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Zhan M, Zhong S, Niu J, Gao X. Activation of immune checkpoint OX40 inhibits HBV replication in a mouse model. Int Immunopharmacol 2025; 149:114120. [PMID: 39923582 DOI: 10.1016/j.intimp.2025.114120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/16/2025] [Accepted: 01/16/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND & AIMS The costimulatory molecules OX40 and OX40L, members of the tumor necrosis factor (receptor) superfamily, play an important role in viral control through the activation of T cells. We speculate that activating the immune checkpoint OX40 may promote the inhibition of hepatitis B virus (HBV) replication. METHODS To test this hypothesis, we investigated the expression dynamics of OX40/OX40L and studied the effects of activation of OX40 on HBV replication, and further explored the possible mechanism. RESULTS We found that the percentage of T cells expressing OX40 was lower in adult patients with chronic hepatitis B (CHB) than in healthy adults and was negatively correlated with serum viral load. In contrast, the percentage of B cells and monocytes expressing OX40L was increased in adult patients with CHB and positively correlated with liver inflammatory indicators. The expression of OX40 in T cells and OX40L in monocytes was positively correlated with age in healthy donors. In addition, the levels of serum HBsAg and intrahepatic HBV DNA decreased in an HBV mouse model with an agonistic antibody that activates OX40. This viral inhibition process coincides with changes in liver inflammation, the ratio of T cell subsets, and T cell-related cytokines. Finally, we found that the OX40 activation-mediated inhibition of HBV replication was more dependent on CD8+ T cells than on CD4+ T cells. CONCLUSIONS The expression levels of the immune checkpoints OX40/OX40L in adult patients with CHB are closely related to virus clearance. The activation of OX40 can suppress HBV replication through a mechanism that is more dependent on CD8+ T cells than on CD4+ T cells. Thus, OX40 is a promising therapeutic target for the treatment of CHB.
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Affiliation(s)
- Mengru Zhan
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shaoling Zhong
- Ultrasound Medical, Hangzhou Lin'an District Third People's Hospital, Hangzhou, China
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Public Laboratory Platform, The First Hospital of Jilin University, Changchun, China.
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Wu D, Kao JH, Piratvisuth T, Wang X, Kennedy PTF, Otsuka M, Ahn SH, Tanaka Y, Wang G, Yuan Z, Li W, Lim YS, Niu J, Lu F, Zhang W, Gao Z, Kaewdech A, Han M, Yan W, Ren H, Hu P, Shu S, Kwo PY, Wang FS, Yuen MF, Ning Q. Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0. Clin Mol Hepatol 2025; 31:S134-S164. [PMID: 39838828 PMCID: PMC11925436 DOI: 10.3350/cmh.2024.0780] [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: 09/09/2024] [Accepted: 01/21/2025] [Indexed: 01/23/2025] Open
Abstract
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.
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Affiliation(s)
- Di Wu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Xiaojing Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Patrick T F Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Academic Fields of Medicine, Dentistry, and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wenhui Li
- National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Jilin, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Meifang Han
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Sainan Shu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Paul Yien Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Fu-Sheng Wang
- Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
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3
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Yu F, Zhu Y, Li S, Hao L, Li N, Ye F, Jiang Z, Hu X. Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies. Front Cell Infect Microbiol 2024; 14:1488527. [PMID: 39717542 PMCID: PMC11663751 DOI: 10.3389/fcimb.2024.1488527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.
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Affiliation(s)
- Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yue Zhu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fanghang Ye
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhi Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Kang S, Chung E, Hong C, Aziz AB, Kirkwood CD, Marks F. Raising the case of hepatitis E: Report from the 2nd international HEV symposium. Vaccine 2024; 42:126398. [PMID: 39357463 DOI: 10.1016/j.vaccine.2024.126398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/02/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
The 2nd International Hepatitis E Virus Symposium was held on April 28 and 29, 2023, in London, UK. The conference was hosted by the International Vaccine Institute and brought together key clinicians, researchers, and private and public stakeholders for a dedicated forum on hepatitis E virus (HEV). The scientific program spanned multiple facets of HEV, from updates on clinical research and diagnostic advances to vaccine development. The conference highlighted presentations on several critical HEV vaccine studies that will greatly impact the field, including the largest effectiveness study of Hecolin vaccine outside of China and the first reactive mass-vaccination campaign in South Sudan. This report summarizes information shared at the convening and offers perspectives on the steps forward for hepatitis E.
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Affiliation(s)
- Sophie Kang
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea.
| | - Eun Chung
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Chloe Hong
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Asma Binte Aziz
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea
| | - Carl D Kirkwood
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Florian Marks
- Epidemiology, Public Health and Impact, International Vaccine Institute, Seoul, South Korea; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany; Madagascar Institute for Vaccine Research, University of Antananarivo, Antananarivo, Madagascar
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5
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Wan X, Wisskirchen K, Jin T, Yang L, Wang X, Wu X, Liu F, Wu Y, Ma C, Pang Y, Li Q, Zhang K, Protzer U, Du S. Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting. Clin Mol Hepatol 2024; 30:735-755. [PMID: 38808361 PMCID: PMC11540345 DOI: 10.3350/cmh.2024.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND/AIMS Hepatitis B virus (HBV)-DNA integration in HBV-related hepatocellular carcinoma (HBV-HCC) can be targeted by HBV-specific T cells. SCG101 is an autologous, HBV-specific T-cell product expressing a T-cell receptor (TCR) after lentiviral transduction recognizing the envelope-derived peptide (S20-28) on HLA-A2. We here validated its safety and efficacy preclinically and applied it to an HBV-related HCC patient (NCT05339321). METHODS Good Manufacturing Practice-grade manufactured cells were assessed for off-target reactivity and functionality against hepatoma cells. Subsequently, a patient with advanced HBV-HCC (Child-Pugh class A, Barcelona Clinic Liver Cancer stage B, Eastern Cooperative Oncology Group performance status 0, hepatitis B e antigen-, serum hepatitis B surface antigen [HBsAg]+, HBsAg+ hepatocytes 10%) received 7.9×107 cells/kg after lymphodepletion. Safety, T-cell persistence, and antiviral and antitumor efficacy were evaluated. RESULTS SCG101, produced at high numbers in a closed-bag system, showed HBV-specific functionality against HBV-HCC cells in vitro and in vivo. Clinically, treatment was well tolerated, and all adverse events, including transient hepatic damage, were reversible. On day 3, ALT levels increased to 1,404 U/L, and concurrently, serum HBsAg started decreasing by 3.84 log10 and remained <1 IU/mL for over six months. HBsAg-expressing hepatocytes in liver biopsies were undetectable after 73 days. The patient achieved a partial response according to modified RECIST with a >70% reduction in target lesion size. Transferred T cells expanded, developed a stem cell-like memory phenotype, and were still detectable after six months in the patient's blood. CONCLUSION SCG101 T-cell therapy showed encouraging efficacy and safety in preclinical models and in a patient with primary HBV-HCC and concomitant chronic hepatitis B with the capability to eliminate HBsAg+ cells and achieve sustained tumor control after single dosing.
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Affiliation(s)
- Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | | | - Tao Jin
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Lu Yang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Xiaorui Wang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Xiang’an Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Fang Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Yu Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Christy Ma
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Yong Pang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Qi Li
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Ke Zhang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
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Bertoletti A, Tan AT. Engineering HBV-specific T cells for the treatment of HBV-related HCC and HBV infection: Past, Present, and Future. Editorial on "Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting". Clin Mol Hepatol 2024; 30:728-734. [PMID: 38934109 PMCID: PMC11540402 DOI: 10.3350/cmh.2024.0469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 06/26/2024] [Indexed: 06/28/2024] Open
Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Anthony T Tan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
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7
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Assefa A, Getie M, Getie B, Yazie T, Enkobahry A. Molecular epidemiology of hepatitis B virus (HBV) in Ethiopia: A review article. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2024; 122:105618. [PMID: 38857639 DOI: 10.1016/j.meegid.2024.105618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/12/2024]
Abstract
Hepatitis B virus (HBV) belongs to the family Hepadnaviridae and is the smallest human DNA virus, with a genome that is only 3200 nucleotides long. The absence of proofreading function in HBV reverse transcriptase provides a wide range of genetic variants for targeted outgrowth at different stages of infection. A number of sub genotypes and ten HBV genotypes (A through J) have been identified through analyses of the divergence of HBV genomic sequences. Numerous clinical outcomes, including the emergence of chronicity, the course of the disease, the effectiveness of treatment, and the response to vaccination, have been related to differences in genotype between HBV isolates. There are just seven studies that have been done in Ethiopia that examine the molecular epidemiology of HBV. Moreover, these studies haven't been compiled and reviewed yet. In this review, we looked at the genetic diversity and molecular epidemiology of HBV, the relationship between HBV genotypes and clinical outcomes, the immunopathogenesis of HBV, and finally the molecular epidemiology of HBV in Ethiopia. PubMed, Embase, and Google Scholar search engines were used to find relevant articles for the review. By using HBV genotyping, clinicians can better tailor vaccination decisions and antiviral therapy for patients with chronic hepatitis B who are more likely to experience the disease's progression.
