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Naidu S, Margeridon S. Chronic Hepatitis B Virus Persistence: Mechanisms and Insights. Cureus 2025; 17:e78944. [PMID: 40092015 PMCID: PMC11910171 DOI: 10.7759/cureus.78944] [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] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Chronic hepatitis B (CHB) virus infection can lead to severe liver diseases, including cirrhosis and hepatocellular carcinoma. The chronicity of the hepatitis B virus (HBV) occurs because of the persistence of viral covalently closed circular DNA (cccDNA) within hepatocytes. The cccDNA serves as the template for viral replication and is central to HBV, maintaining a viral reservoir within the host. Despite therapeutic advancements, eliminating cccDNA remains elusive due to its evasion of immune surveillance. This review explores the formation and maintenance of cccDNA, highlighting host factors influencing cccDNA stability and viral replication. It also discusses current treatment strategies, including interferon-based therapies and nucleoside/nucleotide analogs, which aim to suppress viral replication. Emerging therapies such as gene editing and molecular interventions hold promise for targeting cccDNA directly. Currently, research is focused on making medications that target host factors of interest to disrupt or clear the viral reservoir. However, future research should focus on innovative approaches that directly target the cccDNA minichromosome, aiming for sustained viral suppression and potentially a cure for the HBV infection.
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Affiliation(s)
- Samrita Naidu
- Virology, Rio Americano High School, Sacramento, USA
| | - Severine Margeridon
- Molecular Diagnostics and Assay Development, Bio-Rad Laboratories, San Francisco, USA
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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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Kokiçi J, Preechanukul A, Arellano-Ballestero H, Gorou F, Peppa D. Emerging Insights into Memory Natural Killer Cells and Clinical Applications. Viruses 2024; 16:1746. [PMID: 39599860 PMCID: PMC11599065 DOI: 10.3390/v16111746] [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: 10/09/2024] [Revised: 11/03/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that can rapidly mount a response to their targets by employing diverse mechanisms. Due to their functional attributes, NK cells have been implicated in anti-viral and anti-tumour immune responses. Although traditionally known to mount non-specific, rapid immune responses, in recent years, the notion of memory NK cells with adaptive features has gained more recognition. Memory NK cells emerge in response to different stimuli, such as viral antigens and specific cytokine combinations. They form distinct populations, accompanied by transcriptional, epigenetic and metabolic reprogramming, resulting in unique phenotypic and functional attributes. Several clinical trials are testing the efficacy of memory NK cells due to their enhanced functionality, bioenergetic profile and persistence in vivo. The therapeutic potential of NK cells is being harnessed in viral infections, with wider applications in the cancer field. In this review, we summarise the current state of research on the generation of memory NK cells, along with their clinical applications in viral infection and cancer.
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Affiliation(s)
- Jonida Kokiçi
- Division of Infection and Immunity, University College London, London NW3 2PP, UK
| | - Anucha Preechanukul
- Division of Infection and Immunity, University College London, London NW3 2PP, UK
| | | | - Frances Gorou
- Division of Infection and Immunity, University College London, London NW3 2PP, UK
| | - Dimitra Peppa
- Division of Infection and Immunity, University College London, London NW3 2PP, UK
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Bailey JT, Cangialosi S, Moshkani S, Rexhouse C, Cimino JL, Robek MD. CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice. JHEP Rep 2024; 6:101121. [PMID: 39282227 PMCID: PMC11399595 DOI: 10.1016/j.jhepr.2024.101121] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 05/14/2024] [Indexed: 09/18/2024] Open
Abstract
Background & Aims HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication. Methods Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8+ T cells were quantified in the spleen and liver at the experimental endpoint. Results CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8+ T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8+ T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg). Conclusions Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4+ T cell-dependent limitation on CD40-mediated antiviral efficacy. Impact and implications Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8+ T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4+ cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.
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Affiliation(s)
- Jacob T Bailey
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Sophia Cangialosi
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Safiehkhatoon Moshkani
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Catherine Rexhouse
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Jesse L Cimino
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Michael D Robek
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA
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5
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Ciupe SM, Dahari H, Ploss A. Mathematical Models of Early Hepatitis B Virus Dynamics in Humanized Mice. Bull Math Biol 2024; 86:53. [PMID: 38594319 PMCID: PMC11003933 DOI: 10.1007/s11538-024-01284-2] [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: 10/25/2023] [Accepted: 03/15/2024] [Indexed: 04/11/2024]
Abstract
Analyzing the impact of the adaptive immune response during acute hepatitis B virus (HBV) infection is essential for understanding disease progression and control. Here we developed mathematical models of HBV infection which either lack terms for adaptive immune responses, or assume adaptive immune responses in the form of cytolytic immune killing, non-cytolytic immune cure, or non-cytolytic-mediated block of viral production. We validated the model that does not include immune responses against temporal serum hepatitis B DNA (sHBV) and temporal serum hepatitis B surface-antigen (HBsAg) experimental data from mice engrafted with human hepatocytes (HEP). Moreover, we validated the immune models against sHBV and HBsAg experimental data from mice engrafted with HEP and human immune system (HEP/HIS). As expected, the model that does not include adaptive immune responses matches the observed high sHBV and HBsAg concentrations in all HEP mice. By contrast, while all immune response models predict reduction in sHBV and HBsAg concentrations in HEP/HIS mice, the Akaike Information Criterion cannot discriminate between non-cytolytic cure (resulting in a class of cells refractory to reinfection) and antiviral block functions (of up to 99 % viral production 1-3 weeks following peak viral load). We can, however, reject cytolytic killing, as it can only match the sHBV and HBsAg data when we predict unrealistic levels of hepatocyte loss.
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Affiliation(s)
- Stanca M Ciupe
- Department of Mathematics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
| | - Harel Dahari
- Division of Hepatology, Department of Medicine, Loyola University, Chicago, IL, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
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Jiang Y, Chen X, Ye X, Wen C, Xu T, Yu C, Ning W, Wang G, Xiang X, Liu X, Wang Y, Chen Y, Liu X, Shi C, Liu C, Yuan Q, Chen Y, Zhang T, Luo W, Xia N. A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305316. [PMID: 38342604 PMCID: PMC11022716 DOI: 10.1002/advs.202305316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/22/2023] [Indexed: 02/13/2024]
Abstract
Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2 mg kg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10 mg kg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.
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Affiliation(s)
- Yichao Jiang
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Xiaoqing Chen
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Xinya Ye
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Can Wen
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Tao Xu
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Chao Yu
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Wenjing Ning
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Guosong Wang
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Xinchu Xiang
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Xiaomin Liu
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsNational Institute of Diagnostics and Vaccine Development in Infectious DiseasesNational Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Yalin Wang
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Yuanzhi Chen
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Xue Liu
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Changrong Shi
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsNational Institute of Diagnostics and Vaccine Development in Infectious DiseasesNational Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsNational Institute of Diagnostics and Vaccine Development in Infectious DiseasesNational Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical SciencesXiamen UniversityXiamen361102P.R. China
| | - Yixin Chen
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical SciencesXiamen UniversityXiamen361102P.R. China
| | - Tianying Zhang
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical SciencesXiamen UniversityXiamen361102P.R. China
| | - Wenxin Luo
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical SciencesXiamen UniversityXiamen361102P.R. China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious DiseasesXiang An Biomedicine LaboratorySchool of Public HealthSchool of Life SciencesXiamen UniversityXiamen361102P.R. China
- State Key Laboratory of Vaccines for Infectious DiseasesCenter for Molecular Imaging and Translational MedicineXiang An Biomedicine LaboratorySchool of Public HealthXiamen UniversityXiamen361102P.R. China
- The Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical SciencesXiamen UniversityXiamen361102P.R. China
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Kim SE, Park SH, Park WJ, Kim G, Kim SY, Won H, Hwang YH, Lim H, Kim HG, Kim YJ, Kim D, Lee JA. Evaluation of immunogenicity-induced DNA vaccines against different SARS-CoV-2 variants. PLoS One 2023; 18:e0295594. [PMID: 38060612 PMCID: PMC10703263 DOI: 10.1371/journal.pone.0295594] [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: 07/19/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic worldwide. As of September 2023, the number of confirmed coronavirus cases has reached over 770 million and caused nearly 7 million deaths. The World Health Organization assigned and informed the characterization of variants of concern (VOCs) to help control the COVID-19 pandemic through global monitoring of circulating viruses. Although many vaccines have been proposed, developing an effective vaccine against variants is still essential to reach the endemic stage of COVID-19. We designed five DNA vaccine candidates composed of the first isolated genotype and major SARS-CoV-2 strains from isolated Korean patients classified as VOCs, such as Alpha, Beta, Gamma, and Delta. To evaluate the immunogenicity of each genotype via homologous and heterologous vaccination, mice were immunized twice within a 3-week interval, and the blood and spleen were collected 1 week after the final vaccination to analyze the immune responses. The group vaccinated with DNA vaccine candidates based on the S genotype and the Alpha and Beta variants elicited both humoral and cellular immune responses, with higher total IgG levels and neutralizing antibody responses than the other groups. In particular, the vaccine candidate based on the Alpha variant induced a highly diverse cytokine response. Additionally, we found that the group subjected to homologous vaccination with the S genotype and heterologous vaccination with S/Alpha induced high total IgG levels and a neutralization antibody response. Homologous vaccination with the S genotype and heterologous vaccination with S/Alpha and S/Beta significantly induced IFN-γ immune responses. The immunogenicity after homologous vaccination with S and Alpha and heterologous vaccination with the S/Alpha candidate was better than that of the other groups, indicating the potential for developing novel DNA vaccines against different SARS-CoV-2 variants.
