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Mimura S, Ono M, Fujita K, Takuma K, Nakahara M, Oura K, Tadokoro T, Tani J, Morishita A, Kagawa S, Okano K, Himoto T, Masaki T. Chronic Hepatitis B in Which HBs Antigen Seroclearance Was Induced by Pegpegylated-interferonα-2a after Hepatocellular Carcinoma Treatment with Nucleos(t)ide Analogues: A Five-year Follow-up. Intern Med 2025; 64:225-229. [PMID: 38811223 PMCID: PMC11802215 DOI: 10.2169/internalmedicine.3643-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/11/2024] [Indexed: 05/31/2024] Open
Abstract
We herein report a 40-year-old Japanese man with chronic hepatitis B genotype C (viral load 6.7 Log copies/mL) who developed hepatocellular carcinoma (HCC) despite achieving undetectable hepatitis B virus (HBV)-DNA levels with nucleos(t)ide analog (NA) treatment (entecavir). Notably, his hepatitis B surface antigen (HBsAg) level remained elevated at 388.4 IU/mL. Given the continued risk of carcinogenesis associated with HBsAg positivity, we initiated pegylated interferon (PEG-IFN) therapy one month after HCC surgery. Following three periods of PEG-IFN treatment, HBsAg seroclearance (HBsAg-negative state) was achieved.
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Affiliation(s)
- Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Seiko Kagawa
- Department of Pathology, Faculty of Medicine, Kagawa University, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
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2
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Murugesan G, Paterson RL, Kulkarni R, Ilkow V, Suckling RJ, Connolly MM, Karuppiah V, Pengelly R, Jadhav A, Donoso J, Heunis T, Bunjobpol W, Philips G, Ololade K, Kay D, Sarkar A, Barber C, Raj R, Perot C, Grant T, Treveil A, Walker A, Dembek M, Gibbs-Howe D, Hock M, Carreira RJ, Atkin KE, Dorrell L, Knox A, Leonard S, Salio M, Godinho LF. Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen. Nat Commun 2024; 15:10126. [PMID: 39578466 PMCID: PMC11584656 DOI: 10.1038/s41467-024-54378-9] [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: 02/20/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.
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Affiliation(s)
| | | | - Rakesh Kulkarni
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Veronica Ilkow
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Mary M Connolly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Robert Pengelly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Archana Jadhav
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Jose Donoso
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tiaan Heunis
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Gwilym Philips
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Kafayat Ololade
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Daniel Kay
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Anshuk Sarkar
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Claire Barber
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Ritu Raj
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Carole Perot
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tressan Grant
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Agatha Treveil
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Walker
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Marcin Dembek
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Dawn Gibbs-Howe
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Miriam Hock
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Kate E Atkin
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Lucy Dorrell
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Knox
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Sarah Leonard
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Mariolina Salio
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Luis F Godinho
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK.
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3
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Yang X, Wang H, Yu C. The Mechanism of APOBEC3B in Hepatitis B Virus Infection and HBV Related Hepatocellular Carcinoma Progression, Therapeutic and Prognostic Potential. Infect Drug Resist 2024; 17:4477-4486. [PMID: 39435460 PMCID: PMC11492903 DOI: 10.2147/idr.s484265] [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: 06/25/2024] [Accepted: 10/11/2024] [Indexed: 10/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors globally. Prominent factors include chronic hepatitis B (CHB) and chronic hepatitis C (CHC) virus infections, exposure to aflatoxin, alcohol abuse, diabetes, and obesity. The prevalence of hepatitis B (HBV) is substantial, and the significant proportion of asymptomatic carriers heightens the challenge in diagnosing and treating hepatocellular carcinoma (HCC), necessitating further and more comprehensive research. Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC) family members are single-stranded DNA cytidine deaminases that can restrict viral replication. The APOBEC-related mutation pattern constitutes a primary characteristic of somatic mutations in various cancer types such as lung, breast, bladder, head and neck, cervix, and ovary. Symptoms in the early stages of HCC are often subtle and nonspecific, posing challenges in treatment and monitoring. Furthermore, this article primarily focuses on the established specific mechanism of action of the APOBEC3B (A3B) gene in the onset and progression of HBV-related HCC (HBV-HCC) through stimulating mutations in HBV, activating Interleukin-6 (IL-6) and promoting reactive oxygen species(ROS) production, while also exploring the potential for A3B to serve as a therapeutic target and prognostic indicator in HBV-HCC.
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Affiliation(s)
- Xiaochen 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, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Huanqiu 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, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chengbo Yu
- 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, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
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Geta M, Mengistu G, Yizengaw E, Manyzewal T, Hailu A, Woldeamanuel Y. Efficacy and safety of therapeutic vaccines for the treatment of chronic hepatitis B: A systematic review and meta-analysis of randomized controlled trials update. Medicine (Baltimore) 2024; 103:e39344. [PMID: 39213251 PMCID: PMC11365667 DOI: 10.1097/md.0000000000039344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/08/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Most people diagnosed with chronic hepatitis B (CHB) need treatment to help reduce the risk of liver disease and limit disease transmission. Therapeutic vaccine (TV) candidates have been under study for their clinical effects on inducing HBV-specific host immune responses. This review aimed to systematically synthesize updated evidence on the efficacy and safety of TVs in patients with CHB. METHODS This systematic review was performed by searching different databases from January to February 2021. Completed randomized controlled trials that reported TVs' efficacy and/or safety for treating CHB compared with the standard of care (SOC) or placebo were included. Efficacy and safety estimates were reported as the logarithm of the odds ratio and risk differences, respectively. I2 > 50% was considered significant heterogeneity. Significant publication bias was considered when Egger's test P value < .10. The risk of bias was assessed using the Cochrane Risk of Bias tool. The GRADE methodology was used to assess the certainty of the evidence for each outcome. RESULTS Twenty-four articles with 2889 pooled samples were included. TVs made a significant difference in hepatitis B envelope antigen (HBeAg) SC (log OR = 0.76, P = .01) and (log OR = 0.40, P = .03) compared to placebo and combination therapy, respectively. HBeAg SC was significantly affected by TVs at the end of follow up (log OR = 0.49, P = .01), with significant HBsAg mean difference (MD = -0.62, P = .00). At the end of treatment, the TVs had no significant effect on HBV DNA negativity over the SOC (log OR = 0.62, P = .09) or placebo (log OR = -0.07, P = .91). TVs do not significantly affect the risk of serious adverse events (RD 0.02, 95% CI 0.00-0.04). CONCLUSION In patients with CHB, TVs had significant effects on HBeAg SC compared to the SOC or placebo. There was no significant difference between serious adverse events. TVs are promising treatment strategy to overcome CHB.