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Affiliation(s)
- Ayenew Assefa
- Unit of Immunology, Department of Medical Laboratory Science, Debre Tabor University, Debre Tabor, Ethiopia.
| | - Molla Getie
- College of Medicine and Health Science, Medical Laboratory Science Department, Injibara University, Injibara, Ethiopia
| | - Birhanu Getie
- Unit of Medical Microbiology, Department of Medical Laboratory Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Takilosimeneh Yazie
- College of Health Science, Department of Pharmacy, Debre Tabor University, Debre Tabor, Ethiopia
| | - Aklesya Enkobahry
- College of Medicine and Health Science, Department of Biomedical Science, Injibara University, Injibara, Ethiopia
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Zhang W, Zeng M, Li Y, Yu L. Leveraging oncovirus-derived antigen against the viral malignancies in adoptive cell therapies. Biomark Res 2024; 12:71. [PMID: 39075601 PMCID: PMC11287861 DOI: 10.1186/s40364-024-00617-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/10/2024] [Indexed: 07/31/2024] Open
Abstract
Adoptive cell therapies (ACTs) have revolutionized cancer immunotherapy, prompting exploration into their application against oncoviruses. Oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV) contribute significantly (12-25%) to human malignancies through direct or indirect oncogenic mechanisms. These viruses persistently or latently infect cells, disrupt cellular homeostasis and pathways, challenging current antiviral treatment paradigms. Moreover, viral infections pose additional risks in the setting of long-term cancer therapy and lead to morbidity and mortality. Virally encoded oncoproteins, which are tumor-restricted, immunologically foreign, and even uniformly expressed, represent promising targets for patient-tailored ACTs. This review elucidates the rationale for leveraging viral antigen-specific ACTs in combating viral-associated malignancies. On this basis, ongoing preclinical studies consolidate our understanding of harnessing ACTs against viral malignancies, underscoring their potential to eradicate viruses implicated in cancer progression. Furthermore, we scrutinize the current landscape of clinical trials focusing on virus-specific ACTs and discuss their implications for therapeutic advancement.
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Affiliation(s)
- Wei Zhang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China
| | - Miao Zeng
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China
| | - Yisheng Li
- Shenzhen Haoshi Biotechnology Co., Ltd, No. 155 Hongtian Road, Xinqiao Street, Bao'an District, Shenzhen, Guangdong, 518125, China
- Haoshi Cell Therapy Institute, Shenzhen University, Shenzhen, China
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China.
- Haoshi Cell Therapy Institute, Shenzhen University, Shenzhen, China.
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9
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Schreiber S, Dressler LS, Loffredo-Verde E, Asen T, Färber S, Wang W, Groll T, Chakraborty A, Kolbe F, Kreer C, Kosinska AD, Simon S, Urban S, Klein F, Riddell SR, Protzer U. CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells. Front Immunol 2024; 15:1340619. [PMID: 38711498 PMCID: PMC11072186 DOI: 10.3389/fimmu.2024.1340619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/18/2024] [Indexed: 05/08/2024] Open
Abstract
To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.
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Affiliation(s)
- Sophia Schreiber
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
- German Center for Infection Research, Munich Partner Site, Munich, Germany
| | - Lisa S. Dressler
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Eva Loffredo-Verde
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Theresa Asen
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Stephanie Färber
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Wenshi Wang
- Department of Infectious Diseases, Molecular Virology, University Hospital, Heidelberg, Germany
| | - Tanja Groll
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Anindita Chakraborty
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Fenna Kolbe
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
| | - Christoph Kreer
- Laboratory of Experimental Immunology, Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
| | - Anna D. Kosinska
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
- German Center for Infection Research, Munich Partner Site, Munich, Germany
| | - Sylvain Simon
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital, Heidelberg, Germany
| | - Florian Klein
- Laboratory of Experimental Immunology, Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
| | - Stanley R. Riddell
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Munich, Munich, Germany
- German Center for Infection Research, Munich Partner Site, Munich, Germany
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10
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Zhang F, Ju J, Diao H, Song J, Bian Y, Yang B. Innovative pharmacotherapy for hepatic metabolic and chronic inflammatory diseases in China. Br J Pharmacol 2024. [PMID: 38514420 DOI: 10.1111/bph.16342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/04/2024] [Accepted: 01/27/2024] [Indexed: 03/23/2024] Open
Abstract
Liver disease constitutes a significant global health concern, particularly in China where it has distinctive characteristics. China grapples with a staggering 300 million cases, predominantly due to hepatitis B and metabolic non-alcoholic fatty liver disease. Additionally, hepatocellular carcinoma has become a prevalent which is a lethal type of cancer. Despite the scarcity of innovative treatment options, Chinese hepatologists and researchers have achieved notable breakthroughs in the prevention, diagnosis, management and treatment of liver diseases. Traditional Chinese medicines have found widespread application in the treatment of various liver ailments owing to their commendable pharmacological efficacy and minimal side effects. Furthermore, there is a growing body of research in extracellular vesicles, cell therapy and gene therapy, offering new hope in the fight against liver diseases. This paper provides a comprehensive overview of the epidemiological characteristics of liver diseases and the diverse array of treatments that Chinese scholars and scientists have pursued in critical field.
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Affiliation(s)
- Feng Zhang
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jiaming Ju
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Hongtao Diao
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jinglun Song
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yu Bian
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Baofeng Yang
- Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
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11
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Hu JL, Huang AL. Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics. Virol Sin 2024; 39:9-23. [PMID: 38110037 PMCID: PMC10877440 DOI: 10.1016/j.virs.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 12/13/2023] [Indexed: 12/20/2023] Open
Abstract
The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.
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Affiliation(s)
- Jie-Li Hu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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12
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Lang-Meli J, Neumann-Haefelin C, Thimme R. Targeting virus-specific CD8+ T cells for treatment of chronic viral hepatitis: from bench to bedside. Expert Opin Biol Ther 2024; 24:77-89. [PMID: 38290716 DOI: 10.1080/14712598.2024.2313112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/29/2024] [Indexed: 02/01/2024]
Abstract
INTRODUCTION More than 350 million people worldwide live with chronic viral hepatitis and are thus at risk for severe complications like liver cirrhosis and hepatocellular carcinoma (HCC). To meet the goals of the World Health Organization (WHO) global hepatitis strategy, there is an urgent need for new immunotherapeutic approaches. These are particularly required for chronic hepatitis B virus infection and - B/D coinfection. AREAS COVERED This review summarizes data on mechanisms of CD8+ T cells failure in chronic hepatitis B, D, C and E virus infection. The relative contribution of the different concepts (viral escape, CD8+ T cell exhaustion, defective priming) will be discussed. On this basis, examples for future therapeutic approaches targeting virus-specific CD8+ T cells for the individual hepatitis viruses will be discussed. EXPERT OPINION Immunotherapeutic approaches targeting virus-specific CD8+ T cells have the potential to change clinical practice, especially in chronic hepatitis B virus infection. Further clinical development, however, requires a more detailed understanding of T cell immunology in chronic viral hepatitis. Some important conceptual questions remain to be addressed, e.g. regarding heterogeneity of exhausted virus-specific CD8+ T cells.