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Affiliation(s)
- Se Eun Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - So Hee Park
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Woo-Jung Park
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Gayeong Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Seo Yeon Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Hyeran Won
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Yun-Ho Hwang
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Heeji Lim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Hyeon Guk Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - You-Jin Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Dokeun Kim
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
| | - Jung-Ah Lee
- National Institute of Infectious Disease, National Institute of Health, Korea Disease Control and Prevention Agency, CheongJu, Chungcheongbuk-do, Republic of Korea
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8
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Takahama S, Yoshio S, Masuta Y, Murakami H, Sakamori R, Kaneko S, Honda T, Murakawa M, Sugiyama M, Kurosaki M, Asahina Y, Takehara T, Appay V, Kanto T, Yamamoto T. Hepatitis B surface antigen reduction is associated with hepatitis B core-specific CD8 + T cell quality. Front Immunol 2023; 14:1257113. [PMID: 37920475 PMCID: PMC10619684 DOI: 10.3389/fimmu.2023.1257113] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/07/2023] [Indexed: 11/04/2023] Open
Abstract
Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8+ T cell responses are essential for managing viral replication, but their effect on HBsAg levels remains unclear. We studied the traits of activated CD8+ T cells and HBV-specific CD8+ T cells in the blood of CHB patients undergoing nucleos(t)ide analog (NUC) therapy. For the transcriptome profiling of activated CD8+ T cells in peripheral blood mononuclear cells (PBMCs), CD69+ CD8+ T cells were sorted from six donors, and single-cell RNA sequencing (scRNA-seq) analysis was performed. To detect HBV-specific CD8+ T cells, we stimulated PBMCs from 26 donors with overlapping peptides covering the HBs, HBcore, and HBpol regions of genotype A/B/C viruses, cultured for 10 days, and analyzed via multicolor flow cytometry. scRNA-seq data revealed that CD8+ T cell clusters harboring the transcripts involved in the cytolytic functions were frequently observed in donors with high HBsAg levels. Polyfunctional analysis of HBV-specific CD8+ T cells utilized by IFN-γ/TNFα/CD107A/CD137 revealed that HBcore-specific cells exhibited greater polyfunctionality, suggesting that the quality of HBV-specific CD8+ T cells varies among antigens. Moreover, a subset of HBcore-specific CD8+ T cells with lower cytolytic potential was inversely correlated with HBsAg level. Our results revealed a stimulant-dependent qualitative difference in HBV-specific CD8+ T cells in patients with CHB undergoing NUC therapy. Hence, the induction of HBcore-specific CD8+ T cells with lower cytolytic potential could be a new target for reducing HBsAg levels.
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Affiliation(s)
- Shokichi Takahama
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Sachiyo Yoshio
- Department of Liver Diseases, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Yuji Masuta
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Hirotomo Murakami
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Victor Appay
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Université de Bordeaux, CNRS, Institut national de la santé et de la recherche médicale (INSERM), ImmunoConcEpT, UMR 5164, Bordeaux, France
| | - Tatsuya Kanto
- Department of Liver Diseases, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Takuya Yamamoto
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Laboratory of Translational Cancer Immunology and Biology, Next-generation Precision Medicine Research Center, Osaka International Cancer Institute, Osaka, Japan
- The Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Department of Virology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
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9
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Qing M, Yang D, Shang Q, Peng J, Deng J, Lu J, Li J, Dan H, Zhou Y, Xu H, Chen Q. CD8 + tissue-resident memory T cells induce oral lichen planus erosion via cytokine network. eLife 2023; 12:e83981. [PMID: 37555396 PMCID: PMC10465124 DOI: 10.7554/elife.83981] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 07/25/2023] [Indexed: 08/10/2023] Open
Abstract
CD8+ tissue-resident memory T (CD8+ Trm) cells play key roles in many immune-inflammation-related diseases. However, their characteristics in the pathological process of oral lichen planus (OLP) remains unclear. Therefore, we investigated the function of CD8+ Trm cells in the process of OLP. By using single-cell RNA sequencing profiling and spatial transcriptomics, we revealed that CD8+ Trm cells were predominantly located in the lamina propria adjacent to the basement membrane and were significantly increased in patients with erosive oral lichen planus (EOLP) compared to those with non-erosive oral lichen planus (NEOLP). Furthermore, these cells displayed enhanced cytokine production, including IFN-γ (Interferon-gamma, a pro-inflammatory signaling molecule), TNF-α (Tumor Necrosis Factor-alpha, a cytokine regulating inflammation), and IL-17 (Interleukin-17, a cytokine involved in immune response modulation), in patients with EOLP. And our clinical cohort of 1-year follow-up was also supported the above results in RNA level and protein level. In conclusion, our study provided a novel molecular mechanism for triggering OLP erosion by CD8+ Trm cells to secrete multiple cytokines, and new insight into the pathological development of OLP.
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Affiliation(s)
- Maofeng Qing
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
- Department of Stomatology, The Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Dan Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Qianhui Shang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Jiakuan Peng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Jiaxin Deng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Jiang Lu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - HongXia Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Hao Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Qianming Chen
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of StomatologyHangzhouChina
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10
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Hillaire MLB, Lawrence P, Lagrange B. IFN-γ: A Crucial Player in the Fight Against HBV Infection? Immune Netw 2023; 23:e30. [PMID: 37670813 PMCID: PMC10475827 DOI: 10.4110/in.2023.23.e30] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/04/2023] [Accepted: 05/21/2023] [Indexed: 09/07/2023] Open
Abstract
About 0.8 million people die because of hepatitis B virus (HBV) infection each year. In around 5% of infected adults, the immune system is ineffective in countering HBV infection, leading to chronic hepatitis B (CHB). CHB is associated with hepatocellular carcinoma, which can lead to patient death. Unfortunately, although current treatments against CHB allow control of HBV infection, they are unable to achieve complete eradication of the virus. Cytokines of the IFN family represent part of the innate immune system and are key players in virus elimination. IFN secretion induces the expression of interferon stimulated genes, producing proteins that have antiviral properties and that are essential to cell-autonomous immunity. IFN-α is commonly used as a therapeutic approach for CHB. In addition, IFN-γ has been identified as the main IFN family member responsible for HBV eradication during acute infection. In this review, we summarize the key evidence gained from cellular or animal models of HBV replication or infection concerning the potential anti-HBV roles of IFN-γ with a particular focus on some IFN-γ-inducible genes.
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Affiliation(s)
| | - Philip Lawrence
- Confluence: Sciences et Humanités (EA 1598), Université Catholique de Lyon, Lyon, France
| | - Brice Lagrange
- Confluence: Sciences et Humanités (EA 1598), Université Catholique de Lyon, Lyon, France
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11
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Tiezzi C, Vecchi A, Rossi M, Cavazzini D, Bolchi A, Laccabue D, Doselli S, Penna A, Sacchelli L, Brillo F, Meschi T, Ticinesi A, Nouvenne A, Donofrio G, Zanelli P, Benecchi M, Giuliodori S, Fisicaro P, Montali I, Ceccatelli Berti C, Reverberi V, Montali A, Urbani S, Pedrazzi G, Missale G, Telenti A, Corti D, Ottonello S, Ferrari C, Boni C. Natural heteroclitic-like peptides are generated by SARS-CoV-2 mutations. iScience 2023; 26:106940. [PMID: 37275517 PMCID: PMC10200277 DOI: 10.1016/j.isci.2023.106940] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/13/2023] [Accepted: 05/18/2023] [Indexed: 06/07/2023] Open
Abstract
Humoral immunity is sensitive to evasion by SARS-CoV-2 mutants, but CD8 T cells seem to be more resistant to mutational inactivation. By a systematic analysis of 30 spike variant peptides containing the most relevant VOC and VOI mutations that have accumulated overtime, we show that in vaccinated and convalescent subjects, mutated epitopes can have not only a neutral or inhibitory effect on CD8 T cell recognition but can also enhance or generate de novo CD8 T cell responses. The emergence of these mutated T cell function enhancing epitopes likely reflects an epiphenomenon of SARS-CoV-2 evolution driven by antibody evasion and increased virus transmissibility. In a subset of individuals with weak and narrowly focused CD8 T cell responses selection of these heteroclitic-like epitopes may bear clinical relevance by improving antiviral protection. The functional enhancing effect of these peptides is also worth of consideration for the future development of new generation, more potent COVID-19 vaccines.