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Affiliation(s)
- Mekuanint Geta
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Medical Microbiology, School of Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Getachew Mengistu
- Department of Medical Microbiology, School of Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Department of Laboratory Science, Debre Markos University, Debre Markos, Ethiopia
| | - Endalew Yizengaw
- Department of Medical Laboratory Science, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Institute of Biotechnology, Bahir Dar University, Bahir Dar, Ethiopia
| | - Tsegahun Manyzewal
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Asrat Hailu
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yimtubeznash Woldeamanuel
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Su Y, Bu F, Zhu Y, Yang L, Wu Q, Zheng Y, Zhao J, Yu L, Jiang N, Wang Y, Wu J, Xie Y, Zhang X, Gao Y, Lan K, Deng Q. Hepatitis B virus core protein as a Rab-GAP suppressor driving liver disease progression. Sci Bull (Beijing) 2024; 69:2580-2595. [PMID: 38670853 DOI: 10.1016/j.scib.2024.04.014] [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] [Revised: 02/28/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
Chronic hepatitis B virus (HBV) infection can lead to advanced liver pathology. Here, we establish a transgenic murine model expressing a basic core promoter (BCP)-mutated HBV genome. Unlike previous studies on the wild-type virus, the BCP-mutated HBV transgenic mice manifest chronic liver injury that culminates in cirrhosis and tumor development with age. Notably, agonistic anti-Fas treatment induces fulminant hepatitis in these mice even at a negligible dose. As the BCP mutant exhibits a striking increase in HBV core protein (HBc) expression, we posit that HBc is actively involved in hepatocellular injury. Accordingly, HBc interferes with Fis1-stimulated mitochondrial recruitment of Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15). HBc may also inhibit multiple Rab GTPase-activating proteins, including Rab7-specific TBC1D15 and TBC1D5, by binding to their conserved catalytic domain. In cells under mitochondrial stress, HBc thus perturbs mitochondrial dynamics and prevents the recycling of damaged mitochondria. Moreover, sustained HBc expression causes lysosomal consumption via Rab7 hyperactivation, which further hampers late-stage autophagy and substantially increases apoptotic cell death. Finally, we show that adenovirally expressed HBc in a mouse model is directly cytopathic and causes profound liver injury, independent of antigen-specific immune clearance. These findings reveal an unexpected cytopathic role of HBc, making it a pivotal target for HBV-associated liver disease treatment. The BCP-mutated HBV transgenic mice also provide a valuable model for understanding chronic hepatitis B progression and for the assessment of therapeutic strategies.
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Affiliation(s)
- Yu Su
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Fan Bu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Yuanfei Zhu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China; Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Le Yang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Qiong Wu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Yuan Zheng
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Jianjin Zhao
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Lin Yu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Nan Jiang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Yongxiang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China
| | - Jian Wu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yueqiu Gao
- Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
| | - Qiang Deng
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai 200032, China.
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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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7
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Li Y, Song Y, Xiao Y, Wang T, Li L, Liu M, Li J, Wang J. The Characteristic of HBV Quasispecies Is Related to Occult HBV Infection of Infants Born to Highly Viremic Mothers. Viruses 2024; 16:1104. [PMID: 39066265 PMCID: PMC11281566 DOI: 10.3390/v16071104] [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: 05/19/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Although a combination of immunoprophylaxis and antiviral therapy can effectively prevent mother-to-child transmission (MTCT) of hepatitis B virus (HBV), a considerable number of infants born to highly viremic mothers still develop occult HBV infection (OBI). To uncover the virological factor and risk predictor for OBI in infants, we found that the diversity and complexity of maternal HBV quasispecies in the case group were lower than those in the control group. Mutations with significant differences between the two groups were most enriched in the NTCPbd and PreC regions. Genetic distance at the amino-acid level of the PreC region, especially the combination of three amino-acid mutations in the PreC region, could strongly predict the risk of OBI in infants. HBV quasispecies in OBI infants were highly complex, and the non-synonymous substitutions were mainly found in the RT and HBsAg regions. The sK47E (rtQ55R) and sP49L mutations in OBI infants might contribute to OBI through inhibiting the production of HBV DNA and HBsAg, respectively. This study found the potential virological factors and risk predictors for OBI in infants born to highly viremic mothers, which might be helpful for controlling OBI in infants.
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Affiliation(s)
- Yi Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Yarong Song
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yiwei Xiao
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Tong Wang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lili Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Minmin Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jie Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jie Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
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8
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Wen X, Wu X, Sun Y, Zhou J, Guan G, Chen S, Shan S, Ma H, Zhao X, Wang Y, Ou X, You H, Guo JT, Lu F, Jia J. Long-term antiviral therapy is associated with changes in the profile of transcriptionally active HBV integration in the livers of patients with CHB. J Med Virol 2024; 96:e29606. [PMID: 38818708 DOI: 10.1002/jmv.29606] [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: 01/21/2024] [Revised: 03/10/2024] [Accepted: 04/05/2024] [Indexed: 06/01/2024]
Abstract
Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.
