infection and Immunity, University College London, London, UK; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, QMUL, London, UK
| | - Nekisa Zakeri
- Division of Infection and Immunity, University College London, London, UK
| | | | - Farid Froghi
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Giuseppe Fusai
- Institute for Liver and Digestive Health, University College London, London, UK
| | - William M Rosenberg
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Brian R Davidson
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Anna Schurich
- Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, Kings College London, London, UK
| | - A Katharina Simon
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Mala K Maini
- Division of Infection and Immunity, University College London, London, UK.
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El Costa H, Gouilly J, Abravanel F, Bahraoui E, Peron JM, Kamar N, Jabrane-Ferrat N, Izopet J. Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly. PLoS Pathog 2021; 17:e1009367. [PMID: 33617602 PMCID: PMC7932504 DOI: 10.1371/journal.ppat.1009367] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 03/04/2021] [Accepted: 02/09/2021] [Indexed: 12/17/2022] Open
Abstract
Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. The outcome of Genotype 3 Hepatitis E virus (HEV-3) infection differs among the elderly. Some patients develop severe forms of Hepatitis E while others remain asymptomatic. Nonetheless, parameters which can lead to severe versus silent infection are largely unknown. Therefore, we investigated immunological features of CD8 T cells in infected patients (aged ≥55) with similar viral determinants but distinct clinical outcomes. We show that drastic phenotypic changes were specifically observed within the effector memory (EM) compartment. Compared to asymptomatic patients, symptomatic ones display a strong activation of both HEV-3-specific and -nonspecific EM CD8 T cells associated with qualitative and quantitative alterations in cytokine production. In addition, EM cells are endowed with high cytotoxic capacity and have the ability to rapidly migrate to the liver. Finally, we report that the inflammatory response to HEV-3 infection shape EM cell activation and function in symptomatic elderly patients. In summary, our results present the first report demonstrating that the nature and the magnitude of EM CD8 T cell response play an important role in the outcome of HEV-3 infection in the elderly.
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Affiliation(s)
- Hicham El Costa
- Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France
- Laboratoire de Virologie, Centre National de référence HEV, Institut Fédératif de Biologie, CHU Toulouse, Toulouse, France
- * E-mail:
| | - Jordi Gouilly
- Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France
| | - Florence Abravanel
- Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France
- Laboratoire de Virologie, Centre National de référence HEV, Institut Fédératif de Biologie, CHU Toulouse, Toulouse, France
| | | | - Jean-Marie Peron
- Département de Gastroentérologie, CHU Toulouse, Toulouse, France
| | - Nassim Kamar
- Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France
| | | | - Jacques Izopet
- Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France
- Laboratoire de Virologie, Centre National de référence HEV, Institut Fédératif de Biologie, CHU Toulouse, Toulouse, France
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Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021; 1:48-55. [PMID: 22720211 PMCID: PMC3376967 DOI: 10.4161/onci.1.1.18344] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
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40
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Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2021. [PMID: 22720211 DOI: 10.4161/onc-i.1.1.18344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
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Jansen DT, Dou Y, de Wilde JW, Woltman AM, Buschow SI. Designing the next-generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures. Clin Transl Immunology 2021; 10:e1232. [PMID: 33489122 PMCID: PMC7809700 DOI: 10.1002/cti2.1232] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
In the mid‐90s, hepatitis B virus (HBV)‐directed immune responses were for the first time investigated in detail and revealed suboptimal T‐cell responses in chronic HBV patients. Based on these studies, therapeutic vaccination exploiting the antigen presentation capacity of dendritic cells to prime and/or boost HBV‐specific T‐cell responses was considered highly promising. Now, 25 years later, it has not yet delivered this promise. In this review, we summarise what has been clinically tested in terms of antigen targets and vaccine forms, how the immunological and therapeutic effects of these vaccines were assessed and what major clinical and immunological findings were reported. We combine the lessons learned from these trials with the most recent insights on HBV antigen presentation, T‐cell responses, vaccine composition, antiviral and immune‐modulatory drugs and disease biomarkers to derive novel opportunities for the next generation of therapeutic vaccines designed to cure chronic HBV either alone or in combination therapy.