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Affiliation(s)
- Julia Lang-Meli
- Department of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
- IMM-PACT Programm, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
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13
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Festag J, Festag MM, Asen T, Wettengel JM, Mück-Häusl MA, Abdulhaqq S, Stahl-Hennig C, Sacha JB, Burwitz BJ, Protzer U, Wisskirchen K. Vector-Mediated Delivery of Human Major Histocompatibility Complex-I into Hepatocytes Enables Investigation of T Cell Receptor-Redirected Hepatitis B Virus-Specific T Cells in Mice, and in Macaque Cell Cultures. Hum Gene Ther 2023; 34:1204-1218. [PMID: 37747811 PMCID: PMC10825313 DOI: 10.1089/hum.2023.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 08/28/2023] [Indexed: 09/27/2023] Open
Abstract
Adoptive T cell therapy using natural T cell receptor (TCR) redirection is a promising approach to fight solid cancers and viral infections in liver and other organs. However, clinical efficacy of such TCR+-T cells has been limited so far. One reason is that syngeneic preclinical models to evaluate safety and efficacy of TCR+-T cells are missing. We, therefore, developed an efficient viral vector strategy mediating expression of human major histocompatibility complex (MHC)-I in hepatocytes, which allows evaluation of TCR-T cell therapies targeting diseased liver cells. We designed adeno-associated virus (AAV) and adenoviral vectors encoding either the human-mouse chimeric HLA-A*02-like molecule, or fully human HLA-A*02 and human β2 microglobulin (hβ2m). Upon transduction of murine hepatocytes, the HLA-A*02 construct proved superior in terms of expression levels, presentation of endogenously processed peptides and activation of murine TCR+-T cells grafted with HLA-A*02-restricted, hepatitis B virus (HBV)-specific TCRs. In vivo, these T cells elicited effector function, controlled HBV replication, and reduced HBV viral load and antigen expression in livers of those mice that had received AAV-HBV and AAV-HLA-A*02. We then demonstrated the broad utility of this approach by grafting macaque T cells with the HBV-specific TCRs and enabling them to recognize HBV-infected primary macaque hepatocytes expressing HLA-A*02 upon adenoviral transduction. In conclusion, AAV and adenovirus vectors are suitable for delivery of HLA-A*02 and hβ2m into mouse and macaque hepatocytes. When recognizing their cognate antigen in HLA-A*02-transduced mouse livers or on isolated macaque hepatocytes, HLA-A*02-restricted, HBV-specific TCR+-T cells become activated and exert antiviral effector functions. This approach is applicable to any MHC restriction and target disease, paving the way for safety and efficacy studies of human TCR-based therapies in physiologically relevant preclinical animal models.
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Affiliation(s)
- Julia Festag
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Marvin M. Festag
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Theresa Asen
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Jochen M. Wettengel
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | | | - Shaheed Abdulhaqq
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA
| | | | - Jonah B. Sacha
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA
- Oregon National Primate Research Center (ONPRC), Oregon Health and Science University, Beaverton, Oregon, USA
| | - Benjamin J. Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA
- Oregon National Primate Research Center (ONPRC), Oregon Health and Science University, Beaverton, Oregon, USA
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Karin Wisskirchen
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
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14
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Guo G, He W, Zhou Z, Diao Y, Sui J, Li W. PreS1- targeting chimeric antigen receptor T cells diminish HBV infection in liver humanized FRG mice. Virology 2023; 586:23-34. [PMID: 37478771 DOI: 10.1016/j.virol.2023.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/15/2023] [Accepted: 06/27/2023] [Indexed: 07/23/2023]
Abstract
Current therapies control but rarely achieve a cure for hepatitis B virus (HBV) infection. Restoration of the HBV-specific immunity by cell-based therapy represents a potential approach for a cure. In this study, we generated HBV specific CAR T cells based on an antibody 2H5-A14 targeting a preS1 region of the HBV large envelope protein. We show that the A14 CAR T cell is capable of killing hepatocytes infected by HBV with high specificity; adoptive transfer of A14 CAR T cells to HBV infected humanized FRG mice resulted in reductions of all serum and intrahepatic virological markers to levels below the detection limit. A14 CAR T cells treatment increased the levels of human IFN-γ, GM-CSF, and IL-8/CXCL-8 in the mice. These results show that A14 CAR T cells may be further developed for curative therapy against HBV infection by eliminating HBV-infected hepatocytes and inducing production of pro-inflammatory and antiviral cytokines.
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Affiliation(s)
- Guilan Guo
- College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, China
| | - Wenhui He
- National Institute of Biological Sciences, Beijing, China
| | - Zhongmin Zhou
- College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, China
| | - Yan Diao
- National Institute of Biological Sciences, Beijing, China; Zhongshan School of Medicine, Sun Yet-Sen University, Guangzhou, China
| | - Jianhua Sui
- National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 102206, China
| | - Wenhui Li
- National Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 102206, China.
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15
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Sun MY, Li W, Chen W. Chimeric antigen receptor T cell and regulatory T cell therapy in non-oncology diseases: A narrative review of studies from 2017 to 2023. Hum Vaccin Immunother 2023; 19:2251839. [PMID: 37814513 PMCID: PMC10566417 DOI: 10.1080/21645515.2023.2251839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/10/2023] [Indexed: 10/11/2023] Open
Abstract
Recently, the remarkable success of chimeric antigen receptor T cell (CAR-T) therapy in treating certain tumors has led to numerous studies exploring its potential application to treat non-oncology diseases. This review discusses the progress and evolution of CAR-T cell therapies for treating non-oncology diseases over the past 5 years. Additionally, we summarize the advantages and disadvantages of CAR-T cell therapy in treating non-oncological diseases and identify any difficulties that should be overcome. After conducting an in-depth analysis of the most recent studies on CAR-T technology, we discuss the key elements of CAR-T therapy, such as developing an effective CAR design for non-oncological diseases, controlling the rate and duration of response, and implementing safety measures to reduce toxicity. These studies provide new insights into different delivery strategies, the discovery of new target molecules, and improvements in the safety of CAR-T therapy for non-oncological diseases.
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Affiliation(s)
- Ming-Yao Sun
- Department of Clinical Nutrition, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
- Department of Clinical Nutrition, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Wanyang Li
- Department of Clinical Nutrition, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Wei Chen
- Department of Clinical Nutrition, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
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16
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Salama II, Sami SM, Salama SI, Abdel-Latif GA, Shaaban FA, Fouad WA, Abdelmohsen AM, Raslan HM. Current and novel modalities for management of chronic hepatitis B infection. World J Hepatol 2023; 15:585-608. [PMID: 37305370 PMCID: PMC10251278 DOI: 10.4254/wjh.v15.i5.585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/13/2023] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
Over 296 million people are estimated to have chronic hepatitis B viral infection (CHB), and it poses unique challenges for elimination. CHB is the result of hepatitis B virus (HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV. Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA. Functional HBV “cure” is the durable loss of hepatitis B surface antigen (HBsAg), with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment. The currently approved therapies are nucleos(t)ide analogues, interferon-alpha, and pegylated-interferon. With these therapies, functional cure can be achieved in < 10% of CHB patients. Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV. Novel therapies may allow efficient control of CHB. They include direct acting antivirals and immunomodulators. Reduction of the viral antigen load is a crucial factor for success of immune-based therapies. Immunomodulatory therapy may lead to modulation of the host immune system. It may enhance/restore innate immunity against HBV (as toll-like-receptors and cytosolic retinoic acid inducible gene I agonist). Others may induce adaptive immunity as checkpoint inhibitors, therapeutic HBV vaccines including protein (HBsAg/preS and hepatitis B core antigen), monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV. Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure. Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage. The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues. Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.
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Affiliation(s)
- Iman Ibrahim Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Samia M Sami
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Somaia I Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Ghada A Abdel-Latif
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Fatma A Shaaban
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Walaa A Fouad
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Aida M Abdelmohsen
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Hala M Raslan
- Department of Internal Medicine, National Research Centre, Giza 12411, Dokki, Egypt
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17
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Walker A, Schwarz T, Brinkmann-Paulukat J, Wisskirchen K, Menne C, Alizei ES, Kefalakes H, Theissen M, Hoffmann D, Schulze zur Wiesch J, Maini MK, Cornberg M, Kraft ARM, Keitel V, Bock HH, Horn PA, Thimme R, Wedemeyer H, Heinemann FM, Luedde T, Neumann-Haefelin C, Protzer U, Timm J. Immune escape pathways from the HBV core 18-27 CD8 T cell response are driven by individual HLA class I alleles. Front Immunol 2022; 13:1045498. [PMID: 36439181 PMCID: PMC9686862 DOI: 10.3389/fimmu.2022.1045498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
Background and aims There is growing interest in T cell-based immune therapies for a functional cure of chronic HBV infection including check-point inhibition, T cell-targeted vaccines or TCR-grafted effector cells. All these approaches depend on recognition of HLA class I-presented viral peptides. The HBV core region 18-27 is an immunodominant target of CD8+ T cells and represents the prime target for T cell-based therapies. Here, a high-resolution analysis of the core18-27 specific CD8+ T cell and the selected escape pathways was performed. Methods HLA class I typing and viral sequence analyses were performed for 464 patients with chronic HBV infection. HBV-specific CD8+ T-cell responses against the prototype and epitope variants were characterized by flow cytometry. Results Consistent with promiscuous presentation of the core18-27 epitope, antigen-specific T cells were detected in patients carrying HLA-A*02:01, HLA-B*35:01, HLA-B*35:03 or HLA-B*51:01. Sequence analysis confirmed reproducible selection pressure on the core18-27 epitope in the context of these alleles. Interestingly, the selected immune escape pathways depend on the presenting HLA-class I-molecule. Although cross-reactive T cells were observed, some epitope variants achieved functional escape by impaired TCR-interaction or disturbed antigen processing. Of note, selection of epitope variants was exclusively observed in HBeAg negative HBV infection and here, detection of variants associated with significantly greater magnitude of the CD8 T cell response compared to absence of variants. Conclusion The core18-27 epitope is highly variable and under heavy selection pressure in the context of different HLA class I-molecules. Some epitope variants showed evidence for impaired antigen processing and reduced presentation. Viruses carrying such escape substitutions will be less susceptible to CD8+ T cell responses and should be considered for T cell-based therapy strategies.
