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Ganeshan H, Huang J, Belmonte M, Belmonte A, Inoue S, Velasco R, Maiolatesi S, Limbach K, Patterson N, Sklar MJ, Soisson L, Epstein JE, Edgel KA, Peters B, Hollingdale MR, Villasante E, Duplessis CA, Sedegah M. Human responses to the DNA prime/chimpanzee adenovirus (ChAd63) boost vaccine identify CSP, AMA1 and TRAP MHC Class I-restricted epitopes. PLoS One 2025; 20:e0318098. [PMID: 39946433 PMCID: PMC11825025 DOI: 10.1371/journal.pone.0318098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 10/17/2024] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND A three-antigen DNA-prime/chimpanzee adenovirus 63 (ChAd63) boost vaccine containing pre-erythrocytic Plasmodium falciparum (Pf) circumsporozoite protein (CSP), Pf apical membrane antigen-1 (AMA1) and malaria multiple epitopes (ME) fused to Pf thrombospondin-related adhesion protein (ME-TRAP) elicited higher vaccine efficacy (VE) in an open label, randomized Phase 1 trial against controlled human malaria infection (CHMI) than the two-antigen vaccine DNA/Human Adenovirus 5 (HuAd5) containing CSP and AMA1. The objective of this follow-up study was to determine whether responses to CSP, AMA1 or TRAP MHC Class I-restricted epitopes were associated with VE. METHODOLOGY Protected (n = 6) and non-protected participants (n = 26) were screened in FluoroSpot interferon gamma (IFN-γ) and Granzyme B (GzB) assays using antigen-specific 15mer peptide subpools spanning CSP (n = 9 subpools), AMA1 (n = 12 subpools), and TRAP (n = 11 subpools). Individual antigen-specific 15mers in the subpools with strong responses were then deconvoluted, evaluated for activities, and MHC Class I-restricted epitopes within the active 15mers were predicted using NetMHCpan algorithms. The predicted epitopes were synthesized and evaluated in the FluoroSpot IFN-γ and GzB assays. RESULTS Protected and some non-protected participants had similar responses to individual antigen-specific peptide subpools, which did not distinguish only protected participants. However, deconvoluted antigen-specific positive subpools with high magnitudes of responses revealed individual 15mer peptides containing specific and/or predicted MHC Class I (HLA) epitopes. Responses to epitopes were either IFN-γ-only, IFN-γ and GzB, or GzB-only. Due to limitation of cells, most of the analysis concentrated on the identification of protection associated AMA1 epitopes, since most of the predominant pool specific responses were generated against AMA1 15mer subpools. Furthermore, we previously identified protection associated HLA class I-restricted epitopes in a previous gene-based vaccine trial. Seven predicted minimal epitopes in AMA1 were synthesized and upon testing, five recalled responses from protected participants confirming their possible contribution and association with protection, and two recalled responses from non-protected participants. Two protection-associated epitopes were promiscuous and may have also contributed to protection by recognition of different HLA alleles. In addition, strongly positive antigen-specific 15mers identified within active antigen-specific subpools contained 39 predicted but not tested epitopes were identified in CSP, AMA1 and TRAP. Finally, some non-protected individuals recognized HLA-matched protection-associated minimal epitopes and we discuss possible reasons. Other factors such as HLA allele fine specificity or interaction between other HLA alleles in same individual may also influence protective efficacy. CONCLUSIONS This integrated approach using immunoassays and bioinformatics identified and confirmed AMA1-MHC Class I-restricted epitopes and a list of predicted additional epitopes which could be evaluated in future studies to assess possible association with protection against CHMI in the Phase 1 trial participants. The results suggest that identification of protection-associated epitopes within malaria antigens is feasible and can help design potent next generation multi-antigen, multi-epitope malaria vaccines for a genetically diverse population and to develop robust assays to measure protective cellular immunity against pre-erythrocytic stages of malaria. This approach can be used to develop vaccines for other novel emerging infectious disease pathogens.