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Affiliation(s)
- Xiajie Wen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Jialing Zhou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Guiwen Guan
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, P.R. China
| | - Shuyan Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Shan Shan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, USA
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, P.R. China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, P.R. China
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9
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Gómez-Moreno A, Ploss A. Mechanisms of Hepatitis B Virus cccDNA and Minichromosome Formation and HBV Gene Transcription. Viruses 2024; 16:609. [PMID: 38675950 PMCID: PMC11054251 DOI: 10.3390/v16040609] [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: 03/13/2024] [Revised: 04/11/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatitis B virus (HBV) is the etiologic agent of chronic hepatitis B, which puts at least 300 million patients at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. HBV is a partially double-stranded DNA virus of the Hepadnaviridae family. While HBV was discovered more than 50 years ago, many aspects of its replicative cycle remain incompletely understood. Central to HBV persistence is the formation of covalently closed circular DNA (cccDNA) from the incoming relaxed circular DNA (rcDNA) genome. cccDNA persists as a chromatinized minichromosome and is the major template for HBV gene transcription. Here, we review how cccDNA and the viral minichromosome are formed and how viral gene transcription is regulated and highlight open questions in this area of research.
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Affiliation(s)
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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10
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Tang J, Zhang J, Zhang G, Peng W, Ling N, Zhou Y, Xu H, Ren H, Chen M. Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation. mBio 2024; 15:e0306823. [PMID: 38440978 PMCID: PMC11005361 DOI: 10.1128/mbio.03068-23] [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: 11/17/2023] [Accepted: 02/01/2024] [Indexed: 03/06/2024] Open
Abstract
The chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1β), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers. IMPORTANCE Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the "immune tolerance phase" will transition to the "immune activation phase" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers.
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Affiliation(s)
- Jinglin Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Transfusion Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jiaxuan Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Laboratory Medicine, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
| | - Gaoli Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenhui Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yingzhi Zhou
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hongmei Xu
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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11
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Aasarey R, Yadav K, Kashyap BK, Prabha S, Kumar P, Kumar A, Ruokolainen J, Kesari KK. Role of Immunological Cells in Hepatocellular Carcinoma Disease and Associated Pathways. ACS Pharmacol Transl Sci 2023; 6:1801-1816. [PMID: 38093838 PMCID: PMC10714437 DOI: 10.1021/acsptsci.3c00216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 03/28/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the predominant causes of cancer-related mortality across the globe. It is attributed to obesity, excessive alcohol consumption, smoking, and infection by the hepatitis virus. Early diagnosis of HCC is essential, and local treatments such as surgical excision and percutaneous ablation are effective. Palliative systemic therapy, primarily with the tyrosine kinase inhibitor Sorafenib, is used in advanced cases. However, the prognosis for advanced HCC remains poor. This Review additionally describes the pathophysiological mechanisms of HCC, which include aberrant molecular signaling, genomic instability, persistent inflammation, and the paradoxical position of the immune system in promoting and suppressing HCC. The paper concludes by discussing the growing body of research on the relationship between mitochondria and HCC, suggesting that mitochondrial dysfunction may contribute to the progression of HCC. This Review focuses on immunological interactions between different mechanisms of HCC progression, including obesity, viral infection, and alcohol consumption.
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Affiliation(s)
- Ram Aasarey
- Department
of Laboratory Medicine, All India Institute
of Medical Science, New Delhi-11029, India
| | - Kajal Yadav
- Department
of Biotechnology, All India Institute of
Medical Science, New Delhi-11029, India
| | - Brijendra Kumar Kashyap
- Department
of Biotechnology Engineering, Institute of Engineering and Technology, Bundelkhand University, Jhansi-284128, Uttar Pradesh, India
| | - Sarit Prabha
- Department
of Biological Science and Engineering, Maulana
Azad National Institute of Technology, Bhopal-462003, Madhya Pradesh,India
| | - Pramod Kumar
- Indian
Council of Medical Research, National Institute
of Cancer Prevention and Research (NICPR), l-7, Sector-39, Noida-201301, National Capital Region, India
| | - Anil Kumar
- Department
of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Karmre, Kanke-835222, Ranchi, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
- Research
and Development Cell, Lovely Professional
University, Phagwara-144411, Punjab, India
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12
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Ramakrishnan K, Babu S, Shaji V, Soman S, Leelamma A, Rehman N, Raju R. Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:581-597. [PMID: 38064540 DOI: 10.1089/omi.2023.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.
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Affiliation(s)
| | - Sreeranjini Babu
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Vineetha Shaji
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Anila Leelamma
- Department of Biochemistry, NSS College, Nilamel, Kollam, Kerala, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
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13
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Amin MN, El-Far YM, El-Mowafy M, Elgaml A. Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability. Clin Epigenetics 2023; 15:180. [PMID: 37941056 PMCID: PMC10634085 DOI: 10.1186/s13148-023-01593-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the global health concerns. Hepatitis B virus (HBV) is one of the major causes of HCC. Poor clinical outcome of HCC patients is attributed to a small population of cancer cells known as cancer stem cells (CSCs). In this work, we studied the effect of inhibiting the enhancer of zeste homologue 2 (EZH2), a histone methyltransferase known to be overexpressed in CSCs, using tazemetostat (Taz). The effect of Taz was assessed in the HCC cell line (HEPG2) and Hepatitis B virus-transfected HEPG2 (HBV/HEPG2) cells. MTT assay showed a significant decrease in HEPG2 cells viability after 48 h treatment with either 0.5, 1, 4 or 6 μM Taz. HEPG2 and HBV/HEPG2 cells were incubated with either 0.5 or 1 μM Taz for 48 h, and then, the cells and supernatants were collected for protein expression analysis of EZH2, CD13, epithelial cell adhesion molecule (EpCAM) and β-catenin using enzyme-linked immunosorbent assay (ELISA). Taz showed a significant dose-dependent inhibition of EZH2, CD13 and β-catenin in HEPG2 and HBV/HEPG2 cells. Also, EpCAM protein levels were significantly decreased in HBV/HEPG2 but not in HEPG2 cell line alone. Our results indicate that Taz inhibition of EZH2 leads to downregulation of β-catenin signaling and eventually decreased expression of CD13 and EpCAM, which are characteristic for CSCs. The present study suggests that Taz could be a promising treatment for HCC including HBV-induced HCC that might be used in combination with radio/chemotherapy to target CSCs and prevent tumor relapse.