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Affiliation(s)
- Andreas Walker
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tatjana Schwarz
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Janine Brinkmann-Paulukat
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Karin Wisskirchen
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Site Munich, Munich, Germany
| | - Christopher Menne
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Elahe Salimi Alizei
- Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Helenie Kefalakes
- Institute of Virology, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Martin Theissen
- Research Group Bioinformatics, Faculty of Biology, University of Duisburg-Essen, Essen, Germany
| | - Daniel Hoffmann
- Research Group Bioinformatics, Faculty of Biology, University of Duisburg-Essen, Essen, Germany
| | - Julian Schulze zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Site Hamburg, Hamburg, Germany
| | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Site Hannover, Hannover, Germany
| | - Anke RM Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Site Hannover, Hannover, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Hans H. Bock
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Peter A. Horn
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Site Hannover, Hannover, Germany
| | - Falko M. Heinemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Site Munich, Munich, Germany
| | - Jörg Timm
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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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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Odenwald MA, Paul S. Viral hepatitis: Past, present, and future. World J Gastroenterol 2022; 28:1405-1429. [PMID: 35582678 PMCID: PMC9048475 DOI: 10.3748/wjg.v28.i14.1405] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 03/04/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
Each hepatitis virus-Hepatitis A, B, C, D, E, and G-poses a distinct scenario to the patient and clinician alike. Since the discovery of each virus, extensive knowledge regarding epidemiology, virologic properties, and the natural clinical and immunologic history of acute and chronic infections has been generated. Basic discoveries about host immunologic responses to acute and chronic viral infections, combined with virologic data, has led to vaccines to prevent Hepatitis A, B, and E and highly efficacious antivirals for Hepatitis B and C. These therapeutic breakthroughs are transforming the fields of hepatology, transplant medicine in general, and public and global health. Most notably, there is even an ambitious global effort to eliminate chronic viral hepatitis within the next decade. While attainable, there are many barriers to this goal that are being actively investigated in basic and clinical labs on the local, national, and international scales. Herein, we discuss pertinent clinical information and recent organizational guidelines for each of the individual hepatitis viruses while also synthesizing this information with the latest research to focus on exciting future directions for each virus.
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Affiliation(s)
- Matthew August Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, Center for Liver Diseases, University of Chicago, Chicago, IL 60637, United States
| | - Sonali Paul
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, Center for Liver Diseases, University of Chicago, Chicago, IL 60637, United States
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Ganesan M, Wang W, Mathews S, Makarov E, New-Aaron M, Dagur RS, Malo A, Protzer U, Kharbanda KK, Casey CA, Poluektova LY, Osna NA. Ethanol attenuates presentation of cytotoxic T-lymphocyte epitopes on hepatocytes of HBV-infected humanized mice. Alcohol Clin Exp Res 2022; 46:40-51. [PMID: 34773268 PMCID: PMC8799491 DOI: 10.1111/acer.14740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Weimin Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Saumi Mathews
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Edward Makarov
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Raghubendra Singh Dagur
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Antje Malo
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Centre for Infection Research (DZIF), Munich, Hamburg, and Heidelberg partner sites, Germany
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Carol A Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
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21
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Tan AT, Bertoletti A. HBV-HCC treatment with mRNA electroporated HBV-TCR T cells. IMMUNOTHERAPY ADVANCES 2021; 2:ltab026. [PMID: 35919490 PMCID: PMC9327102 DOI: 10.1093/immadv/ltab026] [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: 11/10/2021] [Accepted: 12/22/2021] [Indexed: 11/28/2022] Open
Abstract
Hepatocellular carcinoma is a significant global health challenge with steadily increasing incidence in the East Asia region. While both Hepatitis C and B virus infections account for the majority of HCC cases, the advent of potent antivirals against HCV infection has biased the aetiology towards chronic HBV infection that at the moment remains without an effective cure. For this reason, HBV-HCC remains a persistent global problem. Treatment options for intermediate to advanced stages of HBV-HCC remain limited, hence novel therapeutic strategies are required to fulfil this medical need. Following the considerable success of adoptive T-cell immunotherapy against B-cell malignancies, it is conceivable to envision whether the same could be achieved against HBV-HCC. In this review, we describe the development of T-cell therapy strategies for HBV-HCC and discuss the safety and the efficacy of the strategies in terms of the direct killing of tumour cells and the other alterations possibly induced by the action of the T cells.
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Affiliation(s)
- Anthony T Tan
- Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Antonio Bertoletti
- Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Agency for Science and Technology (A∗STAR), Singapore
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22
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Abdulhaqq S, Ventura AB, Reed JS, Bashirova AA, Bateman KB, McDonald E, Wu HL, Greene JM, Schell JB, Morrow D, Wisskirchen K, Martin JN, Deeks SG, Carrington M, Protzer U, Früh K, Hansen SG, Picker LJ, Sacha JB, Bimber BN. Identification and Characterization of Antigen-Specific CD8 + T Cells Using Surface-Trapped TNF-α and Single-Cell Sequencing. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2913-2921. [PMID: 34810222 PMCID: PMC9124229 DOI: 10.4049/jimmunol.2100535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 10/15/2021] [Indexed: 12/31/2022]
Abstract
CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and β-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.
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Affiliation(s)
- Shaheed Abdulhaqq
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Abigail B Ventura
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Jason S Reed
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Arman A Bashirova
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Katherine B Bateman
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Eric McDonald
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Helen L Wu
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Justin M Greene
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - John B Schell
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - David Morrow
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Karin Wisskirchen
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich, Munich, Germany
| | - Jeffrey N Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Steven G Deeks
- HIV/AIDS Program, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Mary Carrington
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA; and
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich, Munich, Germany
| | - Klaus Früh
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Louis J Picker
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR
| | - Jonah B Sacha
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR;
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR
| | - Benjamin N Bimber
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR
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23
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Schreiber S, Honz M, Mamozai W, Kurktschiev P, Schiemann M, Witter K, Moore E, Zielinski C, Sette A, Protzer U, Wisskirchen K. Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors. Mol Ther Methods Clin Dev 2021; 23:476-489. [PMID: 34853796 PMCID: PMC8605085 DOI: 10.1016/j.omtm.2021.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/27/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.
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24
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Altstetter SM, Quitt O, Pinci F, Hornung V, Lucko AM, Wisskirchen K, Jung S, Protzer U. Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity. Cells 2021; 10:3253. [PMID: 34831475 PMCID: PMC8619298 DOI: 10.3390/cells10113253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 11/22/2022] Open
Abstract
Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach.
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Affiliation(s)
- Sebastian Maximilian Altstetter
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
| | - Oliver Quitt
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
| | - Francesca Pinci
- Gene Center and Department of Biochemistry, Ludwig-Maximilians—University Munich, 81377 Munich, Germany; (F.P.); (V.H.)
| | - Veit Hornung
- Gene Center and Department of Biochemistry, Ludwig-Maximilians—University Munich, 81377 Munich, Germany; (F.P.); (V.H.)
| | - Aaron Michael Lucko
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
| | - Karin Wisskirchen
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
| | - Stephanie Jung
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
- Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany; (S.M.A.); (O.Q.); (A.M.L.); (K.W.)
- German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany
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25
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Quitt O, Luo S, Meyer M, Xie Z, Golsaz-Shirazi F, Loffredo-Verde E, Festag J, Bockmann JH, Zhao L, Stadler D, Chou WM, Tedjokusumo R, Wettengel JM, Ko C, Noeßner E, Bulbuc N, Shokri F, Lüttgau S, Heikenwälder M, Bohne F, Moldenhauer G, Momburg F, Protzer U. T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice. J Hepatol 2021; 75:1058-1071. [PMID: 34171437 DOI: 10.1016/j.jhep.2021.06.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 05/25/2021] [Accepted: 06/02/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients. METHODS We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study in vivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells. RESULTS The 2 T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. In vivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden. CONCLUSION This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC. LAY SUMMARY T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.