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Affiliation(s)
- Diahann Tsl Jansen
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Yingying Dou
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Janet W de Wilde
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands.,Present address: Department of Viroscience Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Andrea M Woltman
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands.,Present address: Institute of Medical Research Education Rotterdam Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
| | - Sonja I Buschow
- Department of Gastroenterology and Hepatology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
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42
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Chua C, Salimzadeh L, Gehring AJ. Immunopathogenesis of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:73-97. [DOI: 10.1007/978-981-16-3615-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Block PD, Shinn B, Kim JH, Hann HW. Hepatitis B-related hepatocellular carcinoma and stress: untangling the host immune response from clinical outcomes. Hepat Oncol 2020; 8:HEP35. [PMID: 33680431 PMCID: PMC7907965 DOI: 10.2217/hep-2020-0028] [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: 08/02/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major public health challenge on the global scale. Affecting hundreds of millions worldwide, HBV is a leading risk factor for hepatocellular carcinoma (HCC). Clinical outcomes from chronic HBV infection are varied and appear to be influenced by a complex and dysregulated host immune response. In turn, much attention has been given to the immunologic response to HBV in an effort to identify host factors that lead to the development of HCC. However, the role of nonimmunologic host factors, such as chronic stress, in HBV-related HCC is poorly defined. Indeed, a growing appreciation for the effects of stress on chronic liver diseases raises the question of its role in chronic HBV infection. In this light, the present review will untangle the roles of key host factors in HBV-related HCC with an emphasis on chronic stress as a viable contributor. First discussed is the interplay of stress, inflammation and chronic liver disease. The host immune response's role as a driver of HBV-related HCC is then reviewed, allowing for a close exploration of the effects of stress on immune function in chronic hepatitis B and as a potential risk factor for HBV-related HCC.
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Affiliation(s)
- Peter D Block
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Brianna Shinn
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jin Hyang Kim
- Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA
| | - Hie-Won Hann
- Department of Gastroenterology & Hepatology, Liver Disease Prevention Center, Philadelphia, PA 19107, USA
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44
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Gu Y, Li X, Gu L, Lian Y, Wang K, Chen Y, Lai J, Mei Y, Liu J, Huang Z, Zhang M, Chen L, Huang Y. An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B. Aging (Albany NY) 2020; 12:26063-26079. [PMID: 33401245 PMCID: PMC7803537 DOI: 10.18632/aging.202274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 11/13/2020] [Indexed: 12/20/2022]
Abstract
We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.
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Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoyan Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ke Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Youming Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Lai
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yongyu Mei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Min Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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45
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Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020; 2:1001-1012. [PMID: 32958939 DOI: 10.1038/s42255-020-00280-9] [Citation(s) in RCA: 235] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 08/12/2020] [Indexed: 12/13/2022]
Abstract
Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.
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Affiliation(s)
- Fabien Franco
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Alison Jaccard
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Pedro Romero
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Yi-Ru Yu
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
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46
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Abstract
Hepatitis B virus (HBV) infection causes chronic hepatitis and has long term complications. Individuals ever infected with HBV are at risk of viral reactivation under certain circumstances. This review summarizes studies on HBV persistence and reactivation with a focus on the definitions and mechanisms. Emphasis is placed on the interplay between HBV replication and host immunity as this interplay determines the patterns of persistence following viral acquisition. Chronic infections exhibit as overt persistence when a defective immune response fails to control the viral replication. The HBV genome persists despite an immune response in the form of covalently closed circular DNA (cccDNA) and integrated DNA, rendering an occult state of viral persistence in individuals whose infection appears to have been resolved. We have described HBV reactivation that occurs because of changes in the virus or the immune system. This review aims to raise the awareness of HBV reactivation and to understand how HBV persists, and discusses the risks of HBV reactivation in a variety of clinical settings.