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Affiliation(s)
- Mohamed N Amin
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Yousra M El-Far
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mohammed El-Mowafy
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Abdelaziz Elgaml
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
- Microbiology and Immunology Department, Faculty of Pharmacy, Horus University, New Damietta, 34518, Egypt.
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14
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Bertoletti A, Le Bert N. Quest for immunological biomarkers in the management of CHB patients. Gut 2023; 72:2012-2014. [PMID: 36922017 DOI: 10.1136/gutjnl-2023-329437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023]
Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
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15
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Kan K, Wong DKH, Hui RWH, Seto WK, Yuen MF, Mak LY. Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic hepatitis B patients - a retrospective longitudinal study. BMC Gastroenterol 2023; 23:348. [PMID: 37803352 PMCID: PMC10557289 DOI: 10.1186/s12876-023-02983-1] [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: 07/06/2023] [Accepted: 09/28/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND AND AIM In chronic hepatitis B infection (CHB), seroclearance of hepatitis B surface antigen (HBsAg) is associated with favourable clinical outcomes compared to those with persistent HBsAg seropositivity, and thus considered as a desired treatment endpoint. This current study explores the possibility of serum antibody to hepatitis B core antigen (anti-HBc) as a potential predictive factor of HBsAg seroclearance. METHODS This is a retrospective study that analyzed the plasma samples of CHB patients using the LUMIPULSE® G1200 analyzer. The longitudinal anti-HBc level between patients who subsequently achieved HBsAg seroclearance (S-losers) and those with persistent HBsAg-positivity (controls) were compared at multiple time points before the event. RESULTS A total of 240 subjects (120 S-losers and 120 controls; age- and gender-matched) were included (mean age 56.42 ± 10.81, 65% male). Compared to controls, S-losers had significantly lower plasma anti-HBc levels prior to HBsAg seroclearance, with a significant trend of declining plasma anti-HBc 8-5 years prior to HBsAg seroclearance (p < 0.01), while such trend was not observed in controls. ROC curve analysis revealed that plasma anti-HBc at multiple time points before HBsAg seroclearance return AUC greater than 0.7. Plasma anti-HBc level at the cut-off value of 82.50 COI was 68.3% sensitive and 90% specific for HBsAg seroclearance within 1 year. Combining with quantitative HBsAg < 100 IU/mL, anti-HBc < 82.5 COI identified 88.2% patients who would develop HBsAg seroclearance within 1 year. CONCLUSION Plasma anti-HBc level began to decline 10 years prior to HBsAg seroclearance and can serve as a potential predictor for subsequent HBsAg seroclearance.
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Affiliation(s)
- Karin Kan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
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16
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Xu H, Kang J, Zhong S, Chen M, Hu P, Ren H, Zhou Z, Lei Y. Function and autophagy of monocyte-derived dendritic cells is affected by hepatitis B virus infection. BMC Immunol 2023; 24:31. [PMID: 37752416 PMCID: PMC10521579 DOI: 10.1186/s12865-023-00571-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 09/14/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND The role of dendritic cells and the autophagy state of dendritic cells in the immune response of hepatitis B virus (HBV) infection was still controversial. In this study, we carefully examined the phenotype, function and autophagy pathway of dendritic cells in HBV infection. METHODS Monocyte-derived dendritic cells from healthy blood donors and patients with chronic HBV infection were stimulated by lipopolysaccharide, supernatant of HepG2.2.15 cells or supernatant of HepG2 cells respectively. Phenotype of dendritic cells was examined by flow cytometry and cytokines secretion was detected by enzyme-linked immunosorbent assay. Autophagy related proteins were detected by western blot and immunofluorescence analysis. RESULTS Our results showed that the expression of both major histocompatibility complex II molecules and co-stimulated molecules including cluster of differentiation antigen 80, cluster of differentiation antigen 86 in the monocyte-derived dendritic cells from patients with chronic HBV infection was significantly higher than that from healthy donors when cultured with supernatant of HepG2.2.15 cells. The amount of cytokines, including tumour necrosis factor-α, interleukin-10 and interleukin-12, secreted by monocyte-derived dendritic cells from patients with chronic HBV infection was also significantly higher than that from healthy donors when stimulate by HBV. Interestingly, the expression level of autophagy-related proteins including autophagy-related protein5 and associated protein 1 light chain in dendritic cells from patients with chronic HBV infection was significantly increased when compared with that from healthy donors when re-exposed to HBV. CONCLUSIONS Our results indicated that dendritic cells from patients with chronic HBV infection could intensively present antigen and express co-stimulatory molecules. The increased activation of dendritic cells might be related to the enhanced autophagy of dendritic cells in HBV infection.
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Affiliation(s)
- Hua Xu
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China
- Department of oncology, Chongqing Hospital of Traditional Chinese Medicine, No. 6, 7 Branch Road, Panxi, Jiangbei District, Chongqing, 400021, China
| | - Juan Kang
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China
| | - Shan Zhong
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China
| | - Min Chen
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China
| | - Zhi Zhou
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China
| | - Yu Lei
- 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, No.288 Tianwen Rd., Nan Ping District, Chongqing, 400060, People's Republic of China.