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Affiliation(s)
- Oliver Quitt
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Shanshan Luo
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Marten Meyer
- Antigen Presentation and T/NK Cell Activation Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Centre, Heidelberg, Germany
| | - Zhe Xie
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Eva Loffredo-Verde
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Julia Festag
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Jan Hendrik Bockmann
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research (DZIF), Munich and Hamburg Partner sites, Germany; Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lili Zhao
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Daniela Stadler
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Wen-Min Chou
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Raindy Tedjokusumo
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Jochen Martin Wettengel
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Chunkyu Ko
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Elfriede Noeßner
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Nadja Bulbuc
- Antigen Presentation and T/NK Cell Activation Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Centre, Heidelberg, Germany
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sandra Lüttgau
- Department of Translational Immunology, German Cancer Research Centre, Heidelberg, Germany
| | - Mathias Heikenwälder
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Felix Bohne
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | - Gerhard Moldenhauer
- Department of Translational Immunology, German Cancer Research Centre, Heidelberg, Germany
| | - Frank Momburg
- Antigen Presentation and T/NK Cell Activation Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Centre, Heidelberg, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research (DZIF), Munich and Hamburg Partner sites, Germany.
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26
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Lang-Meli J, Neumann-Haefelin C, Thimme R. Immunotherapy and therapeutic vaccines for chronic HBV infection. Curr Opin Virol 2021; 51:149-157. [PMID: 34710645 DOI: 10.1016/j.coviro.2021.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 09/08/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health burden causing severe complications like liver cirrhosis or hepatocellular carcinoma. Curative treatment options are lacking. Therefore, there is an urgent need for new therapeutic options. Immunotherapy with the goal to restore dysfunctional HBV-specific T cell immunity is an interesting new therapeutic strategy. Based on current evidence on dysfunction of the HBV-specific CD8+ T cell response in chronic HBV infection, we will review the growing field of immunotherapeutic approaches for treatment of chronic HBV infection. The review will focus on therapies targeting T cells and will cover checkpoint inhibitors, T cell engineering, Toll-like receptor agonists and therapeutic vaccination.
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Affiliation(s)
- Julia Lang-Meli
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany; IMM-PACT Programm, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.
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27
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Dietz CA, Wedemeyer H. [Vaccination against hepatitis B as prevention for hepatocellular carcinoma]. DER ONKOLOGE : ORGAN DER DEUTSCHEN KREBSGESELLSCHAFT E.V 2021; 28:15-22. [PMID: 34658542 PMCID: PMC8511853 DOI: 10.1007/s00761-021-01036-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 09/06/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Chronic infection with the hepatitis B virus (HBV) is an important risk factor for the development of hepatocellular carcinoma (HCC). Even though treatment options for HCC are constantly improving, preventive measures must not be neglected. CONCLUSION The vaccination against hepatitis B has proven effective in preventing infection with HBV. As shown more than 20 years ago in Taiwan, vaccination programs lower not only the prevalence of HBsAg carriers but also decrease the incidence of HCC. By achieving immunity against HBV, the infection with hepatitis D virus can also be prevented. This is important in the light of HCC prevention as HBV/HDV coinfection is known to drastically increase the risk of HCC. New approaches aim for the development of therapeutic HBV vaccines ideally curing chronic infections. Beside the prevention of infections, it is pivotal to detect existing infections. This helps to minimize the HCC risk by initiating treatment in those who need it.
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Affiliation(s)
- Christopher A. Dietz
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Deutschland
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Deutschland
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28
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Klopp A, Schreiber S, Kosinska AD, Pulé M, Protzer U, Wisskirchen K. Depletion of T cells via Inducible Caspase 9 Increases Safety of Adoptive T-Cell Therapy Against Chronic Hepatitis B. Front Immunol 2021; 12:734246. [PMID: 34691041 PMCID: PMC8527178 DOI: 10.3389/fimmu.2021.734246] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/17/2021] [Indexed: 12/18/2022] Open
Abstract
T-cell therapy with T cells that are re-directed to hepatitis B virus (HBV)-infected cells by virus-specific receptors is a promising therapeutic approach for treatment of chronic hepatitis B and HBV-associated cancer. Due to the high number of target cells, however, side effects such as cytokine release syndrome or hepatotoxicity may limit safety. A safeguard mechanism, which allows depletion of transferred T cells on demand, would thus be an interesting means to increase confidence in this approach. In this study, T cells were generated by retroviral transduction to express either an HBV-specific chimeric antigen receptor (S-CAR) or T-cell receptor (TCR), and in addition either inducible caspase 9 (iC9) or herpes simplex virus thymidine kinase (HSV-TK) as a safety switch. Real-time cytotoxicity assays using HBV-replicating hepatoma cells as targets revealed that activation of both safety switches stopped cytotoxicity of S-CAR- or TCR-transduced T cells within less than one hour. In vivo, induction of iC9 led to a strong and rapid reduction of transferred S-CAR T cells adoptively transferred into AAV-HBV-infected immune incompetent mice. One to six hours after injection of the iC9 dimerizer, over 90% reduction of S-CAR T cells in the blood and the spleen and of over 99% in the liver was observed, thereby limiting hepatotoxicity and stopping cytokine secretion. Simultaneously, however, the antiviral effect of S-CAR T cells was diminished because remaining S-CAR T cells were mostly non-functional and could not be restimulated with HBsAg. A second induction of iC9 was only able to deplete T cells in the liver. In conclusion, T cells co-expressing iC9 and HBV-specific receptors efficiently recognize and kill HBV-replicating cells. Induction of T-cell death via iC9 proved to be an efficient means to deplete transferred T cells in vitro and in vivo containing unwanted hepatotoxicity.
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MESH Headings
- Adoptive Transfer/adverse effects
- Animals
- Caspase 9/biosynthesis
- Caspase 9/genetics
- Cell Death
- Cell Line
- Coculture Techniques
- Cytokines/metabolism
- Cytotoxicity, Immunologic
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Disease Models, Animal
- Enzyme Induction
- Female
- Hepatitis B Antigens/immunology
- Hepatitis B virus/immunology
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/metabolism
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Humans
- Interleukin Receptor Common gamma Subunit/genetics
- Interleukin Receptor Common gamma Subunit/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Simplexvirus/enzymology
- Simplexvirus/genetics
- T-Lymphocytes/enzymology
- T-Lymphocytes/immunology
- T-Lymphocytes/pathology
- T-Lymphocytes/transplantation
- Thymidine Kinase/genetics
- Thymidine Kinase/metabolism
- Transduction, Genetic
- Mice
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Affiliation(s)
- Alexandre Klopp
- School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Sophia Schreiber
- School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Anna D. Kosinska
- School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Martin Pulé
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Ulrike Protzer
- School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Karin Wisskirchen
- School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
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29
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Abstract
Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
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30
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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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31
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Abstract
PURPOSE OF REVIEW Antiviral therapy for chronic hepatitis B infection is rarely curative, thus research in HBV cure strategies is a priority. Drug development and testing has been hampered by the lack of robust cell culture systems and small animal models. This review summarizes existing models for HBV cure research and focuses on recent developments since 2017 until today. RECENT FINDINGS The field has progressed in the development of cell culture and animal models to study HBV. Although early cell culture systems relied on transfection of HBV genomes in hepatoma cell lines, novel models expressing the entry receptor for HBV are susceptible to infection. Improved culture conditions for primary human hepatocytes, the primary target of HBV, have enabled the screening and validation of novel antivirals. Mouse models grafted with partially humanized livers are suitable for testing viral entry inhibitors or direct acting antivirals, and can be reconstituted with human immune cells to analyze immunotherapies. Other immunocompetent models include mice transduced with HBV genomes or woodchucks infected with their native hepatitis virus. SUMMARY Model systems for HBV research have helped lay the groundwork for the development and optimization of antiviral and immune-based therapeutic approaches that are now moving to clinical trials.
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32
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Rapid and Robust Continuous Purification of High-Titer Hepatitis B Virus for In Vitro and In Vivo Applications. Viruses 2021; 13:v13081503. [PMID: 34452368 PMCID: PMC8402639 DOI: 10.3390/v13081503] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/06/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Available treatments for hepatitis B can control the virus but are rarely curative. This led to a global initiative to design new curative therapies for the 257 million patients affected. Discovery and development of these new therapies is contingent upon functional in vitro and in vivo hepatitis B virus (HBV) infection models. However, low titer and impurity of conventional HBV stocks reduce significance of in vitro infections and moreover limit challenge doses in current in vivo models. Therefore, there is a critical need for a robust, simple and reproducible protocol to generate high-purity and high-titer infectious HBV stocks. Here, we outline a three-step protocol for continuous production of high-quality HBV stocks from supernatants of HBV-replicating cell lines. This purification process takes less than 6 h, yields to high-titer stocks (up to 1 × 1011 enveloped, DNA-containing HBV particles/mL each week), and is with minimal equipment easily adaptable to most laboratory settings.