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Affiliation(s)
- Harini Ganeshan
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Jun Huang
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Maria Belmonte
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Arnel Belmonte
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- General Dynamics Information Technology, Falls Church, Virginia, United States of America
| | - Sandra Inoue
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- General Dynamics Information Technology, Falls Church, Virginia, United States of America
| | - Rachel Velasco
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- General Dynamics Information Technology, Falls Church, Virginia, United States of America
| | - Santina Maiolatesi
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Keith Limbach
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Noelle Patterson
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Marvin J. Sklar
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
| | - Lorraine Soisson
- United States Agency for International Development (USAID), Washington, DC, United States of America
| | - Judith E. Epstein
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Kimberly A. Edgel
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
| | - Bjoern Peters
- La Jolla Institute of Allergy and Immunology, La Jolla, California, United States of America
| | - Michael R. Hollingdale
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, United States of America
| | - Eileen Villasante
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
| | | | - Martha Sedegah
- Naval Medical Research Command, Silver Spring, Maryland, United States of America
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Cheng J, Ju H, Wang G, He C, Wang W. Association of Systemic Inflammation Response Index with Short-Term All-Cause Mortality in Decompensated Liver Cirrhosis Patients. J Inflamm Res 2024; 17:8985-8995. [PMID: 39583863 PMCID: PMC11583772 DOI: 10.2147/jir.s476743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024] Open
Abstract
Background The Systemic Inflammation Response Index (SIRI) has demonstrated predictive capabilities for clinical outcomes in various diseases. However, its prognostic utility in decompensated liver cirrhosis (DLC) remains underexplored. This study aimed to investigate the association between SIRI and the risk of short-term (3 and 6 months) all-cause mortality in DLC patients. Methods A total of 926 eligible patients with DLC from diverse etiologies was included in this study. In the initial cohort, the predictive accuracy of SIRI was evaluated using receiver operating characteristic (ROC) curve analysis. Patients were categorized into high- and low-SIRI groups based on the Youden index. Multivariable logistic regression analysis was employed to evaluate the independent association between SIRI and all-cause mortality. Restricted cubic spline (RCS) analysis was utilized to visualize the relationship between the continuous variable SIRI and mortality risk. These findings were validated in a validation cohort. Results The initial cohort had mortality rates of 8.8% and 11.6% at 3 and 6 months, respectively. The SIRI level was significantly higher in the deceased group compared to the survival group. At both time points, SIRI was an independent indicator of all-cause mortality. RCS analysis demonstrated the risk of the risk of increased with an increase in SIRI value. The Validation cohort validated the independent association between higher SIRI levels and lower short-term all-cause mortality. Conclusion This study's findings underscore the prognostic value of SIRI in DLC patients, indicating that higher SIRI levels are significantly associated with short-term adverse outcomes.
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Affiliation(s)
- Jin Cheng
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Honglei Ju
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Guixiang Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Chiyi He
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Wei Wang
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
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Zhou J, He X, Ou Y, Peng S, Li D, Zhou Q, Fu J, Long Y, Tan Y. Role of CXCR5 + CD8 + T cells in human hepatitis B virus infection. J Viral Hepat 2023; 30:638-645. [PMID: 37129474 DOI: 10.1111/jvh.13840] [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: 02/01/2023] [Revised: 04/05/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
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Affiliation(s)
- Juan Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xiaojing He
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yangjing Ou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Shuang Peng
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Dan Li
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Qing Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jingli Fu
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yunzhu Long
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yingzheng Tan
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment. Vaccines (Basel) 2023; 11:681. [PMID: 36992265 PMCID: PMC10056334 DOI: 10.3390/vaccines11030681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.
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Affiliation(s)
| | | | - Eva Billerbeck
- Division of Hepatology, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Du Y, Wu J, Liu J, Zheng X, Yang D, Lu M. Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection. Front Immunol 2022; 13:965018. [PMID: 35967443 PMCID: PMC9372436 DOI: 10.3389/fimmu.2022.965018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.