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Affiliation(s)
- Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, 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
| | - Davide Cavazzini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Angelo Bolchi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center Biopharmanet-Tec, University of Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Sara Doselli
- 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
| | - Luca Sacchelli
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Federica Brillo
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Tiziana Meschi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Andrea Ticinesi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Antonio Nouvenne
- Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Gaetano Donofrio
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Paola Zanelli
- Unità di Immunogenetica dei Trapianti, Azienda Ospedaliero Universitaria di Parma, Parma, Italy
| | - Magda Benecchi
- Unità di Immunogenetica dei Trapianti, Azienda Ospedaliero Universitaria di Parma, Parma, Italy
| | - Silvia Giuliodori
- Unità di Immunogenetica dei Trapianti, Azienda Ospedaliero Universitaria di Parma, Parma, Italy
| | - Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Valentina Reverberi
- Laboratory of Viral Immunopathology, 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 Urbani
- UO Immunoematologia e Medicina Trasfusionale, Dipartimento Diagnostico, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Giuseppe Pedrazzi
- Department of Neuroscience - Biophysics and Medical Physics Unit, University of 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
| | | | - Davide Corti
- Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland
| | - Simone Ottonello
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center Biopharmanet-Tec, 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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12
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Walsh MJ, Stump CT, Kureshi R, Lenehan P, Ali LR, Dougan M, Knipe DM, Dougan SK. IFNγ is a central node of cancer immune equilibrium. Cell Rep 2023; 42:112219. [PMID: 36881506 PMCID: PMC10214249 DOI: 10.1016/j.celrep.2023.112219] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 01/09/2023] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Tumors in immune equilibrium are held in balance between outgrowth and destruction by the immune system. The equilibrium phase defines the duration of clinical remission and stable disease, and escape from equilibrium remains a major clinical problem. Using a non-replicating HSV-1 vector expressing interleukin-12 (d106S-IL12), we developed a mouse model of therapy-induced immune equilibrium, a phenomenon previously seen only in humans. This immune equilibrium was centrally reliant on interferon-γ (IFNγ). CD8+ T cell direct recognition of MHC class I, perforin/granzyme-mediated cytotoxicity, and extrinsic death receptor signaling such as Fas/FasL were all individually dispensable for equilibrium. IFNγ was critically important and played redundant roles in host and tumor cells such that IFNγ sensing in either compartment was sufficient for immune equilibrium. We propose that these redundant mechanisms of action are integrated by IFNγ to protect from oncogenic or chronic viral threats and establish IFNγ as a central node in therapy-induced immune equilibrium.
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Affiliation(s)
- Michael J Walsh
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Program in Virology, Boston, MA, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Courtney T Stump
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Rakeeb Kureshi
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Patrick Lenehan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Lestat R Ali
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Michael Dougan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - David M Knipe
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA.
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13
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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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14
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Yosyingyong P, Viriyapong R. Global dynamics of multiple delays within-host model for a hepatitis B virus infection of hepatocytes with immune response and drug therapy. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:7349-7386. [PMID: 37161155 DOI: 10.3934/mbe.2023319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
In this paper, a mathematical model describing the hepatitis B virus (HBV) infection of hepatocytes with the intracellular HBV-DNA containing capsids, cytotoxic T-lymphocyte (CTL), antibodies including drug therapy (blocking new infection and inhibiting viral production) with two-time delays is studied. It incorporates the delay in the productively infected hepatocytes and the delay in an antigenic stimulation generating CTL. We verify the positivity and boundedness of solutions and determine the basic reproduction number. The local and global stability of three equilibrium points (infection-free, immune-free, and immune-activated) are investigated. Finally, the numerical simulations are established to show the role of these therapies in reducing viral replication and HBV infection. Our results show that the treatment by blocking new infection gives more significant results than the treatment by inhibiting viral production for infected hepatocytes. Further, both delays affect the number of infections and duration i.e. the longer the delay, the more severe the HBV infection.
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Affiliation(s)
- Pensiri Yosyingyong
- Department of Mathematics, Faculty of Science, Naresuan University, Phitsanulok, 65000, Thailand
| | - Ratchada Viriyapong
- Department of Mathematics, Faculty of Science, Naresuan University, Phitsanulok, 65000, Thailand
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15
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Sun L, Feng H, Misumi I, Shirasaki T, Hensley L, González-López O, Shiota I, Chou WC, Ting JPY, Cullen JM, Cowley DO, Whitmire JK, Lemon SM. Viral protease cleavage of MAVS in genetically modified mice with hepatitis A virus infection. J Hepatol 2023; 78:271-280. [PMID: 36152761 DOI: 10.1016/j.jhep.2022.09.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/17/2022] [Accepted: 09/14/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Consistent with its relatively narrow host species range, hepatitis A virus (HAV) cannot infect C57BL/6 mice. However, in Mavs-/- mice with genetic deficiency of the innate immune signaling adaptor MAVS, HAV replicates robustly in the absence of disease. The HAV 3ABC protease cleaves MAVS in human cells, thereby disrupting virus-induced IFN responses, but it cannot cleave murine MAVS (mMAVS) due to sequence differences at the site of scission. Here, we sought to elucidate the role of 3ABC MAVS cleavage in determining HAV pathogenesis and host species range. METHODS Using CRISPR/Cas9 gene editing, we established two independent lineages of C57BL/6 mice with knock-in mutations altering two amino acids in mMAVS ('mMAVS-VS'), rendering it susceptible to 3ABC cleavage without loss of signaling function. We challenged homozygous Mavsvs/vs mice with HAV, and compared infection outcomes with C57BL/6 and genetically deficient Mavs-/- mice. RESULTS The humanized murine mMAVS-VS protein was cleaved as efficiently as human MAVS when co-expressed with 3ABC in Huh-7 cells. In embyronic fibroblasts from Mavsvs/vs mice, mMAVS-VS was cleaved by ectopically expressed 3ABC, significantly disrupting Sendai virus-induced IFN responses. However, in contrast to Mavs-/- mice with genetic MAVS deficiency, HAV failed to establish infection in Mavsvs/vs mice, even with additional genetic knockout of Trif or Irf1. Nonetheless, when crossed with permissive Ifnar1-/- mice lacking type I IFN receptors, Mavsvs/vsIfnar1-/- mice demonstrated enhanced viral replication coupled with significant reductions in serum alanine aminotransferase, hepatocellular apoptosis, and intrahepatic inflammatory cell infiltrates compared with Ifnar1-/- mice. CONCLUSIONS MAVS cleavage by 3ABC boosts viral replication and disrupts disease pathogenesis, but it is not by itself sufficient to break the host-species barrier to HAV infection in mice. IMPACT AND IMPLICATIONS The limited host range of human hepatitis viruses could be explained by species-specific viral strategies that disrupt innate immune responses. Both hepatitis A virus (HAV) and hepatitis C virus express viral proteases that cleave the innate immune adaptor protein MAVS, in human but not mouse cells. However, the impact of this immune evasion strategy has never been assessed in vivo. Here we show that HAV 3ABC protease cleavage of MAVS enhances viral replication and lessens liver inflammation in mice lacking interferon receptors, but that it is insufficient by itself to overcome the cross-species barrier to infection in mice. These results enhance our understanding of how hepatitis viruses interact with the host and their impact on innate immune responses.