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33
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Abstract
Infectious hepatitis in pregnancy is clinically significant in both the acute and chronic phases. Here, we review the perinatal implications of chronic hepatitis B and C and acute hepatitis A and E. Familiarity with screening, transmission, diagnosis, and management of infectious hepatitis is of ongoing importance during obstetric care, as these diseases are endemic in much of the world. Pregnancy and interpregnancy care provide opportunities to prevent infection and transmission of hepatitis.
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34
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Tsounis EP, Tourkochristou E, Mouzaki A, Triantos C. Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. World J Gastroenterol 2021; 27:2727-2757. [PMID: 34135551 PMCID: PMC8173382 DOI: 10.3748/wjg.v27.i21.2727] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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35
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Dash PK, Gorantla S, Poluektova L, Hasan M, Waight E, Zhang C, Markovic M, Edagwa B, Machhi J, Olson KE, Wang X, Mosley RL, Kevadiya B, Gendelman HE. Humanized Mice for Infectious and Neurodegenerative disorders. Retrovirology 2021; 18:13. [PMID: 34090462 PMCID: PMC8179712 DOI: 10.1186/s12977-021-00557-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.
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Affiliation(s)
- Prasanta K Dash
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Santhi Gorantla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Larisa Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahmudul Hasan
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Emiko Waight
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chen Zhang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Milica Markovic
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Benson Edagwa
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Katherine E Olson
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Xinglong Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Bhavesh Kevadiya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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36
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Ma Y, Ou J, Lin T, Chen L, Chen J, Wang M. Next Generation Sequencing-Based Identification of T-Cell Receptors for Immunotherapy Against Hepatocellular Carcinoma. Hepatol Commun 2021; 5:1106-1119. [PMID: 34141993 PMCID: PMC8183181 DOI: 10.1002/hep4.1697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/19/2021] [Accepted: 02/04/2021] [Indexed: 01/02/2023] Open
Abstract
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains a global health concern, and HBV proteins may be ideal targets for T cell-based immunotherapy for HCC. There is a need for fast and efficient identification of HBV-specific T cell receptors (TCRs) for the development of TCR-transduced T (TCR-T) cell-based immunotherapy. Two widely employed TCR identification approaches, T cell clonal expansion and single-cell sequencing, involve a TCR singularization process for the direct identification of Vα and Vβ pairs of TCR chains. Clonal expansion of T cells is well known to have tedious time and effort requirements due to the use of T cell cultures, whereas single-cell sequencing is limited by the requirements of cell sorting and the preparation of a single-cell immune-transcriptome library as well as the massive cost of the whole procedure. Here, we present a next-generation sequencing (NGS)-based HBV-specific TCR identification that does not require the TCR singularization process. Conclusion: Two pairing strategies, ranking-based strategy and α-β chain mixture-based strategy, have proved to be useful for NGS-based TCR identification, particularly for polyclonal T cells purified by a peptide-major histocompatibility complex (pMHC) multimer-based approach. Functional evaluation confirmed the specificity and avidity of two identified HBV-specific TCRs, which may potentially be used to produce TCR-T cells to treat patients with HBV-related HCC.
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Affiliation(s)
- Yipeng Ma
- Department of Research and DevelopmentShenzhen Institute for Innovation and Translational MedicineShenzhen International Biological Valley-Life Science Industrial ParkShenzhenChina
| | - Jiayu Ou
- Department of Research and DevelopmentShenzhen Institute for Innovation and Translational MedicineShenzhen International Biological Valley-Life Science Industrial ParkShenzhenChina
| | - Tong Lin
- Department of Research and DevelopmentShenzhen Institute for Innovation and Translational MedicineShenzhen International Biological Valley-Life Science Industrial ParkShenzhenChina
| | - Lei Chen
- Department of Research and DevelopmentShenzhen Institute for Innovation and Translational MedicineShenzhen International Biological Valley-Life Science Industrial ParkShenzhenChina
| | - Junhui Chen
- Intervention and Cell Therapy CenterPeking University Shenzhen HospitalShenzhenChina
| | - Mingjun Wang
- Department of Research and DevelopmentShenzhen Institute for Innovation and Translational MedicineShenzhen International Biological Valley-Life Science Industrial ParkShenzhenChina
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37
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Maepa MB, Bloom K, Ely A, Arbuthnot P. Hepatitis B virus: promising drug targets and therapeutic implications. Expert Opin Ther Targets 2021; 25:451-466. [PMID: 33843412 DOI: 10.1080/14728222.2021.1915990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Current therapy for infection with hepatitis B virus (HBV) rarely clears the virus, and viremia commonly resurges following treatment withdrawal. To prevent serious complications of the infection, research has been aimed at identifying new viral and host targets that can be exploited to inactivate HBV replication.Areas covered: This paper reviews the use of these new molecular targets to advance anti-HBV therapy. Emphasis is on appraising data from pre-clinical and early clinical studies described in journal articles published during the past 10 years and available from PubMed.Expert opinion: The wide range of viral and host factors that can be targeted to disable HBV is impressive and improved insight into HBV molecular biology continues to provide the basis for new drug design. In addition to candidate therapies that have direct or indirect actions on HBV covalently closed circular DNA (cccDNA), compounds that inhibit HBsAg secretion, viral entry, destabilize viral RNA and effect enhanced immune responses to HBV show promise. Preclinical and clinical evaluation of drug candidates, as well as investigating use of treatment combinations, are encouraging. The field is poised at an interesting stage and indications are that reliably achieving functional cure from HBV infection is a tangible goal.
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Affiliation(s)
- Mohube Betty Maepa
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Kristie Bloom
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Abdullah Ely
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Patrick Arbuthnot
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
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38
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Xiao D, Wang J, Chen Z, Jin X, Xie Y, Yan D, Yang J. Restricted TcR β chain CDR3 clonotype is associated with resolved acute hepatitis B subjects. BMC Infect Dis 2021; 21:111. [PMID: 33485302 PMCID: PMC7825183 DOI: 10.1186/s12879-021-05816-2] [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: 08/16/2020] [Accepted: 01/17/2021] [Indexed: 02/08/2023] Open
Abstract
Background T cells play an important role in the prognosis of hepatitis B virus (HBV) infection, and are involved in the seroconversion of a patient from HBsAb negative to positive. To compare the T-cell receptor β-chain variable region (TcRBV) complementarity-determining region 3 (CDR3) in subjects with or without hepatitis B surface antigen (HBsAg) convert to hepatitis B surface antibody (HBsAb), the TcRBV was determined using high throughput sequencing (HTS). Methods The clonotype and diversity of CDR3 in peripheral blood mononuclear cells of subjects with resolved acute hepatitis B (AHB, HBsAb+, HBsAg-) (n = 5), chronic hepatitis B (CHB, HBsAb-, HBsAg+) (n = 5), and healthy controls (HC, HBsAb-, HBsAg-) (n = 3) were determined and analyzed using HTS (MiSeq). Results The overlapping rate of CDR3 clones of any two samples in AHB group was 2.00% (1.74% ~ 2.30%), CHB group was 1.77% (1.43% ~ 2.61%), and HC group was 1.82% (1.62% ~ 2.12%), and there was no significant difference among the three groups by Kruskal-Wallis H test. However, among the top 10 cumulative frequencies of clonotypes, only the frequency of clonotype (TcRBV20–1/BD1/BJ1–2) in AHB group was lower than that of HC group (P < 0.001). Moreover, exclude the 10 top clonotypes, there are 57 markedly different frequency of clones between AHB and CHB groups (18 clones up, 39 clones down), 179 (180–1) different clones between AHB and HC groups, and 134 different clones between CHB and HC groups. With regard to BV and BJ genotypes, there was no significant different frequency among the groups. Furthermore, there was no significant difference in the diversity of TcRBV CDR3 among the three groups (P > 0.05). Conclusions Thus, there are 57 TcRBV clonotypes that may be related to HBsAg seroconversion of AHB subjects, but the diversity of TcRBV CDR3 is not significantly related to the HBsAb positive status. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-021-05816-2.
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Affiliation(s)
- Dangsheng Xiao
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, Department of Geriatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China
| | - Ju Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China
| | - Zhitao Chen
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China
| | - Xiuyuan Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China
| | - Yirui Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China.
| | - Jiezuan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310003, Hangzhou, China.
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39
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Fergusson JR, Wallace Z, Connolly MM, Woon AP, Suckling RJ, Hine DW, Barber C, Bunjobpol W, Choi B, Crespillo S, Dembek M, Dieckmann N, Donoso J, Godinho LF, Grant T, Howe D, McCully ML, Perot C, Sarkar A, Seifert FU, Singh PK, Stegmann KA, Turner B, Verma A, Walker A, Leonard S, Maini MK, Wiederhold K, Dorrell L, Simmons R, Knox A. Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells. Hepatology 2020; 72:1528-1540. [PMID: 32770836 PMCID: PMC7702151 DOI: 10.1002/hep.31503] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/17/2020] [Accepted: 07/01/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA). APPROACH AND RESULTS ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. CONCLUSIONS The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.