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Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Mengji Lu,
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Zhao HJ, Hu YF, Han QJ, Zhang J. Innate and adaptive immune escape mechanisms of hepatitis B virus. World J Gastroenterol 2022; 28:881-896. [PMID: 35317051 PMCID: PMC8908287 DOI: 10.3748/wjg.v28.i9.881] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 08/09/2021] [Accepted: 01/29/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is an international health problem with extremely high mortality and morbidity rates. Although current clinical chronic hepatitis B (CHB) treatment strategies can partly inhibit and eliminate HBV, viral breakthrough may result due to non-adherence to treatment, the emergence of viral resistance, and a long treatment cycle. Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems. Therefore, understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control. This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.
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Affiliation(s)
- Hua-Jun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Fei Hu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Qiu-Ju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
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Mohseninia A, Dehghani P, Bargahi A, Rad-Malekshahi M, Rahimikian R, Movahed A, Reza Farzaneh M, Mohammadi M. Harnessing self-assembling peptide nanofibers toprime robust tumor-specific CD8 T cell responses in mice. Int Immunopharmacol 2022; 104:108522. [PMID: 35032825 DOI: 10.1016/j.intimp.2022.108522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/30/2021] [Accepted: 01/05/2022] [Indexed: 11/27/2022]
Abstract
Induction of tumor-specific CD8 + T cell responses is known as a major challenge for cancer vaccine development; here we presented a strategy to improve peptide nanofibers-mounted antitumor immune responses. To this end, peptide nanofibers bearing class I (Kb)-restricted epitope (Epi-Nano) were formulated with polyethylene imine backbone (Epi-Nano-PEI), and characterized using morphological and physicochemicalcharacterizationtechniques. Nanofibers were studied in terms of their uptake by antigen-presenting cells (APCs), antigen cross-presentation capacity, and cytotoxic activity. Furthermore, nanofibers were assessed by their potency to induce NLRP3 inflammasome-related cytokines and factors. Finally, the ability of nanofibers to induce tumor-specific CD8 T cells and tumor protection were investigated in tumor-bearing mice. The formulation of Epi-Nano with PEI led to the formation of short strand nanofibers with a positive surface charge, a low critical aggregation concentration (CAC), and an increased resistancetoproteolytic degradation. Epi-Nano-PEI was significantly taken up more efficiently by antigen-presenting cells (APCs), and was more potent in cross-presentation when compared to Epi-Nano. Moreover, Epi-Nano-PEI, in comparison to Epi-Nano, efficiently up-regulated the expression of NLRP3, caspase-1, IL-1b, IL18 and IL-6. Cell viability analysis showed that formulation of PEI with Epi-Nano not only abolished its cytotoxic activity, but surprisingly induced macrophage proliferation. Furthermore, it demonstrated that Epi-Nano-PEI triggered robust antigen-specific CD8+ T cell responses, and induced maximum antitumor response (tumor growth inhibition and prolonged survival) in tumor-bearing mice that were significantly higher compared to Epi-Nano. Taken together, the formulation of Epi-Nano with PEI is suggested as a promising strategy to improve nanofibers-mounted antitumor immune response.
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Affiliation(s)
- Atefeh Mohseninia
- Department of Biochemistry, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Parva Dehghani
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University Of Medical Sciences, Bushehr, Iran
| | - Afshar Bargahi
- Department of Biochemistry, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mazda Rad-Malekshahi
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Raha Rahimikian
- Department of Biochemistry, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Ali Movahed
- Department of Biochemistry, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | | | - Mohsen Mohammadi
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University Of Medical Sciences, Bushehr, Iran.