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Affiliation(s)
- Lu Sun
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Hui Feng
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Ichiro Misumi
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - Takayoshi Shirasaki
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Lucinda Hensley
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Olga González-López
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Itoe Shiota
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - Wei-Chun Chou
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA
| | - John M Cullen
- College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, USA
| | - Dale O Cowley
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA; Animal Models Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Jason K Whitmire
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599 USA; Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Stanley M Lemon
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
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16
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Wu C, Zhang J, Wang H, Zhang W, Liu J, Zhou N, Chen K, Wang Y, Peng S, Fu L. TRAF2 as a key candidate gene in clinical hepatitis B-associated liver fibrosis. Front Mol Biosci 2023; 10:1168250. [PMID: 37091870 PMCID: PMC10113534 DOI: 10.3389/fmolb.2023.1168250] [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: 02/17/2023] [Accepted: 03/28/2023] [Indexed: 04/25/2023] Open
Abstract
Objectives: Approximately 240 million individuals are infected with chronic hepatitis B virus (HBV) worldwide. HBV infection can develop into liver fibrosis. The mechanism of HBV-related liver fibrosis has not been fully understood, and there are few effective treatment options. The goal of this study was to use transcriptomics in conjunction with experimental validation to identify new targets to treat HBV-related liver fibrosis. Methods: To identify differentially expressed genes (DEGs), five liver tissues were collected from both healthy individuals and patients with chronic hepatitis B. NovoMagic and Java GSEA were used to screen DEGs and key genes, respectively. Immunocell infiltration analysis of RNA-seq data was, and the results were confirmed by Western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry. Results: We evaluated 1,105 genes with differential expression, and 462 and 643 genes showed down- and upregulation, respectively. The essential genes, such as tumor necrosis factor (TNF) receptor-associated factor-2 (TRAF2), were screened out of DEGs. TRAF2 expression was abnormally high in hepatic fibrosis in patients with hepatitis B compared with healthy controls. The degree of hepatic fibrosis and serum levels of glutamate transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were positively linked with TRAF2 expression. TRAF2 may be crucial in controlling T lymphocyte-mediated liver fibrosis. Conclusion: Our findings imply that TRAF2 is essential for HBV-induced liver fibrosis progression, and it may potentially be a promising target for the treatment of hepatic fibrosis in hepatitis B.
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Affiliation(s)
- Cichun Wu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Jian Zhang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Huiwen Wang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Wei Zhang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Jingqing Liu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Nianqi Zhou
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Keyu Chen
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Ying Wang
- Department of Pathology, Xiangya Hospital Central South University, Changsha, China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
- *Correspondence: Lei Fu, ; Shifang Peng,
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
- *Correspondence: Lei Fu, ; Shifang Peng,
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18
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Debelec-Butuner B, Quitt O, Schreiber S, Momburg F, Wisskirchen K, Protzer U. Activation of distinct antiviral T-cell immunity: A comparison of bi- and trispecific T-cell engager antibodies with a chimeric antigen receptor targeting HBV envelope proteins. Front Immunol 2022; 13:1029214. [DOI: 10.3389/fimmu.2022.1029214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Despite the availability of an effective prophylactic vaccine, 820,000 people die annually of hepatitis B virus (HBV)-related liver disease according to WHO. Since current antiviral therapies do not provide a curative treatment for the 296 million HBV carriers around the globe, novel strategies to cure HBV are urgently needed. A promising approach is the redirection of T cells towards HBV-infected hepatocytes employing chimeric antigen receptors or T-cell engager antibodies. We recently described the effective redirection of T cells employing a second-generation chimeric antigen receptor directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR) as well as bispecific antibodies that engage CD3 or CD28 on T cells employing the identical HBV envelope protein (HBVenv) binder. In this study, we added a trispecific antibody comprising all three moieties to the tool-box. Cytotoxic and non-cytolytic antiviral activities of these bi- and trispecific T-cell engager antibodies were assessed in co-cultures of human PBMC with HBV-positive hepatoma cells, and compared to that of S-CAR-grafted T cells. Activation of T cells via the S-CAR or by either a combination of the CD3- and CD28-targeting bispecific antibodies or the trispecific antibody allowed for specific elimination of HBV-positive target cells. While S-CAR-grafted effector T cells displayed faster killing kinetics, combinatory treatment with the bispecific antibodies or single treatment with the trispecific antibody was associated with a more pronounced cytokine release. Clearance of viral antigens and elimination of the HBV persistence form, the covalently closed circular (ccc) DNA, through cytolytic as well as cytokine-mediated activity was observed in all three settings with the combination of bispecific antibodies showing the strongest non-cytolytic, cytokine-mediated antiviral effect. Taken together, we demonstrate that bi- and trispecific T-cell engager antibodies can serve as a potent, off-the-shelf alternative to S-CAR-grafted T cells to cure HBV.
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19
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Xie S, Yang L, Bi X, Deng W, Jiang T, Lin Y, Wang S, Zhang L, Liu R, Chang M, Wu S, Gao Y, Hao H, Shen G, Xu M, Chen X, Hu L, Lu Y, Song R, Xie Y, Li M. Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B. Front Immunol 2022; 13:1036612. [PMID: 36353632 PMCID: PMC9637985 DOI: 10.3389/fimmu.2022.1036612] [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: 09/04/2022] [Accepted: 10/12/2022] [Indexed: 08/30/2023] Open
Abstract
OBJECTIVE We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV. METHODS This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg. RESULTS The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (β=-0.025, t=-2.613, P=0.014; β=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (β=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (β=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (β=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (β=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (β=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (β=-0.137, t=-3.273, P=0.003). CONCLUSIONS The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.
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Affiliation(s)
- Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Rui Song
- Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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20
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Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022; 76:233-250. [PMID: 34990029 DOI: 10.1002/hep.32314] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.
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Affiliation(s)
- Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
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21
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Zhu Z, Qin Y, Liang Q, Xia W, Zhang T, Wang W, Zhang M, Jiang T, Wu H, Tian Y. Increased HBV Coinfection and Decreased IFN-γ-Producing HBV-Specific CD8+ T Cell Numbers During HIV Disease Progression. Front Immunol 2022; 13:861804. [PMID: 35432386 PMCID: PMC9005981 DOI: 10.3389/fimmu.2022.861804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/09/2022] [Indexed: 12/11/2022] Open
Abstract
Objective To investigate the characteristics and mechanism of the dynamics of HBV infection with the progression of HIV disease and to explore the different responses of T lymphocytes to HBV in HIV patients in different stages of disease. Methods We compared the rates and characteristics of HBV coinfection between 372 early HIV-infected and 306 chronically HIV-infected men who have sex with men (MSM) in the Beijing Youan Hospital from October 2006 to November 2014. We further analysed IFN-γ-producing HBV-specific CD8+ T cells in 15 early HIV-infected individuals and 20 chronic HIV-infected individuals with HBV coinfection. Results Twenty-three HBsAg-positive cases were detected among the 372 early HIV-infected patients of this cohort, and the coinfection rate was 6.18%, while 35 HBsAg-positive cases were detected among the 306 chronically HIV-infected patients, with a coinfection rate of 11.44%. The coinfection rate of the chronically HIV-infected patients was significantly higher than that of the early-infected patients (p=0.0005). The median CD4+ T cell count in the early HIV infection patients was 445 cells/μL (196-1,030 cells/μL), which was higher than that in the chronic HIV infection patients [358 cells/μL (17-783 cells/μL)] (p<0.001). The proportion of IFN-γ-producing CD8+ T cells in early HIV-infected patients was significantly higher than that in chronically HIV-infected patients. Conclusion The coinfection rate of HBV in HIV patients increases with HIV disease progression, which might be related to the decreased IFN-γ-producing HBV-specific CD8+ T cell numbers. The closely monitored HBV serum markers from the early stage of HIV infection are warranted.
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Affiliation(s)
- Zhiqiang Zhu
- Department of Urology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Qin
- Beijing Key Laboratory for HIV/AIDS Research, Capital Medical University, Beijing, China
| | - Qi Liang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, China
| | - Wei Xia
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Wen Wang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Mengmeng Zhang
- Department of Urology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Taiyi Jiang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hao Wu
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ye Tian
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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22
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Kitamura K, Fukano K, Que L, Li Y, Wakae K, Muramatsu M. Activities of endogenous APOBEC3s and uracil-DNA-glycosylase affect the hypermutation frequency of hepatitis B virus cccDNA. J Gen Virol 2022; 103. [PMID: 35438620 DOI: 10.1099/jgv.0.001732] [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: 11/18/2022] Open
Abstract
The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) plays a key role in the persistence of viral infection. We have previously shown that overexpression of an antiviral factor APOBEC3G (A3G) induces hypermutation in duck HBV (DHBV) cccDNA, whereas uracil-DNA-glycosylase (UNG) reduces these mutations. In this study, using cell-culture systems, we examined whether endogenous A3s and UNG affect HBV cccDNA mutation frequency. IFNγ stimulation induced a significant increase in endogenous A3G expression and cccDNA hypermutation. UNG inhibition enhanced the IFNγ-mediated hypermutation frequency. Transfection of reconstructed cccDNA revealed that this enhanced hypermutation caused a reduction in viral replication. These results suggest that the balance of endogenous A3s and UNG activities affects HBV cccDNA mutation and replication competency.