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MESH Headings
- Antibodies, Monoclonal/genetics
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- CD3 Complex/antagonists & inhibitors
- Cell Line, Tumor
- Epitopes/immunology
- HLA-A2 Antigen/immunology
- Hepatitis B Surface Antigens/immunology
- Hepatitis B virus/immunology
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/virology
- Hepatocytes
- Humans
- Immunoconjugates/genetics
- Immunoconjugates/immunology
- Immunoconjugates/pharmacology
- Immunoconjugates/therapeutic use
- Lymphocyte Activation/drug effects
- Primary Cell Culture
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/therapeutic use
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/immunology
- Recombinant Fusion Proteins/pharmacology
- Recombinant Fusion Proteins/therapeutic use
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Dawn Howe
- Immunocore LtdAbingdonUnited Kingdom
| | | | | | | | | | | | - Kerstin A. Stegmann
- Division of Infection and ImmunityInstitute of Immunity and TransplantationUniversity College LondonLondonUnited Kingdom
| | | | | | | | | | - Mala K. Maini
- Division of Infection and ImmunityInstitute of Immunity and TransplantationUniversity College LondonLondonUnited Kingdom
| | | | - Lucy Dorrell
- Immunocore LtdAbingdonUnited Kingdom
- Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
- Oxford NIHR Biomedical Research CentreUniversity of OxfordOxfordUnited Kingdom
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40
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Dandri M, Petersen J. cccDNA Maintenance in Chronic Hepatitis B - Targeting the Matrix of Viral Replication. Infect Drug Resist 2020; 13:3873-3886. [PMID: 33149632 PMCID: PMC7605611 DOI: 10.2147/idr.s240472] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma, despite an effective prophylactic vaccine and well-tolerated and effective oral antivirals. Both the incapacity of the immune system to clear hepatitis B virus (HBV) infection and the unique replication strategies adopted by HBV are considered key determinants of HBV chronicity. In this regard, the formation of the HBV DNA minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, is essential not only for the production of all viral proteins but also for HBV persistence even after long-term antiviral therapy. Licensed polymerase inhibitors target the HBV reverse transcriptase activity, control the disease with long-term therapy but fail to eliminate the cccDNA. Consequently, the production of viral RNAs and proteins, including the hepatitis B surface antigen (HBsAg), is not abolished. Novel therapeutic efforts that are in the pipeline for early clinical trials explore novel targets and molecules. Such therapeutic efforts focus on achieving a functional cure, which is defined by the loss of HBsAg and undetectable HBV DNA levels in serum. Since a true cure of HBV infection requires the elimination of the cccDNA from infected cells, comprehension of the mechanisms implicated in cccDNA biogenesis, regulation and stability appears necessary to achieve HBV eradication. In this review, we will summarize the state of knowledge on cccDNA metabolism, focusing on insights suggesting potential weak points of the cccDNA that may be key for the development of therapeutic approaches and design of clinical trials aiming at lowering cccDNA loads and activity.
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Affiliation(s)
- Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg - Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Hamburg-Luebeck-Borstel-Riems Site, Germany
| | - Joerg Petersen
- Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, University of Hamburg, Hamburg, Germany
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41
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Ivics Z, Amberger M, Zahn T, Hildt E. [Immunotherapies for the treatment of chronic hepatitis B virus infections-an overview with a focus on CAR T cells]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63:1357-1364. [PMID: 32995895 PMCID: PMC7647999 DOI: 10.1007/s00103-020-03223-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/09/2020] [Indexed: 11/25/2022]
Abstract
Derzeit leiden weltweit mehr als 250 Mio. Menschen an einer chronischen Infektion mit Hepatitis-B-Virus (CHB). Eine chronische Infektion geht mit einem erhöhten Risiko der Entwicklung einer Leberfibrose/-zirrhose und der Entwicklung eines hepatozellulären Karzinoms einher. Derzeit versterben jährlich ca. 0,8–1 Mio. Menschen an den Folgen einer chronischen Infektion. Eine Schwierigkeit bei der Therapie der CHB besteht darin, dass das virale Genom in Form eines Minichroms sehr lange Zeit persistieren kann bzw. dass virale Sequenzen in das Wirtsgenom inserieren können. Chronische Infektionen sind häufig durch funktionale Defekte der zellulären Immunantwort, insbesondere der T‑Zell-Antwort charakterisiert, was einer Eliminierung HBV-infizierter Zellen entgegensteht. Immuntherapien zur Heilung der CHB zielen daher darauf ab, die antivirale Funktion der zellulären Immunantwort wiederherzustellen. Im Rahmen dieser Übersicht sollen verschiedene aktuelle Ansätze zur Immuntherapie der CHB beschrieben werden, insbesondere gentechnisch veränderte autologe T‑Zellen als mögliches Werkzeug zur Therapie der CHB. Weiterhin werden die Modulation von Checkpointinhibitoren der Immunantwort, metabolische T‑Zelltherapien und die therapeutische Impfung zur Stimulation der T‑Zellantwort als immuntherapeutische Strategien zur Therapie der chronischen HBV-Infektion zusammenfassend dargestellt.
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Affiliation(s)
- Zoltan Ivics
- Abteilung Biotechnologie, Paul-Ehrlich-Institut, Langen, Deutschland
| | | | - Tobias Zahn
- Abteilung Virologie, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225, Langen, Deutschland
| | - Eberhard Hildt
- Abteilung Virologie, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225, Langen, Deutschland.
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Abstract
Hepatitis B virus (HBV) infection causes chronic hepatitis and has long term complications. Individuals ever infected with HBV are at risk of viral reactivation under certain circumstances. This review summarizes studies on HBV persistence and reactivation with a focus on the definitions and mechanisms. Emphasis is placed on the interplay between HBV replication and host immunity as this interplay determines the patterns of persistence following viral acquisition. Chronic infections exhibit as overt persistence when a defective immune response fails to control the viral replication. The HBV genome persists despite an immune response in the form of covalently closed circular DNA (cccDNA) and integrated DNA, rendering an occult state of viral persistence in individuals whose infection appears to have been resolved. We have described HBV reactivation that occurs because of changes in the virus or the immune system. This review aims to raise the awareness of HBV reactivation and to understand how HBV persists, and discusses the risks of HBV reactivation in a variety of clinical settings.
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Affiliation(s)
- Yu Shi
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, China
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, China
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43
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Kothari A, Singh V, Nath UK, Kumar S, Rai V, Kaushal K, Omar BJ, Pandey A, Jain N. Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat? BIOLOGY 2020; 9:E243. [PMID: 32846906 PMCID: PMC7563789 DOI: 10.3390/biology9090243] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/28/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic threat with more than 11.8 million confirmed cases and more than 0.5 million deaths as of 3 July 2020. Given the lack of definitive pharmaceutical interventions against SARS-CoV-2, multiple therapeutic strategies and personal protective applications are being used to reduce the risk of high mortality and community spread of this infection. Currently, more than a hundred vaccines and/or alternative therapeutic regimens are in clinical trials, and some of them have shown promising results in improving the immune cell environment and controlling the infection. In this review, we discussed high-performance multi-directory strategies describing the uncontrolled deregulation of the host immune landscape associated with coronavirus disease (COVID-19) and treatment strategies using an anti-neoplastic regimen. We also followed selected current treatment plans and the most important on-going clinical trials and their respective outcomes for blocking SARS-CoV-2 pathogenesis through regenerative medicine, such as stem cell therapy, chimeric antigen receptors, natural killer (NK) cells, extracellular vesicular-based therapy, and others including immunomodulatory regimens, anti-neoplastic therapy, and current clinical vaccine therapy.