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Yang J, Li Y, Ye J, Wang J, Lu H, Yao X. Characterization of the TCR β Chain Repertoire in Peripheral Blood from Hepatitis B Vaccine Responders and Non-Responders. J Inflamm Res 2022; 15:939-951. [PMID: 35210805 PMCID: PMC8856041 DOI: 10.2147/jir.s347702] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/26/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B (HepB) vaccination can effectively prevent the prevalence of hepatitis B virus (HBV) infection. However, the incidence of vaccination failure is about 5~10% and the underlying molecular mechanisms are poorly understood. T cells have an essential role in the recipient's immune response to vaccine, which could be elucidated by high-throughput sequencing (HTS) and bioinformatics analysis. METHODS We conducted HTS of the T cell receptor β chain (TRB) complementarity-determining region 3 (CDR3) repertoires in eighteen positive responders (responders) and 10 negative responders (non-responders) who all had HepB vaccination, the repertoire features of BV, BJ and V-J genes and their diversity, respectively, were compared between the positive and negative responders using the Mann-Whitney test. Moreover, the relatively conserved motifs in CDR3 were revealed and compared to those in the other group's report. RESULTS The diversity of TRB CDR3 and the frequencies of BV27 and BV7-9 are significantly increased for HepB vaccine responders compared to those in non-responders. The motifs of CDR3s in BV27/J1-1, BV27/J2-5, and BV7-9/J2-5, respectively, were most expressed as "NTE", "QETQ", and "GG-Q (E)-ETQ". Moreover, the motif "KLNSPL" was determined in nearly 80% CDR3s in BV27/J1-6 from HepB vaccine responders for the first time. CONCLUSION Our results present the comprehensive profiles of TRB CDR3 in the HepB vaccine responders and non-responders after standard vaccination protocol and determine the relatively conservative motifs of CDR3s that may respond to the HepB vaccine. Further results suggest that the profile of TRB repertoire could distinguish the HepB vaccine responders from non-responders and provide a new target for optimizing and improving the efficiency of the HepB vaccine.
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Affiliation(s)
- Jiezuan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Infectious Diseases, Hangzhou, People’s Republic of China
| | - Yongtao Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Infectious Diseases, Hangzhou, People’s Republic of China
| | - Jing Ye
- Department of Surgical ICU, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China
| | - Ju Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Infectious Diseases, Hangzhou, People’s Republic of China
| | - Haifeng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Infectious Diseases, Hangzhou, People’s Republic of China
| | - Xinsheng Yao
- Department of Immunology, Research Center for Medicine & Biology, Innovation & Practice Base for Graduate Students Education, Zunyi Medical University, Zunyi, People’s Republic of China
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Ganesan M, Wang W, Mathews S, Makarov E, New-Aaron M, Dagur RS, Malo A, Protzer U, Kharbanda KK, Casey CA, Poluektova LY, Osna NA. Ethanol attenuates presentation of cytotoxic T-lymphocyte epitopes on hepatocytes of HBV-infected humanized mice. Alcohol Clin Exp Res 2022; 46:40-51. [PMID: 34773268 PMCID: PMC8799491 DOI: 10.1111/acer.14740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Weimin Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Saumi Mathews
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Edward Makarov
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Raghubendra Singh Dagur
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Antje Malo
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Centre for Infection Research (DZIF), Munich, Hamburg, and Heidelberg partner sites, Germany
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Carol A Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
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10
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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11
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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: 38] [Impact Index Per Article: 9.5] [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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12
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Kawashima K, Isogawa M, Onishi M, Baudi I, Saito S, Nakajima A, Fujita T, Tanaka Y. Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation. JCI Insight 2021; 6:145761. [PMID: 33400688 PMCID: PMC7934883 DOI: 10.1172/jci.insight.145761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus–specific (HBV-specific) CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunction is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFN-α treatment. Importantly, a strong induction of type I interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs’ expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunction. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection. Functional defects of hepatitis B virus–specific CD8+ T cells correlate with impairment of type I interferon signaling after intrahepatic priming.
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Affiliation(s)
- Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Masanori Isogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaya Onishi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ian Baudi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takashi Fujita
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Science, and.,Laboratory of Molecular and Cellular Immunology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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13
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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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14
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Lurje I, Hammerich L, Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J Mol Sci 2020; 21:ijms21197378. [PMID: 33036244 PMCID: PMC7583774 DOI: 10.3390/ijms21197378] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.
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15
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Ficht X, Iannacone M. Immune surveillance of the liver by T cells. Sci Immunol 2020; 5:5/51/eaba2351. [PMID: 32887842 DOI: 10.1126/sciimmunol.aba2351] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver. Here, we provide an overview of the current knowledge on liver immune surveillance by conventional and invariant T cells and explore the complex cross-talk between immune cell subsets that determines the balance between hepatic immunity and tolerance.