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Affiliation(s)
- Kouichi Kitamura
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Kento Fukano
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Lusheng Que
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Yingfang Li
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Kousho Wakae
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Murayama branch, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan
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23
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Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System. Viruses 2022; 14:v14020373. [PMID: 35215970 PMCID: PMC8874586 DOI: 10.3390/v14020373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/28/2022] [Accepted: 02/08/2022] [Indexed: 12/10/2022] Open
Abstract
During viral evolution and adaptation, many viruses have utilized host cellular factors and machinery as their partners. HBx, as a multifunctional viral protein encoded by the hepatitis B virus (HBV), promotes HBV replication and greatly contributes to the development of HBV-associated hepatocellular carcinoma (HCC). HBx interacts with several host factors in order to regulate HBV replication and evolve carcinogenesis. The cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) is a major factor that functions in a variety of cellular pathways and specifically in apoptosis. It has been shown that the interaction between HBx and c-FLIP determines HBV fate. In this review, we provide a comprehensive and detailed overview of the interplay between c-FLIP and HBV in various environmental circumstances. We describe strategies adapted by HBV to establish its chronic infection. We also summarize the conventional roles of c-FLIP and highlight the functional outcome of the interaction between c-FLIP and HBV or other viruses in viral replication and the innate immune system.
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24
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Nosaka T, Naito T, Murata Y, Matsuda H, Ohtani M, Hiramatsu K, Nishizawa T, Okamoto H, Nakamoto Y. Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular DNA in primary human hepatocytes. Hepatol Res 2022; 52:141-152. [PMID: 34697871 DOI: 10.1111/hepr.13722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/13/2021] [Accepted: 10/17/2021] [Indexed: 12/12/2022]
Abstract
AIM Curing hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA (cccDNA). Interferon (IFN)-γ has noncytolytic antiviral potential; however, elimination of cccDNA could not be achieved. To enhance the regulatory effect, we comprehensively analyzed the host factors associated with cccDNA amplification and IFN-γ and IFN-α effects using an in vitro HBV infection system showing various transcription levels. METHODS Primary human hepatocytes were infected with HBV using genomic plasmids carrying the basic core promoter mutation A1762T/G1764A and/or the precore mutation G1896A and treated with IFN-γ and IFN-α. Comprehensive and functional studies involving microarray and small interfering RNA analysis revealed the host factors related to cccDNA regulation. RESULTS The HBV infection system reproduced the HBV life cycle and showed various propagation levels. Microarray analysis revealed 53 genes correlated with the cccDNA levels. Of the 53 genes, expression of IFN-induced protein 44-like (IFI44L) was significantly upregulated by IFN-γ and IFN-α. The anti-HBV effect of IFI44L is exerted regardless of IFN-γ or IFN-α by inhibiting the activation of nuclear factor-κB and signal transducer and activator of transcription 1 pathways. CONCLUSIONS Using the in vitro HBV infection system, an IFN-inducible molecule, IFI44L, associated with cccDNA amplification, was identified. These results suggest an innovative molecular strategy for the regulation of HBV cccDNA by controlling a novel host factor, IFI44L.
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Affiliation(s)
- Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yosuke Murata
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Abstract
Patients with chronic hepatitis B (CHB) represent a living and permanent reservoir of hepatitis B virus (HBV). Millions of these CHB patients will eventually develop complications such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma if they are not treated properly. Accordingly, several antiviral drugs have been developed for the treatment of CHB, but these drugs can neither eradicate all forms of HBV nor contain the progression of complications in most patients with CHB. Thus, the development of new and novel therapeutics for CHB remains a pressing need. The molecular and cellular mechanisms underlying the pathogenesis of CHB indicate that immune dysregulations may be responsible for HBV persistence and progressive liver damage in CHB. This provided the scientific and ethical basis for the immune therapy of CHB patients. Around 30 years have passed since the initiation of immune therapies for CHB in the early 1990s, and hundreds of clinical trials have been accomplished to substantiate this immune treatment. Despite these approaches, an acceptable regimen of immune therapy is yet to be realized. However, most immune therapeutic agents are safe for human usage, and many of these protocols have inspired considerable optimism. In this review, the pros and cons of different immune therapies, observed in patients with CHB during the last 30 years, will be discussed to derive insights into the development of an evidence-based, effective, and patient-friendly regimen of immune therapy for the treatment of CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan.
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
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26
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Abstract
Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver - and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis - profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.
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27
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Wang J, Du L, Tang H. Suppression of Interferon-α Treatment Response by Host Negative Factors in Hepatitis B Virus Infection. Front Med (Lausanne) 2021; 8:784172. [PMID: 34901094 PMCID: PMC8651562 DOI: 10.3389/fmed.2021.784172] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/03/2021] [Indexed: 02/05/2023] Open
Abstract
Chronic hepatitis B virus (CHB) infection remains a major global public health issue for which there is still lacking effective curative treatment. Interferon-α (IFN-α) and its pegylated form have been approved as an anti-HBV drug with the advantage of antiviral activity and host immunity against HBV infection enhancement, however, IFN-α treatment failure in CHB patients is a challenging obstacle with 70% of CHB patients respond poorly to exogenous IFN-α treatment. The IFN-α treatment response is negatively regulated by both viral and host factors, and the role of viral factors has been extensively illustrated, while much less attention has been paid to host negative factors. Here, we summarized evidence of host negative regulators and parameters involved in IFN-α therapy failure, review the mechanisms responsible for these effects, and discuss the possible improvement of IFN-based therapy and the rationale of combining the inhibitors of negative regulators in achieving an HBV cure.
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Affiliation(s)
- Jiayi Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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28
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Knolle PA, Huang LR, Kosinska A, Wohlleber D, Protzer U. Improving Therapeutic Vaccination against Hepatitis B-Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection. Vaccines (Basel) 2021; 9:1333. [PMID: 34835264 PMCID: PMC8623083 DOI: 10.3390/vaccines9111333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 12/02/2022] Open
Abstract
Chronic hepatitis B affects more than 250 million individuals worldwide, putting them at risk of developing liver cirrhosis and liver cancer. While antiviral immune responses are key to eliminating hepatitis B virus (HBV) infections, insufficient antiviral immunity characterized by failure to eliminate HBV-infected hepatocytes is associated with chronic hepatitis B. Prophylactic vaccination against hepatitis B successfully established protective immunity against infection with the hepatitis B virus and has been instrumental in controlling hepatitis B. However, prophylactic vaccination schemes have not been successful in mounting protective immunity to eliminate HBV infections in patients with chronic hepatitis B. Here, we discuss the current knowledge on the development and efficacy of therapeutic vaccination strategies against chronic hepatitis B with particular emphasis on the pathogenetic understanding of dysfunctional anti-viral immunity. We explore the development of additional immune stimulation measures within tissues, in particular activation of immunogenic myeloid cell populations, and their use for combination with therapeutic vaccination strategies to improve the efficacy of therapeutic vaccination against chronic hepatitis B.
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Affiliation(s)
- Percy A. Knolle
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
- German Center for infection Research (DZIF), Munich Site, 81675 Munich, Germany;
| | - Li-Rung Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli City 350, Taiwan;
| | - Anna Kosinska
- Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
| | - Dirk Wohlleber
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
| | - Ulrike Protzer
- German Center for infection Research (DZIF), Munich Site, 81675 Munich, Germany;
- Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
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29
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A quantitative systems pharmacology model for acute viral hepatitis B. Comput Struct Biotechnol J 2021; 19:4997-5007. [PMID: 34589180 PMCID: PMC8449028 DOI: 10.1016/j.csbj.2021.08.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 08/31/2021] [Accepted: 08/31/2021] [Indexed: 12/25/2022] Open
Abstract
Mechanistic model characterizing acute immune response and HBV system interactions. Key role of the cellular and regulatory response triggering hepatitis B chronicity. Modelling framework to easily incorporate and explore additional biological mechanisms. Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80–90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B. In this work, a quantitative systems pharmacology model for acute hepatitis B characterizing viral dynamics and the main components of the innate, adaptive, and tolerant immune response has been successfully developed. To do so, information from multiple sources and across different organization levels has been integrated in a common mechanistic framework. The final model adequately describes the chronology and plausibility of an HBV-triggered immune response, as well as clinical data from acute patients reported in the literature. Given the holistic nature of the framework, the model can be used to illustrate the relevance of the different immune pathways and biological processes to ultimate response, observing the negligible contribution of the innate response and the key contribution of the cellular response on viral clearance. More specifically, moderate reductions of the proliferation of activated cytotoxic CD8+ lymphocytes or increased immunoregulatory effects can drive the system towards chronicity.