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Affiliation(s)
- Yu Shi
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, China
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, China
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47
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Le Bert N, Gill US, Hong M, Kunasegaran K, Tan DZM, Ahmad R, Cheng Y, Dutertre CA, Heinecke A, Rivino L, Tan A, Hansi NK, Zhang M, Xi S, Chong Y, Pflanz S, Newell EW, Kennedy PTF, Bertoletti A. Effects of Hepatitis B Surface Antigen on Virus-Specific and Global T Cells in Patients With Chronic Hepatitis B Virus infection. Gastroenterology 2020; 159:652-664. [PMID: 32302614 DOI: 10.1053/j.gastro.2020.04.019] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/03/2020] [Accepted: 04/06/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen [HBsAg]) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations. METHODS We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, hepatitis B e antigen, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMCs). In PBMCs from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer and T cells by mass cytometry. PBMCs from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry. We used multivariate linear regression and performed variable selection using the Akaike information criterion to identify covariates associated with HBV-specific responses of T cells. RESULTS Although T- and natural killer cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r = 0.3367; P < .00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P = .000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decreased to 7.14% in patients older than 30 years. CONCLUSIONS In an analysis of immune cells from patients with chronic HBV infection, we found that the duration of HBsAg exposure, rather than the quantity of HBsAg, was associated with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for the clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should be considered in patients younger than 30 years.
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Affiliation(s)
- Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Upkar S Gill
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Michelle Hong
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Kamini Kunasegaran
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Damien Z M Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Raidah Ahmad
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Yang Cheng
- Singapore Immunology Network, A∗STAR, Singapore
| | - Charles-A Dutertre
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A∗STAR, Singapore
| | | | - Laura Rivino
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; School of Cellular and Molecular Medicine, University of Bristol, United Kingdom
| | - Anthony Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Navjyot K Hansi
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Min Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sujuan Xi
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Stefan Pflanz
- Gilead Sciences, Inc, Department of Biology, Foster City, California
| | | | - Patrick T F Kennedy
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A∗STAR, Singapore.
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48
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Fisicaro P, Barili V, Rossi M, Montali I, Vecchi A, Acerbi G, Laccabue D, Zecca A, Penna A, Missale G, Ferrari C, Boni C. Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches. Front Immunol 2020; 11:849. [PMID: 32477347 PMCID: PMC7235343 DOI: 10.3389/fimmu.2020.00849] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/14/2020] [Indexed: 12/12/2022] Open
Abstract
A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.
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Affiliation(s)
- Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Greta Acerbi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Alessandra Zecca
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carlo Ferrari
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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49
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Tan AT, Schreiber S. Adoptive T-cell therapy for HBV-associated HCC and HBV infection. Antiviral Res 2020; 176:104748. [DOI: 10.1016/j.antiviral.2020.104748] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/14/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023]
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50
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Hoogeveen RC, Boonstra A. Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection. Front Immunol 2020; 11:401. [PMID: 32194573 PMCID: PMC7064714 DOI: 10.3389/fimmu.2020.00401] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
Treatment of chronic hepatitis B virus (HBV) infection is highly effective in suppressing viral replication, but complete cure is rarely achieved. In recent years, substantial progress has been made in the development of immunotherapy to treat cancer. Applying these therapies to improve the management of chronic HBV infection is now being attempted, and has become an area of active research. Immunotherapy with vaccines and checkpoint inhibitors can boost T cell functions in vitro, and therefore may be used to reinvigorate the impaired HBV-specific T cell response. However, whether these approaches will suffice and restore antiviral T cell immunity to induce long-term HBV control remains an open question. Recent efforts have begun to describe the phenotype and function of HBV-specific T cells on the single epitope level. An improved understanding of differing T cell specificities and their contribution to HBV control will be instrumental for advancement of the field. In this review, we outline correlates of successful versus inadequate T cell responses to HBV, and discuss the rationale behind therapeutic vaccines and checkpoint inhibitors for the treatment of chronic HBV infection.
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Affiliation(s)
- Ruben C Hoogeveen
- Division of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - André Boonstra
- Division of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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