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Affiliation(s)
- Ashish Kothari
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh 249203, India; (A.K.); (V.S.)
| | - Vanya Singh
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh 249203, India; (A.K.); (V.S.)
| | - Uttam Kumar Nath
- Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh 249203, India;
| | - Sandeep Kumar
- School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Vineeta Rai
- Department of Entomology & Plant Pathology, North Carolina State University, Raleigh, NC 27695, USA;
| | - Karanvir Kaushal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh 249203, India;
| | - Balram Ji Omar
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh 249203, India; (A.K.); (V.S.)
| | - Atul Pandey
- Department of Ecology, Evolution and Behavior, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Neeraj Jain
- Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh 249203, India;
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44
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Tham CYL, Kah J, Tan AT, Volz T, Chia A, Giersch K, Ladiges Y, Loglio A, Borghi M, Sureau C, Lampertico P, Lütgehetmann M, Dandri M, Bertoletti A. Hepatitis Delta Virus Acts as an Immunogenic Adjuvant in Hepatitis B Virus-Infected Hepatocytes. CELL REPORTS MEDICINE 2020; 1:100060. [PMID: 33205065 PMCID: PMC7659593 DOI: 10.1016/j.xcrm.2020.100060] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/30/2020] [Accepted: 07/02/2020] [Indexed: 12/15/2022]
Abstract
Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) to complete its infection cycle and causes severe hepatitis, with limited therapeutic options. To determine the prospect of T cell therapy in HBV/HDV co-infection, we study the impact of HDV on viral antigen processing and presentation. Using in vitro models of HBV/HDV co-infection, we demonstrate that HDV boosts HBV epitope presentation, both in HBV/HDV co-infected and neighboring mono-HBV-infected cells through the upregulation of the antigen processing pathway mediated by IFN-β/λ. Liver biopsies of HBV/HDV patients confirm this upregulation. We then validate in vitro and in a HBV/HDV preclinical mouse model that HDV infection increases the anti-HBV efficacy of T cells with engineered T cell receptors. Thus, by unveiling the effect of HDV on HBV antigen presentation, we provide a framework to better understand HBV/HDV immune pathology, and advocate the utilization of engineered HBV-specific T cells as a potential treatment for HBV/HDV co-infection.
HDV infection affects viral antigen processing and presentation HDV boosts HBV epitope presentation on HBV/HDV and mono-HBV-infected hepatocytes Anti-HBV efficacy of T cells engineered with T cell receptors is enhanced by HDV
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Affiliation(s)
- Christine Y L Tham
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.,Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Janine Kah
- Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anthony T Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
| | - Tassilo Volz
- Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Adeline Chia
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
| | - Katja Giersch
- Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yvonne Ladiges
- Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandro Loglio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A.M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Marta Borghi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A.M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Camille Sureau
- Institut National de la Transfusion Sanguine, INSERM U1134, CNRS, Paris
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - Division of Gastroenterology and Hepatology - CRC "A.M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.,University of Milan, Milan, Italy
| | - Marc Lütgehetmann
- Institute of Microbiology, Virology, and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems Partner Site, Hamburg, Germany
| | - Maura Dandri
- Medical Department, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems Partner Site, Hamburg, Germany
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.,Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (ASTAR), Singapore, Singapore
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Nyarko E, Obirikorang C, Owiredu WKBA, Adu EA, Acheampong E, Aidoo F, Ofori E, Addy BS, Asare-Anane H. NTCP gene polymorphisms and hepatitis B virus infection status in a Ghanaian population. Virol J 2020; 17:91. [PMID: 32620148 PMCID: PMC7333392 DOI: 10.1186/s12985-020-01376-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/30/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND SLC10A1 gene codes NTCP, a receptor through which the hepatitis B virus (HBV) gets access into hepatocytes - a stage of the viral cycle necessary for replication. Polymorphism variants of SLC10A1 play roles in HBV infection, viral clearance, treatment outcome, and complications, in diverse ethnic groups and countries. However, no such study has been conducted in the Ghanaian population, a country with HBV endemicity. Therefore, an exploratory study was conducted to investigate the presence of three (3) single nucleotide polymorphisms (SNPs) in the SLC10A1 gene (rs2296651, rs61745930, and rs4646287) and assessed the risk of HBV infection among the Ghanaian population. METHOD Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the presence of the SNPs among 292 participants comprising 146 HBV infected persons as case-subjects and 146 HBV non-infected persons as control-subjects. RESULTS The minor allele frequency (T) of rs2296651 was present in a significantly high proportion of cases compared with the control group (11.6% vs. 3.1%, p < 0.0001). The homozygote recessive variant of rs61745930 was present in 2.7% of the control group and 5.5% of the case group. Moreover, the minor allele frequencies of rs4646287 were 9.3 and 8.2% among the control and the case group, respectively (p = 0.767). Under the dominant (CC) genetic model of inheritance, rs2296651 was found to be protective of HBV infection [OR = 0.18 (0.07-0.44)], whereas under the co-dominant and additive model, rs2296651 was a potential risk factor for HBV infection [OR = 5.2 (95%CI: 2.1-12.8); 3.5 (95%CI: 1.6-7.6], respectively. Variants of rs61745930 and rs4646287 were not associated with HBV infection (p > 0.05). Polymorphisms in SLC10A1, however, did not show any significant association with HBV infectivity (p > 0.05). CONCLUSION The study highlights some polymorphism proof that variants rs2296651, rs61745930, and rs4646287 exist in HBV-infected individuals in Ghana. Although variant rs2296651 was found to be associated with HBV infection, this association warrants more studies. Polymorphisms in SLC10A1 were not associated with HBV infectivity among the Ghanaian population. Further investigation is warranted to assess the offensive role of the relationship between rs2296651 and HBV infectivity.
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Affiliation(s)
- Eric Nyarko
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Christian Obirikorang
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
| | - W K B A Owiredu
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Evans Asamoah Adu
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Emmanuel Acheampong
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.,School of Medical and Health Science, Edith Cowan University, Joondalup, Australia
| | - Freeman Aidoo
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Emmanuel Ofori
- Department of Molecular Medicine, School of Medicine and Dentistry
- , Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | | | - Henry Asare-Anane
- Department of Chemical Pathology, University of Ghana Medical School, Accra, Ghana
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46
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Haque M, Lei F, Xiong X, Ren Y, Kumar A, Das JK, Ren X, Fang D, de Figueiredo P, Yang JM, Song J. Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺. iScience 2020; 23:101333. [PMID: 32679546 PMCID: PMC7364173 DOI: 10.1016/j.isci.2020.101333] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/13/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023] Open
Abstract
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.
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Affiliation(s)
- Mohammad Haque
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Fengyang Lei
- Department of Ophthalmology, Harvard Medical School, Boston, MA 02215, USA
| | - Xiaofang Xiong
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Yijie Ren
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Anil Kumar
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Jugal Kishore Das
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Paul de Figueiredo
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, MREB II, Room 3344, 8447 Riverside Pkwy, Bryan, TX 77807, USA.
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47
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Singh VK, Mishra A, Singh S, Kumar P, Singh M, Jagannath C, Khan A. Emerging Prevention and Treatment Strategies to Control COVID-19. Pathogens 2020; 9:E501. [PMID: 32585805 PMCID: PMC7350294 DOI: 10.3390/pathogens9060501] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 12/18/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has now become a serious global threat after inflicting more than 8 million infections and 425,000 deaths in less than 6 months. Currently, no definitive treatment or prevention therapy exists for COVID-19. The unprecedented rise of this pandemic has rapidly fueled research efforts to discover and develop new vaccines and treatment strategies against this novel coronavirus. While hundreds of vaccines/therapeutics are still in the preclinical or early stage of clinical development, a few of them have shown promising results in controlling the infection. Here, in this review, we discuss the promising vaccines and treatment options for COVID-19, their challenges, and potential alternative strategies.
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Affiliation(s)
- Vipul K. Singh
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.M.); (C.J.)
| | - Abhishek Mishra
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.M.); (C.J.)
| | - Shubhra Singh
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.S.); (M.S.)
| | - Premranjan Kumar
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Manisha Singh
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.S.); (M.S.)
| | - Chinnaswamy Jagannath
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.M.); (C.J.)
| | - Arshad Khan
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.M.); (C.J.)
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48
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Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies. Cells 2020; 9:cells9061471. [PMID: 32560123 PMCID: PMC7349849 DOI: 10.3390/cells9061471] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.
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49
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Abstract
While therapy with T cells engineered with a chimeric antigen receptor (CAR) or a classical T cell receptor (TCR) is revolutionizing cancer treatment, its adoption in infectious diseases has been met with considerable resistance. Can we find its value for the cure of infections?
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Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Agency of Science Technology and Research (ASTAR), Singapore
| | - Anthony Tanoto Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
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50
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Bertoletti A, Tan AT. HBV as a target for CAR or TCR-T cell therapy. Curr Opin Immunol 2020; 66:35-41. [PMID: 32361634 DOI: 10.1016/j.coi.2020.04.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/24/2020] [Accepted: 04/04/2020] [Indexed: 01/02/2023]
Abstract
Engineering HBV-specific T cells utilizing a chimeric antigen receptor (CAR) or a classical T cell receptor (TCR) provides a well characterized, sizeable and functionally intact population of HBV-specific T cells with identical in vitro functionality to the T cells isolated in patients who resolved acute HBV infection. In this review we present evidences of the virological and immunological features of chronic HBV infection, alone or in combination with Hepatitis Delta that might make it amenable for CAR/TCR-T cells therapy.
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Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network (SigN), Agency of Science Technology and Research (ASTAR), Singapore.
| | - Anthony Tanoto Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
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