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17
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Barkay O, Erol S, Senbayrak S. Unraveling the Complexity of Atypical Serological Profiles in Chronic Hepatitis B: Insights Into Disease Dynamics and Clinical Implications. Cureus 2023; 15:e44899. [PMID: 37814733 PMCID: PMC10560487 DOI: 10.7759/cureus.44899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2023] [Indexed: 10/11/2023] Open
Abstract
Introduction Chronic hepatitis B (CHB) continues to be a significant global public health problem. Conventional serological markers play a pivotal role in diagnosing and prognosticating CHB, but atypical serological profiles deviating from established norms pose challenges. Methods A cohort of 35 CHB patients who did not receive an antiviral treatment with atypical serological markers was followed for five years (2017-2022). Demographics, serological parameters, and changes were documented. Serological parameters and serum viral loads (hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) levels) were assayed at the central laboratory during their routine follow-ups. Three groups of atypical serological markers are defined: hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) positivity; hepatitis B e antigen (HBeAg) and anti-hepatitis B e-antigen (anti-HBe) positivity; and isolated core (anti-hepatitis B core (anti-HBc) immunoglobulin G (IgG)) positivity. Patients with concomitant HBsAg and anti-HBs were also stratified into seroreversion groups. Changes in serological markers and HBV-DNA levels across the study period were documented and evaluated at the end of the study period. Statistical analysis was conducted using the Kruskal-Wallis test and IBM SPSS Statistics software for Windows, Version 23.0 (IBM Corp., Armonk, NY, USA). Results In a cohort of 35 patients with atypical hepatitis B serology, demographic analysis revealed that 51.4% (n=18) were female and 48.6% (n=17) were male, with a mean age of 45.7 years. Educational distribution showed that 45.7% (n=16) completed primary education, 22.8% (n=8) had a high school education, and 31.5% (n=11) held university degrees. Among these patients, 10 displayed the concurrent presence of HBsAg and anti-HBs, with 60% (n=6) being female. Serum HBV-DNA was detectable in all cases. After five years, 60% (n=6) exhibited seroconversion from HBsAg to anti-HBs, particularly notable in females (66.7%). These patients showed lower HBsAg titers and serum HBV-DNA levels (p = 0.048, p = 0.036). A subset of 15 patients demonstrated simultaneous HBeAg and anti-HBe positivity. The HBeAg seropositivity waned over time, with 40% (n=6) and 26.7% (n=4) females and males, respectively, retaining positivity by the fifth year. During this period, serum HBV-DNA levels decreased. The remaining five patients sustained HBeAg and anti-HBe positivity. Among 10 patients solely positive for anti-HBc IgG, three had concurrent HBV-DNA positivity. Strikingly, three patients with negative HBV-DNA developed anti-HBs positivity after five years. Conclusion The complexity of CHB infection demands a comprehensive understanding. Atypical serological profiles suggest distinct disease stages, immune response variations, and viral mutations. This study enhances comprehension of viral replication, immune responses, and disease progression, potentially guiding tailored therapeutic strategies.
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Affiliation(s)
- Orçun Barkay
- Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan, TUR
| | - Serpil Erol
- Infectious Diseases, Health Sciences University Haydarpaşa Numune Research and Training Hospital, Istanbul, TUR
| | - Seniha Senbayrak
- Infectious Diseases, Health Sciences University Haydarpaşa Numune Research and Training Hospital, Istanbul, TUR
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18
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Zeng DY, Chen Z, Hong MZ, Jiang LP, Chen XN, Xue HX, Pan JS, Zhu Y. Traditional Chinese medicine invigorating the spleen and kidney promotes HBsAg seroclearance in the mouse model. J Med Virol 2023; 95:e28979. [PMID: 37522253 DOI: 10.1002/jmv.28979] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 07/05/2023] [Accepted: 07/11/2023] [Indexed: 08/01/2023]
Abstract
Traditional Chinese medicine (TCM) is often used as an adjuvant or alternative therapy for abnormal liver biochemistry or liver fibrosis associated with chronic hepatitis B (CHB). However, the role of TCM in HBsAg seroclearance remains unclear. We aimed at exploring the role and possible mechanisms of TCM in HBsAg seroclearance. Fifteen widely used TCM granules invigorating the spleen and kidneys were screened. C57BL/6J mice were administered daily with TCM granules by gavage for 1 week. The effect of TCM on the M1 polarization of macrophages was measured using a CD86 assay. According to the principles of formulating prescriptions, three single TCM with the most noticeable effect on M1 polarization, accompanied by two other TCM granules, were used to develop a TCM formula. The hepatitis B virus-expressing mouse model was constructed by hydrodynamic injection of the pAAV/HBV1.2 plasmid. Hepatitis B virus-expressing mice were gavaged daily with phosphate-buffered saline (PBS), TCM formula, or Codonopsis Radix, for 1 week. HBsAg, HBeAg, and hepatitis B virus DNA levels were measured. In addition, gut microbiota was profiled using 16S rDNA sequencing. Several TCM granules showed significant effects on M1 polarization. The TCM formula accelerated HBsAg seroclearance compared with the Codonopsis Radix and PBS groups. Intrahepatic M1 polarization, as indicated by flow cytometry and immunohistochemistry, was induced in the TCM formula and Codonopsis Radix groups. The abundance of Alloprevotella significantly increased in the TCM formula and Codonopsis Radix groups. These results demonstrate that the TCM formula for invigorating the spleen and kidney can accelerate HBsAg seroclearance. This effect can be attributed, at least in part, to M1 polarization of intrahepatic macrophages.
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Affiliation(s)
- Dan-Yi Zeng
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhan Chen
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Mei-Zhu Hong
- Department of Traditional Chinese Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Ling-Ping Jiang
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiao-Ning Chen
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Han-Xin Xue
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Jin-Shui Pan
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Yueyong Zhu
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
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19
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Tao N, Xu X, Ying Y, Hu S, Sun Q, Lv G, Gao J. Thymosin α1 and Its Role in Viral Infectious Diseases: The Mechanism and Clinical Application. Molecules 2023; 28:molecules28083539. [PMID: 37110771 PMCID: PMC10144173 DOI: 10.3390/molecules28083539] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Thymosin α1 (Tα1) is an immunostimulatory peptide that is commonly used as an immune enhancer in viral infectious diseases such as hepatitis B, hepatitis C, and acquired immune deficiency syndrome (AIDS). Tα1 can influence the functions of immune cells, such as T cells, B cells, macrophages, and natural killer cells, by interacting with various Toll-like receptors (TLRs). Generally, Tα1 can bind to TLR3/4/9 and activate downstream IRF3 and NF-κB signal pathways, thus promoting the proliferation and activation of target immune cells. Moreover, TLR2 and TLR7 are also associated with Tα1. TLR2/NF-κB, TLR2/p38MAPK, or TLR7/MyD88 signaling pathways are activated by Tα1 to promote the production of various cytokines, thereby enhancing the innate and adaptive immune responses. At present, there are many reports on the clinical application and pharmacological research of Tα1, but there is no systematic review to analyze its exact clinical efficacy in these viral infectious diseases via its modulation of immune function. This review offers an overview and discussion of the characteristics of Tα1, its immunomodulatory properties, the molecular mechanisms underlying its therapeutic effects, and its clinical applications in antiviral therapy.