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Key Words
- AHB, acute hepatitis B
- ALT, alanine aminotransferase
- CHB, chronic hepatitis B
- CTL*, activated CTL
- CTL, antigen-specific cytotoxic T lymphocytes
- CTLm, memory CTL
- DC*, activated dendritic cells
- DC, dendritic cells
- HB, Hepatitis B
- HBV, hepatitis B virus, HBV DNA, circulating DNA levels of HBV
- HBsAg, hepatitis B surface antigen
- Hep, hepatocytes
- Hepatitis B
- Heptot, total hepatocytes
- IFN, interferon
- Immune system dynamics
- LN, lymph node
- LPC, long-lived plasma cells
- LV, liver
- MDSC, myeloid-derived suppressor cells
- Mechanistic modeling
- NK*, activated NK
- NK, natural killer cells
- ODE, ordinary differential equations
- PB, plasmablasts
- PC, plasma cells
- PL, plasma
- QSP, quantitative systems pharmacology
- Quantitative systems pharmacology
- SPC, short-lived plasma cells
- TRAIL, tumor necrosis factor–related apoptosis-inducing ligand
- Th0, naïve T cells
- Treg, regulatory T cells
- Viral dynamics
- anti-HBc, specific antibodies against core hepatitis B antigen
- anti-HBs, specific antibodies against surface hepatitis B antigen
- dHep, debris hepatocytes
- iHep, infected hepatocytes
- pDC, plasmacytoid DC
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Boni C, Cavazzini D, Bolchi A, Rossi M, Vecchi A, Tiezzi C, Barili V, Fisicaro P, Ferrari C, Ottonello S. Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm. Front Immunol 2021; 12:730051. [PMID: 34566990 PMCID: PMC8455995 DOI: 10.3389/fimmu.2021.730051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/11/2021] [Indexed: 01/01/2023] Open
Abstract
There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these "hot" concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.
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Affiliation(s)
- Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Davide Cavazzini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Angelo Bolchi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center Biopharmanet-Tec, 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
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Camilla Tiezzi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di 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
| | - 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
| | - 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
| | - Simone Ottonello
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center Biopharmanet-Tec, University of Parma, Parma, Italy
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Alvarez-de Miranda FJ, Alonso-Sánchez I, Alcamí A, Hernaez B. TNF Decoy Receptors Encoded by Poxviruses. Pathogens 2021; 10:pathogens10081065. [PMID: 34451529 PMCID: PMC8401223 DOI: 10.3390/pathogens10081065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/29/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection. This TNF-based host response is essential to limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms to counteract TNF antiviral action. These include the expression of poxvirus-encoded soluble receptors or proteins able to bind and neutralize TNF and other members of the TNF ligand superfamily, acting as decoy receptors. This article reviews in detail the various TNF decoy receptors identified to date in the genomes from different poxvirus species, with a special focus on their impact on poxvirus pathogenesis and their potential use as therapeutic molecules.
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Reuther P, Martin K, Kreutzfeldt M, Ciancaglini M, Geier F, Calabrese D, Merkler D, Pinschewer DD. Persistent RNA virus infection is short-lived at the single-cell level but leaves transcriptomic footprints. J Exp Med 2021; 218:212556. [PMID: 34398180 PMCID: PMC8493862 DOI: 10.1084/jem.20210408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/14/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022] Open
Abstract
Several RNA viruses can establish life-long persistent infection in mammalian hosts, but the fate of individual virus-infected cells remains undefined. Here we used Cre recombinase-encoding lymphocytic choriomeningitis virus to establish persistent infection in fluorescent cell fate reporter mice. Virus-infected hepatocytes underwent spontaneous noncytolytic viral clearance independently of type I or type II interferon signaling or adaptive immunity. Viral clearance was accompanied by persistent transcriptomic footprints related to proliferation and extracellular matrix remodeling, immune responses, and metabolism. Substantial overlap with persistent epigenetic alterations in HCV-cured patients suggested a universal RNA virus-induced transcriptomic footprint. Cell-intrinsic clearance occurred in cell culture, too, with sequential infection, reinfection cycles separated by a period of relative refractoriness to infection. Our study reveals that systemic persistence of a prototypic noncytolytic RNA virus depends on continuous spread and reinfection. Yet undefined cell-intrinsic mechanisms prevent viral persistence at the single-cell level but give way to profound transcriptomic alterations in virus-cleared cells.
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Affiliation(s)
- Peter Reuther
- Department of Biomedicine, Division of Experimental Virology, University of Basel, Basel, Switzerland
| | - Katrin Martin
- Department of Biomedicine, Division of Experimental Virology, University of Basel, Basel, Switzerland
| | - Mario Kreutzfeldt
- Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Geneva University and University Hospital, Geneva, Switzerland
| | - Matias Ciancaglini
- Department of Biomedicine, Division of Experimental Virology, University of Basel, Basel, Switzerland
| | - Florian Geier
- Department of Biomedicine, Bioinformatics Core Facility, University Hospital Basel, Basel, Switzerland
| | - Diego Calabrese
- Department of Biomedicine, Histology Core Facility, University Hospital Basel, Basel, Switzerland
| | - Doron Merkler
- Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Geneva University and University Hospital, Geneva, Switzerland
| | - Daniel D Pinschewer
- Department of Biomedicine, Division of Experimental Virology, University of Basel, Basel, Switzerland
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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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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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McGee HM, Marciscano AE, Campbell AM, Monjazeb AM, Kaech SM, Teijaro JR. Parallels Between the Antiviral State and the Irradiated State. J Natl Cancer Inst 2021; 113:969-979. [PMID: 33252657 PMCID: PMC8502484 DOI: 10.1093/jnci/djaa190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/07/2020] [Accepted: 11/16/2020] [Indexed: 01/12/2023] Open
Abstract
Improved understanding of host antiviral defense and antitumor immunity have elucidated molecular pathways important to both processes. During viral infection, RNA or DNA in the host cell serves as a danger signal that initiates the antiviral response. Recent studies have elucidated similarities in the signaling pathways activated by viruses and the signaling pathways induced by tumor DNA that is released into the cytoplasm of irradiated tumor cells. Both the host defense to viral infection and the sterile inflammation provoked by radiotherapy induce a type I interferon response that is necessary for pathogen control and immune-mediated tumor control, respectively. These findings have led to the hypothesis that radiotherapy employs a form of viral mimicry.
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Affiliation(s)
- Heather M McGee
- NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Ariel E Marciscano
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Allison M Campbell
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Arta M Monjazeb
- Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Susan M Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - John R Teijaro
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA
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B-Catenin Signaling Regulates the In Vivo Distribution of Hepatitis B Virus Biosynthesis across the Liver Lobule. J Virol 2021; 95:e0078021. [PMID: 34319157 DOI: 10.1128/jvi.00780-21] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
β-catenin (Ctnnb1) supports high levels of liver gene expression in hepatocytes in proximity to the central vein functionally defining zone 3 of the liver lobule. This region of the liver lobule supports the highest levels of viral biosynthesis in wildtype HBV transgenic mice. Liver-specific β-catenin-null HBV transgenic mice exhibit a stark loss of high levels of pericentral viral biosynthesis. Additionally, viral replication that does not depend directly on β-catenin activity appears to expand to include hepatocytes of zone 1 of the liver lobule in proximity to the portal vein, a region of the liver that typically lacks significant HBV biosynthesis in wildtype HBV transgenic mice. While the average amount of viral RNA transcripts does not change, viral DNA replication is reduced approximately three-fold. Together, these observations demonstrate that β-catenin signaling represents a major determinant of HBV biosynthesis governing the magnitude and distribution of viral replication across the liver lobule in vivo. Additionally, these findings reveal a novel mechanism for the regulation of HBV biosynthesis that is potentially relevant to the expression of additional liver-specific genes. IMPORTANCE Viral biosynthesis is highest around the central vein in the HBV transgenic mouse model of chronic infection. The associated HBV biosynthetic gradient across the liver lobule is primarily dependent upon β-catenin. In the absence of β-catenin, the gradient of viral gene expression spanning the liver lobule is absent and HBV replication is reduced. Therefore, therapeutically manipulating β-catenin activity in the liver of chronic HBV carriers may reduce circulating infectious virions without greatly modulating viral protein production. Together, these change in viral biosynthesis might limit infection of additional hepatocytes while permitting immunological clearance of previously infected cells, potentially limiting disease persistence.