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Affiliation(s)
- Xenia Ficht
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.,Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. .,Vita-Salute San Raffaele University, 20132 Milan, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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16
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Mechanisms of HBV immune evasion. Antiviral Res 2020; 179:104816. [PMID: 32387476 DOI: 10.1016/j.antiviral.2020.104816] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/29/2020] [Accepted: 05/03/2020] [Indexed: 02/07/2023]
Abstract
The concept of immune evasion is a longstanding topic of debate during chronic Hepatitis B Virus infection. The 292 million individuals chronically infected by HBV are clear evidence that the virus avoids elimination by the immune system. The exact mechanisms of immune evasion remain undefined and are distinct, but likely interconnected, between innate and adaptive immunity. There is a significant body of evidence that supports peripheral tolerance and exhaustion of adaptive immunity but our understanding of the role that central tolerance plays is still developing. Innate immunity instructs the adaptive immune response and subversion of its functionality will impact both T and B cell responses. However, literature around the interaction of HBV with innate immunity is inconsistent, with reports suggesting that HBV avoids innate recognition, suppresses innate recognition, or activates innate immunity. This complexity has led to confusion and controversy. This review will discuss the mechanisms of central and peripheral tolerance/exhaustion of adaptive immunity in the context of chronic HBV infection. We also cover the interaction of HBV with cells of the innate immune system and propose concepts for the heterogeneity of responses in chronically infected patients.
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17
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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18
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Heim K, Neumann-Haefelin C, Thimme R, Hofmann M. Heterogeneity of HBV-Specific CD8 + T-Cell Failure: Implications for Immunotherapy. Front Immunol 2019; 10:2240. [PMID: 31620140 PMCID: PMC6763562 DOI: 10.3389/fimmu.2019.02240] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 09/04/2019] [Indexed: 12/18/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health burden affecting around 257 million people worldwide. The consequences of chronic HBV infection include progressive liver damage, liver cirrhosis, and hepatocellular carcinoma. Although current direct antiviral therapies successfully lead to suppression of viral replication and deceleration of liver cirrhosis progression, these treatments are rarely curative and patients often require a life-long therapy. Based on the ability of the immune system to control HBV infection in at least a subset of patients, immunotherapeutic approaches are promising treatment options to achieve HBV cure. In particular, T cell-based therapies are of special interest since CD8+ T cells are not only capable to control HBV infection but also to eliminate HBV-infected cells. However, recent data show that the molecular mechanisms underlying CD8+ T-cell failure in chronic HBV infection depend on the targeted antigen and thus different strategies to improve the HBV-specific CD8+ T-cell response are required. Here, we review the current knowledge about the heterogeneity of impaired HBV-specific T-cell populations and the potential consequences for T cell-based immunotherapeutic approaches in HBV cure.
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Affiliation(s)
- Kathrin Heim
- Department of Medicine II, Faculty of Medicine, University Hospital Freiburg, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Faculty of Medicine, University Hospital Freiburg, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Faculty of Medicine, University Hospital Freiburg, University of Freiburg, Freiburg, Germany
| | - Maike Hofmann
- Department of Medicine II, Faculty of Medicine, University Hospital Freiburg, University of Freiburg, Freiburg, Germany
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19
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Bertoletti A, Kennedy PTF. HBV antiviral immunity: not all CD8 T cells are born equal. Gut 2019; 68:770-773. [PMID: 30700541 DOI: 10.1136/gutjnl-2018-317959] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 01/10/2019] [Accepted: 01/10/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, A*STAR, Singapore
| | - Patrick T F Kennedy
- Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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20
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Isogawa M, Murata Y, Kawashima K, Tanaka Y. How are HBV-specific CD8+ T-cell responses induced? Future Virol 2018. [DOI: 10.2217/fvl-2018-0164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Masanori Isogawa
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan
| | - Yasuhiro Murata
- Department of Hepatobiliary Pancreatic & Transplant Surgery, Mie University Graduate School of Medicine, 2–174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Keigo Kawashima
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan
- Department of Gastroenterology & Hepatology, Yokohama City University School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yasuhito Tanaka
- Department of Virology & Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan
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