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Affiliation(s)
- Nana Tao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xie Xu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yuyuan Ying
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Shiyu Hu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Qingru Sun
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Guiyuan Lv
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jianli Gao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
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20
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Zhang Y, Chi Z, Cui Z, Chang S, Wang Y, Zhao P. Inflammatory response triggered by avian hepatitis E virus in vivo and in vitro. Front Immunol 2023; 14:1161665. [PMID: 37063902 PMCID: PMC10098337 DOI: 10.3389/fimmu.2023.1161665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/06/2023] [Indexed: 04/03/2023] Open
Abstract
Hepatitis E virus (HEV) is relevant to public health worldwide, and it affects a variety of animals. Big liver and spleen disease (BLS) and hepatitis-splenomegaly syndrome (HSS) associated with avian HEV (aHEV) were first reported in 1988 and in 1991, respectively. Here, cell culture–adapted aHEV genotype 3 strain, YT-aHEV (YT strain), a typical genotype isolated in China, was used for basic and applied research. We evaluated liver injury during the early stages of infection caused by the YT strain in vivo. Both in vivo and in vitro experimental data demonstrated that viral infection induces innate immunity, with mRNA expression levels of two key inflammatory factors, interleukin-1β (IL-1β) and IL-18, significantly upregulated. The YT strain infection was associated with the activation of Toll-like receptors (TLRs), nuclear factor kappa B (NF-κB), caspase-1, and NOD-like receptors (NLRs) in the liver and primary hepatocellular carcinoma epithelial cells (LMH). Moreover, inhibiting c-Jun N-terminal kinase, extracellular signal–regulated kinase (ERK1 or 2), P38, NF-κB, or caspase-1 activity has different effects on NLRs, and there is a mutual regulatory relationship between these signaling pathways. The results show that SB 203580, U0126, and VX-765 inhibited IL-1β and IL-18 induced by the YT strain, whereas Pyrrolidinedithiocarbamate (PDTC) had no significant effect on the activity of IL-1β and IL-18. Pretreatment of cells with SP600125 had an inhibitory effect on IL-18 but not on IL-1β. The analysis of inhibition results suggests that there is a connection between Mitogen-activated protein kinase (MAPK), NF-κB, and the NLRs signaling pathways. This study explains the relationship between signaling pathway activation (TLRs, NF-κB, MAPK, and NLR–caspase-1) and viral-associated inflammation caused by YT strain infection, which will help to dynamic interaction between aHEV and host innate immunity.
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Affiliation(s)
- Yawen Zhang
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
| | - Zengna Chi
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
| | - Zhizhong Cui
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
| | - Shuang Chang
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
| | - Yixin Wang
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
| | - Peng Zhao
- College of Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Tai’an, Shandong, China
- *Correspondence: Peng Zhao,
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21
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Akbar SMF, Al Mahtab M, Khan S. Cellular and Molecular Mechanisms of Pathogenic and Protective Immune Responses to SARS-CoV-2 and Implications of COVID-19 Vaccines. Vaccines (Basel) 2023; 11:vaccines11030615. [PMID: 36992199 DOI: 10.3390/vaccines11030615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/26/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has devastated the world with coronavirus disease 2019 (COVID-19), which has imparted a toll of at least 631 million reported cases with 6.57 million reported deaths. In order to handle this pandemic, vaccines against SARS-CoV-2 have been developed and billions of doses of various vaccines have been administered. In the meantime, several antiviral drugs and other treatment modalities have been developed to treat COVID-19 patients. At the end of the day, it seems that anti-SARS-CoV-2 vaccines and newly developed antiviral drugs may be improved based on various new developments. COVID-19 represents a virus-induced, immune-mediated pathological process. The severity of the disease is related to the nature and properties of the host immune responses. In addition, host immunity plays a dominant role in regulating the extent of COVID-19. The present reality regarding the role of anti-SARS-CoV-2 vaccines, persistence of SARS-CoV-2 infection even three years after the initiation of the pandemic, and divergent faces of COVID-19 have initiated several queries among huge populations, policy makers, general physicians, and scientific communities. The present review aims to provide some information regarding the molecular and cellular mechanisms underlying SARS-CoV-2 infection.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Ehime, Japan
| | - Mamun Al Mahtab
- Interventional Hepatology Division, Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, BSMMU, Dhaka 1000, Bangladesh
| | - Sakirul Khan
- Department of Microbiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan
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22
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Stephan AS, Kosinska AD, Mück-Häusl M, Muschaweckh A, Jäger C, Röder N, Heikenwälder M, Dembek C, Protzer U. Evaluation of the Effect of CD70 Co-Expression on CD8 T Cell Response in Protein-Prime MVA-Boost Vaccination in Mice. Vaccines (Basel) 2023; 11:vaccines11020245. [PMID: 36851121 PMCID: PMC9966001 DOI: 10.3390/vaccines11020245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Here, we investigate the potential of CD70 co-expression during viral vector boost vaccination to improve an antigen-specific T cell response. To determine the chance of activating antigen-specific T cells by CD70, we used the HBV core antigen as a model antigen in a heterologous protein-prime, Modified Vaccinia virus Ankara (MVA) boost vaccination scheme. Both the HBV core and a CD70 expression cassette were co-expressed upon delivery by an MVA vector under the same promoter linked by a P2A site. To compare immunogenicity with and without CD70 co-expression, HBV-naïve, C57BL/6 (wt) mice and HBV-transgenic mice were prime-vaccinated using recombinant HBV core antigen followed by the MVA vector boost. Co-expression of CD70 increased the number of vaccine-induced HBV core-specific CD8 T cells by >2-fold and improved their effector functions in HBV-naïve mice. In vaccinated HBV1.3tg mice, the number and functionality of HBV core-specific CD8 T cells was slightly increased upon CD70 co-expression in low-viremic, but not in high-viremic animals. CD70 co-expression did not impact liver damage as indicated by ALT levels in the serum, but increased the number of vaccine-induced, proliferative T cell clusters in the liver. Overall, this study indicates that orchestrated co-expression of CD70 and a vaccine antigen may be an interesting and safe means of enhancing antigen-specific CD8 T cell responses using vector-based vaccines, although in our study it was not sufficient to break immune tolerance.