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37
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Zhang X, Wang X, Wu M, Ghildyal R, Yuan Z. Animal Models for the Study of Hepatitis B Virus Pathobiology and Immunity: Past, Present, and Future. Front Microbiol 2021; 12:715450. [PMID: 34335553 PMCID: PMC8322840 DOI: 10.3389/fmicb.2021.715450] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/18/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem that plagues approximately 240 million people. Chronic hepatitis B (CHB) often leads to liver inflammation and aberrant repair which results in diseases ranging from liver fibrosis, cirrhosis, to hepatocellular carcinoma. Despite its narrow species tropism, researchers have established various in vivo models for HBV or its related viruses which have provided a wealth of knowledge on viral lifecycle, pathogenesis, and immunity. Here we briefly revisit over five decades of endeavor in animal model development for HBV and summarize their advantages and limitations. We also suggest directions for further improvements that are crucial for elucidation of the viral immune-evasion strategies and for development of novel therapeutics for a functional cure.
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Affiliation(s)
- Xiaonan Zhang
- Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia.,Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiaomeng Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Min Wu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Reena Ghildyal
- Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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38
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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Abstract
The CD8+ T cell noncytotoxic antiviral response (CNAR) was discovered during studies of asymptomatic HIV-infected subjects more than 30 years ago. In contrast to CD8+ T cell cytotoxic lymphocyte (CTL) activity, CNAR suppresses HIV replication without target cell killing. This activity has characteristics of innate immunity: it acts on all retroviruses and thus is neither epitope specific nor HLA restricted. The HIV-associated CNAR does not affect other virus families. It is mediated, at least in part, by a CD8+ T cell antiviral factor (CAF) that blocks HIV transcription. A variety of assays used to measure CNAR/CAF and the effects on other retrovirus infections are described. Notably, CD8+ T cell noncytotoxic antiviral responses have now been observed with other virus families but are mediated by different cytokines. Characterizing the protein structure of CAF has been challenging despite many biologic, immunologic, and molecular studies. It represents a low-abundance protein that may be identified by future next-generation sequencing approaches. Since CNAR/CAF is a natural noncytotoxic activity, it could provide promising strategies for HIV/AIDS therapy, cure, and prevention.
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Affiliation(s)
- Maelig G Morvan
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Fernando C Teque
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | | | - Jay A Levy
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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Chiale C, Marchese AM, Robek MD. Innate immunity and HBV persistence. Curr Opin Virol 2021; 49:13-20. [PMID: 33992859 DOI: 10.1016/j.coviro.2021.04.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) causes chronic infections that are associated with immune dysfunction. Though T cell impairment is perhaps the most prominent immune change contributing to viral persistence, HBV interaction with the innate immune system is also likely key, as the lack of effective innate immunity has functional consequences that promote chronic infection. In addition to an intrinsic ability to fight viral infections, the innate immune system also impacts T cell responses and other adaptive immune mechanisms critical for HBV control. Therefore, it is essential to understand the relationships between HBV and innate immunity, as these interactions may be useful immunotherapeutic targets to manage the infection.
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Affiliation(s)
- Carolina Chiale
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Anthony M Marchese
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Michael D Robek
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
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Li J, Shi TD, Han JF, Zeng XG, Fan CL, Han C, Liu HL, Wu YZ. A systematic study of Tupaia as a model for human acute hepatitis B infection. J Vet Med Sci 2021; 83:1004-1011. [PMID: 33952781 PMCID: PMC8267197 DOI: 10.1292/jvms.21-0026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The molecular features of hepatitis B virus (HBV) infection, eradication, and pathogenesis are poorly understood, partly due to the lack of an adequate animal model that faithfully reproduces the course of infection. Although Tupaia belangeri were previously recognized as HBV-susceptible animals, the course of infection in adult tupaias remains obscure. Herein, we performed a longitudinal study and demonstrated that adult tupaias were efficiently infected (90% infection rate) with 108 copies of the HBV genome. HBV replicated vigorously, produced high levels of covalently closed circular DNA (cccDNA) in hepatocytes, and released hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and HBV DNA into the serum at day 9 post-inoculation (p.i.), which then decreased on day 15 p.i. The kinetics were consistent with the expression of liver HBsAg and HBeAg, as determined with immunohistochemistry. The viral products in serum at day 9 and 15 p.i. represented de novo synthesized viral products, as treatment with a viral entry inhibitor completely abolished these products from the serum. Viral clearance and serological conversion occurred at day 21 p.i. and were accompanied by elevated alanine transaminase (ALT) levels and liver pathology, such as inflammatory infiltration and hepatocyte ballooning degeneration. Although ALT levels eventually returned to normal levels by day 42 p.i., the liver pathology persisted until at least day 120 p.i. The HBV infection process in tupaia, therefore, exhibits features similar to that of human acute HBV infection, including viral replication, viral eradication, ALT elevation, and liver pathology. Thus, adopting the tupaia model to study host-HBV interactions presents an important advance which could facilitate further investigation and understanding of human HBV infection, especially for features like cccDNA that current small-animal models cannot effectively model.
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Affiliation(s)
- Jun Li
- Institute of Immunology, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Tong-Dong Shi
- Division of Infectious Diseases, The Second Affiliated of Chongqing University of Medical Science, No. 74 Linjiang Rd, Yuzhong District, Chongqing 400038, China
| | - Jun-Feng Han
- Institute of Immunology, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Xing-Guang Zeng
- Pharm Star Biotechnology Co., Ltd., No. 99 Hongcaofang Street, Chongqing 400038, China
| | - Cui-Li Fan
- HEP Biotechnology Co., Ltd., No. 720 Cailun Rd, Shanghai 201203, China
| | - Chao Han
- Institute of Immunology, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Hong-Li Liu
- HEP Biotechnology Co., Ltd., No. 720 Cailun Rd, Shanghai 201203, China
| | - Yu-Zhang Wu
- Institute of Immunology, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
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Liu Y, Maya S, Ploss A. Animal Models of Hepatitis B Virus Infection-Success, Challenges, and Future Directions. Viruses 2021; 13:v13050777. [PMID: 33924793 PMCID: PMC8146732 DOI: 10.3390/v13050777] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/23/2021] [Accepted: 04/24/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide, which greatly increases the risk for terminal liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC). Even though current approved antiviral therapies, including pegylated type I interferon (IFN) and nucleos(t)ide analogs, can effectively suppress viremia, HBV infection is rarely cured. Since HBV exhibits a narrow species tropism and robustly infects only humans and higher primates, progress in HBV research and preclinical testing of antiviral drugs has been hampered by the scarcity of suitable animal models. Fortunately, a series of surrogate animal models have been developed for the study of HBV. An increased understanding of the barriers towards interspecies transmission has aided in the development of human chimeric mice and has greatly paved the way for HBV research in vivo, and for evaluating potential therapies of chronic hepatitis B. In this review, we summarize the currently available animal models for research of HBV and HBV-related hepadnaviruses, and we discuss challenges and future directions for improvement.
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Suslov A, Meier MA, Ketterer S, Wang X, Wieland S, Heim MH. Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity. J Hepatol 2021; 74:794-800. [PMID: 33188905 DOI: 10.1016/j.jhep.2020.11.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/30/2020] [Accepted: 11/05/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS HBeAg seroconversion during the natural history of chronic hepatitis B (CHB) is associated with a strong drop in serum HBV DNA levels and a reduction of intrahepatic covalently closed circular DNA (cccDNA) content. Of particular interest is the transition to HBeAg-negative chronic infection (ENCI). ENCI, previously known as inactive carrier state, is characterized by very low or negative viremia and the absence of liver disease. The molecular mechanisms responsible for the transition to ENCI and for the control of viral replication in ENCI are still poorly understood. METHODS To identify which step(s) in the viral life cycle are controlled during the transition to ENCI, we quantified cccDNA, pre-genomic RNA (pgRNA), total HBV RNA and DNA replicative intermediates in 68 biopsies from patients in different phases of CHB. RESULTS HBeAg seroconversion is associated with a reduction of cccDNA amounts as well as transcriptional activity. Silencing of cccDNA is particularly pronounced in ENCI, where there was ~46 times less pgRNA per cccDNA compared to HBeAg-negative CHB. Furthermore, a subgroup of patients with HBeAg-negative CHB can be characterized by reduced replication efficiency downstream of pgRNA. CONCLUSIONS The reduction in serum viral load during the transition to ENCI seems to primarily result from strong inhibition of the transcriptional activity of cccDNA which can be maintained in the absence of liver disease. LAY SUMMARY During the natural course of chronic hepatitis B virus infections, the immune response can gain control of viral replication. Quantification of viral DNA and RNA in liver biopsies of patients in different stages of chronic hepatitis B allowed us to identify the steps in the viral life cycle that are affected during the transition from active to inactive disease. Therapeutic targeting of these steps might induce sustained inhibition of viral transcription.
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Affiliation(s)
- Aleksei Suslov
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland
| | - Marie-Anne Meier
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland; Division of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel, CH-4002, Switzerland
| | - Sylvia Ketterer
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland
| | - Xueya Wang
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland
| | - Stefan Wieland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland.
| | - Markus Hermann Heim
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland; Division of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel, CH-4002, Switzerland.
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CD8 T cell-Derived Perforin and TNF-α Are Crucial Mediators of Neuronal Destruction in Experimental Autoimmune Enteric Ganglionitis. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1064-1076. [PMID: 33713685 DOI: 10.1016/j.ajpath.2021.02.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/05/2021] [Accepted: 02/18/2021] [Indexed: 12/22/2022]
Abstract
In neuron-specific ovalbumin-transgenic CKTAC mice, antigen-specific OT-I CD8 T cells home to the enteric nervous system, where they attack and destroy neurons of the myenteric and submucosal plexus. Clinically, experimental autoimmune enteric ganglionitis (EAEG) manifests with gastrointestinal dysmotility and rapidly progresses to lethal ileus. Although interferon-γ has been identified as capable of damaging neurons in EAEG, the role of perforin, Fas/FasL, and tumor necrosis factor-α (TNF-α) in this disease is still a matter of debate. Thus, CKTAC mice were adoptively transferred with either perforin-/- or wild-type OT-I CD8 T cells. In addition, CKTAC mice that had received wild-type OT-I CD8 T cells were treated by either anti-TNF-α or anti-FasL. Furthermore, wild-type OT-I CD8 T cells were adoptively transferred into CKTAC mice with neuron-specific deletion of Fas. Although neither inactivation of enteric neuronal Fas nor anti-FasL treatment improved the disease, the absence of perforin from OT-I CD8 T cells and anti-TNF-α treatment significantly ameliorated EAEG and prevented lethal ileus by rescue of enteric neurons. Thus, these experiments identify perforin and TNF-α as important in the pathogenesis of EAEG.
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Fumagalli V, Di Lucia P, Venzin V, Bono EB, Jordan R, Frey CR, Delaney W, Chisari FV, Guidotti LG, Iannacone M. Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. J Exp Med 2021; 217:152002. [PMID: 32761167 PMCID: PMC7596822 DOI: 10.1084/jem.20200298] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/20/2020] [Accepted: 06/18/2020] [Indexed: 12/23/2022] Open
Abstract
Antibody-mediated clearance of hepatitis B surface antigen (HBsAg) from the circulation of chronically infected patients (i.e., seroconversion) is usually associated with increased HBV-specific T cell responsiveness. However, a causative link between serum HBsAg levels and impairment of intrahepatic CD8+ T cells has not been established. Here we addressed this issue by using HBV replication-competent transgenic mice that are depleted of circulating HBsAg, via either spontaneous seroconversion or therapeutic monoclonal antibodies, as recipients of HBV-specific CD8+ T cells. Surprisingly, we found that serum HBsAg clearance has only a minimal effect on the expansion of HBV-specific naive CD8+ T cells undergoing intrahepatic priming. It does not alter their propensity to become dysfunctional, nor does it enhance the capacity of IL-2–based immunotherapeutic strategies to increase their antiviral function. In summary, our results reveal that circulating HBsAg clearance does not improve HBV-specific CD8+ T cell responses in vivo and may have important implications for the treatment of chronic HBV infection.
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Affiliation(s)
- Valeria Fumagalli
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Pietro Di Lucia
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Valentina Venzin
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Elisa B Bono
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | | | | | | | - Francis V Chisari
- Deparment of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA
| | - Luca G Guidotti
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy.,Experimental Imaging Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
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Ninyio NN, Ho KL, Yong CY, Chee HY, Hamid M, Ong HK, Mariatulqabtiah AR, Tan WS. Chimeric Virus-Like Particles of Prawn Nodavirus Displaying Hepatitis B Virus Immunodominant Region: Biophysical Properties and Cytokine Response. Int J Mol Sci 2021; 22:ijms22041922. [PMID: 33672018 PMCID: PMC7919259 DOI: 10.3390/ijms22041922] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/29/2021] [Accepted: 02/05/2021] [Indexed: 01/12/2023] Open
Abstract
Hepatitis B is a major global health challenge. In the absence of an effective treatment for the disease, hepatitis B vaccines provide protection against the viral infection. However, some individuals do not have positive immune responses after being vaccinated with the hepatitis B vaccines available in the market. Thus, it is important to develop a more protective vaccine. Previously, we showed that hepatitis B virus (HBV) ‘a’ determinant (aD) displayed on the prawn nodavirus capsid (Nc) and expressed in Spodoptera frugiperda (Sf9) cells (namely, Nc-aD-Sf9) self-assembled into virus-like particles (VLPs). Immunisation of BALB/c mice with the Nc-aD-Sf9 VLPs showed significant induction of humoral, cellular and memory B-cell immunity. In the present study, the biophysical properties of the Nc-aD-Sf9 VLPs were studied using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was used to determine the antigenicity of the Nc-aD-Sf9 VLPs, and multiplex ELISA was employed to quantify the cytokine response induced by the VLPs administered intramuscularly into BALB/c mice (n = 8). CD spectroscopy of Nc-aD-Sf9 VLPs showed that the secondary structure of the VLPs predominantly consisted of beta (β)-sheets (44.8%), and they were thermally stable up to ~52 °C. ELISA revealed that the aD epitope of the VLPs was significantly antigenic to anti-HBV surface antigen (HBsAg) antibodies. In addition, multiplex ELISA of serum samples from the vaccinated mice showed a significant induction (p < 0.001) of IFN-γ, IL-4, IL-5, IL-6, IL-10, and IL-12p70. This cytokine profile is indicative of natural killer cell, macrophage, dendritic cell and cytotoxic T-lymphocyte activities, which suggests a prophylactic innate and adaptive cellular immune response mediated by Nc-aD-Sf9 VLPs. Interestingly, Nc-aD-Sf9 induced a more robust release of the aforementioned cytokines than that of Nc-aD VLPs produced in Escherichia coli and a commercially used hepatitis B vaccine. Overall, Nc-aD-Sf9 VLPs are thermally stable and significantly antigenic, demonstrating their potential as an HBV vaccine candidate.
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Affiliation(s)
- Nathaniel Nyakaat Ninyio
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (N.N.N.); (C.Y.Y.); (M.H.)
- Department of Microbiology, Faculty of Science, Kaduna State University, P.M.B. 2339, Tafawa Balewa Way, Kaduna 800241, Nigeria
| | - Kok Lian Ho
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (K.L.H.); (H.K.O.)
| | - Chean Yeah Yong
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (N.N.N.); (C.Y.Y.); (M.H.)
| | - Hui Yee Chee
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia;
| | - Muhajir Hamid
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (N.N.N.); (C.Y.Y.); (M.H.)
| | - Hui Kian Ong
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (K.L.H.); (H.K.O.)
| | - Abdul Razak Mariatulqabtiah
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia;
- Laboratory of Vaccine and Biomolecules, Institute of Bioscience, Universiti Putra Malaysia, Selangor 43400, Malaysia
| | - Wen Siang Tan
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia; (N.N.N.); (C.Y.Y.); (M.H.)
- Laboratory of Vaccine and Biomolecules, Institute of Bioscience, Universiti Putra Malaysia, Selangor 43400, Malaysia
- Correspondence: ; Tel.: +603-9769-6715; Fax: +603-9769-7590
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Vinhaes CL, Araujo-Pereira M, Tibúrcio R, Cubillos-Angulo JM, Demitto FO, Akrami KM, Andrade BB. Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV. Life (Basel) 2021; 11:life11010065. [PMID: 33477581 PMCID: PMC7831327 DOI: 10.3390/life11010065] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/19/2022] Open
Abstract
Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.
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Affiliation(s)
- Caian L. Vinhaes
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, Salvador 40290-000, Brazil
| | - Mariana Araujo-Pereira
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Rafael Tibúrcio
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Juan M. Cubillos-Angulo
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
| | - Fernanda O. Demitto
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
| | - Kevan M. Akrami
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
- Divisions of Infectious Diseases and Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Bruno B. Andrade
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil; (C.L.V.); (M.A.-P.); (R.T.); (J.M.C.-A.); (K.M.A.)
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador 40210-320, Brazil;
- Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, Salvador 40290-000, Brazil
- Faculdade de Medicina, Universidade Federal da Bahia, Salvador 40110-100, Brazil
- Curso de Medicina, Centro Universitário Faculdade de Tecnologia e Ciências (UniFTC), Salvador 41741-590, Brazil
- Correspondence: ; Tel.: +55-71-3176-2264
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Abstract
BACKGROUND Chemokine (C-C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. METHODS We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C-C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. RESULTS From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. CONCLUSIONS Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.
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50
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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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