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Affiliation(s)
- Ann-Sophie Stephan
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Anna D. Kosinska
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
| | - Martin Mück-Häusl
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Andreas Muschaweckh
- Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, 81675 Munich, Germany
| | - Clemens Jäger
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Natalie Röder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
| | - Mathias Heikenwälder
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany
| | - Claudia Dembek
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich, Helmholtz Zentrum München, 81675 Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany
- Correspondence: (C.D.); (U.P.); Tel.: +49-89-4140-6821 (U.P.)
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Harris AM, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:1125-1133.e4. [DOI: 10.1016/b978-0-323-75608-2.00213-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fiorino S, Carusi A, Hong W, Cernuschi P, Gallo CG, Ferrara E, Maloberti T, Visani M, Lari F, de Biase D, Zippi M. SARS-CoV-2 vaccines: What we know, what we can do to improve them and what we could learn from other well-known viruses. AIMS Microbiol 2022; 8:422-453. [PMID: 36694588 PMCID: PMC9834075 DOI: 10.3934/microbiol.2022029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/24/2022] [Accepted: 11/06/2022] [Indexed: 11/18/2022] Open
Abstract
In recent weeks, the rate of SARS-CoV-2 infections has been progressively increasing all over the globe, even in countries where vaccination programs have been strongly implemented. In these regions in 2021, a reduction in the number of hospitalizations and deaths compared to 2020 was observed. This decrease is certainly associated with the introduction of vaccination measures. The process of the development of effective vaccines represents an important challenge. Overall, the breakthrough infections occurring in vaccinated subjects are in most cases less severe than those observed in unvaccinated individuals. This review examines the factors affecting the immunogenicity of vaccines against SARS-CoV-2 and the possible role of nutrients in modulating the response of distinct immune cells to the vaccination.
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Affiliation(s)
- Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital, Budrio (Bologna), Azienda USL, Bologna, Italy
| | - Andrea Carusi
- Internal Medicine Unit, Budrio Hospital, Budrio (Bologna), Azienda USL, Bologna, Italy
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang, The People's Republic of China
| | - Paolo Cernuschi
- Internal Medicine Unit, Quisana Private Hospital, Ferrara, Italy
| | | | | | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna, Italy
| | - Federico Lari
- Internal Medicine Unit, Budrio Hospital, Budrio (Bologna), Azienda USL, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maddalena Zippi
- Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy
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Sacherl J, Kosinska AD, Kemter K, Kächele M, Laumen SC, Kerth HA, Öz EA, Wolff LS, Su J, Essbauer S, Sutter G, Scholz M, Singethan K, Altrichter J, Protzer U. Efficient stabilization of therapeutic hepatitis B vaccine components by amino-acid formulation maintains its potential to break immune tolerance. JHEP Rep 2022; 5:100603. [PMID: 36714793 PMCID: PMC9880034 DOI: 10.1016/j.jhepr.2022.100603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 09/05/2022] [Accepted: 10/05/2022] [Indexed: 11/07/2022] Open
Abstract
Background & Aims Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach. Methods We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice. Results In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice. Conclusion SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide. Impact and implications Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.
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Key Words
- AAV, adeno-associated virus
- ALT, alanine aminotransferase
- CHB, chronic hepatitis B
- CTC, controlled temperature chain
- Ctrl, control
- DLS, dynamic light scattering
- HBcAg
- HBcAg, hepatitis B core antigen
- HBeAg, hepatitis B e antigen
- HBsAg
- HBsAg, hepatitis B surface antigen
- Heat-stable vaccine
- ICS, intracellular cytokine staining
- IFNα, interferon alpha
- MVA
- MVA, Modified Vaccinia virus Ankara
- NAGE, native agarose gel electrophoresis
- RH, relative humidity
- RT, room temperature
- SAA, stabilizing amino acids
- SEC-HPLC, size exclusion-high performance liquid chromatography
- SPS®
- TCID50, median tissue culture infection dose
- TherVacBCtrl, non-lyophilized
- WHO, World Health Organization
- anti-HBc, hepatitis B core antibodies
- anti-HBs, hepatitis B surface antibodies
- cccDNA, covalently closed circular DNA
- formulation
- hepatitis B virus
- heterologous prime/boost vaccination
- lyophilization
- non-stressed, non-stabilized TherVacB
- stabilization
- stabilizing amino acid-based formulation
- stabilizing excipients
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Affiliation(s)
- Julia Sacherl
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Anna D. Kosinska
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | | | - Martin Kächele
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Sabine C. Laumen
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Hélène A. Kerth
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Edanur Ates Öz
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Lisa S. Wolff
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Jinpeng Su
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | | | - Gerd Sutter
- Institute of Infectious Diseases and Zoonoses, Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | | | - Katrin Singethan
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- Bundeswehr Institute of Microbiology, Munich, Germany
| | | | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
- Corresponding author. Address: Institute of Virology, Trogerstr. 30, 81675 Munich, Germany; Tel.: +49-89-4140-6821, fax: +49-89-4140-6823.
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27
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Yan LR, Liu AR, Jiang LY, Wang BG. Non-coding RNA and hepatitis B virus-related hepatocellular carcinoma: A bibliometric analysis and systematic review. Front Med (Lausanne) 2022; 9:995943. [PMID: 36203765 PMCID: PMC9530602 DOI: 10.3389/fmed.2022.995943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Objectives A bibliometric analysis for non-coding RNA and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) was performed to describe international research status and visualize the research scope and emerging trends over the last two decades on this topic. Materials and methods Research data of non-coding RNA and HBV-related HCC were retrieved and extracted from the Web of Science Core Collection (WoSCC) database from 1 January 2003 to 13 June 2022 and then analyzed by means of bibliometric methods. A total of 1,036 articles published in this field were assessed for specific characteristics, including the year of publication, journal, author, institution, country/region, references, and keywords. VOSviewer was employed to perform co-authorship, co-occurrence, and co-citation analyses accompanied by constructing a visual network. Results Overall, 1,036 reports on non-coding RNA and HBV-related HCC from 2003 to 2022 were retrieved from WoSCC. The publication has gradually increased during the last two decades with 324 journals involved. Most research records (748 publications and 23,184 citations) were concentrated in China. A co-occurrence cluster analysis for the top 100 keywords was performed and four clusters were generated: (1) non-coding RNA as a molecular marker for the diagnosis and prognosis of HBV-related HCC; (2) dysregulation of non-coding RNA by hepatitis B virus X protein (HBx); (3) non-coding RNA affecting the biological behaviors of HBV-related HCC; and (4) epidemiological study for the effects of non-coding RNA on the risk of HBV-related HCC. Conclusion The publications and citations involved in non-coding RNA and HBV-related HCC have increased over the last two decades associated with many countries, institutions, and authors. Our study revealed current development trends, global cooperation models, basic knowledge, research hotspots, and emerging frontiers in this field.
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Affiliation(s)
- Li-rong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Ao-ran Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Li-yue Jiang
- Tangdu Hospital of the Fourth Military Medical University, Xi’an, China
| | - Ben-gang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
- Department of Hepatobiliary Surgery, Institute of General Surgery, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Ben-gang Wang,
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Shaha M, Majumder S, Hossain MS, Jahan M, Rahmat R, Asma R, Islam MA, Rahman MH, Das KC, Sarker PK, Mahtab MA, Akbar SMF, Salimullah M. Identification of a novel variant of hepatitis B virus isolated from patient co-infected with hepatitis C virus. Virus Res 2022; 319:198859. [PMID: 35809696 DOI: 10.1016/j.virusres.2022.198859] [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: 02/24/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 11/16/2022]
Abstract
Hepatitis B virus (HBV) is a major public health concern worldwide. Co-infection of hepatitis B patients with other pathogens intensifies the severity of the disease. We report a novel variant of hepatitis B virus (HBV) in Bangladesh isolated from a patient co-infected with hepatitis C virus (HCV) who exhibited liver cirrhosis. From 150 collected plasma samples, we sequenced HBV complete genome from one HBV-HCV co-infected patient. The complete genome was analysed using bioinformatics tools, NCBI BLAST, Geno2Pheno, and SnapGene software. The strain belongs to genotype A and subgenotype A1. Upon analysing the complete genome of this strain, we found a frameshift deletion of 54 nucleotides at the pre-S2 region, a functional regulator of HBV surface protein. Furthermore, we observed a Y126H mutation in the polymerase protein of this strain. This is the first report with such an unusual pre-S deletion event of the HBV genome in an HCV-co-infected patient associated with liver cirrhosis. These findings may inform scientists about genomic modifications in the HBV genome associated with HCV co-infection.
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Affiliation(s)
- Modhusudon Shaha
- Microbial Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Sumen Majumder
- Microbial Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh; Department of Microbiology, Jagannath University, Dhaka 1000, Bangladesh
| | - Md Saddam Hossain
- Microbial Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh
| | - Munira Jahan
- Department of Virology, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka 1000, Bangladesh
| | - Raad Rahmat
- Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Mohakhali, Dhaka 1212, Bangladesh
| | - Ridwana Asma
- Department of Virology, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka 1000, Bangladesh
| | | | - Md Hadisur Rahman
- Molecular Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh
| | - Keshob Chandra Das
- Molecular Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh
| | - Palash Kumar Sarker
- Microbial Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka 1000, Bangladesh
| | | | - Md Salimullah
- Molecular Biotechnology Division, National Institute of Biotechnology, Savar, Dhaka 1349, Bangladesh.
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Ye C, Li W, Li L, Zhang K. Glucocorticoid Treatment Strategies in Liver Failure. Front Immunol 2022; 13:846091. [PMID: 35371046 PMCID: PMC8965693 DOI: 10.3389/fimmu.2022.846091] [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: 12/30/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.
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Affiliation(s)
- Chao Ye
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenyuan Li
- Department of Infectious Diseases, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lei Li
- Department of Infectious Diseases, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Kaiguang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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30
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Chen CY, Hajinicolaou C, Walabh P, Ingasia LAO, Song E, Kramvis A. Molecular characterization of hepatitis B virus (HBV) isolated from a pediatric case of acute lymphoid leukemia, with a delayed response to antiviral treatment: a case report. BMC Pediatr 2022; 22:168. [PMID: 35361141 PMCID: PMC8969373 DOI: 10.1186/s12887-022-03204-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed case of virologic breakthrough (VBT) in a pediatric case has been reported. CASE PRESENTATION Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy. CONCLUSION Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.
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Affiliation(s)
- Chien-Yu Chen
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Christina Hajinicolaou
- Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.,Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.,Paediatric Gastroentrology, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Priya Walabh
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Luicer Anne Olubayo Ingasia
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Ernest Song
- Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.
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Samudh N, Shrilall C, Arbuthnot P, Bloom K, Ely A. Diversity of Dysregulated Long Non-Coding RNAs in HBV-Related Hepatocellular Carcinoma. Front Immunol 2022; 13:834650. [PMID: 35154157 PMCID: PMC8831247 DOI: 10.3389/fimmu.2022.834650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
Infection with the hepatitis B virus (HBV) continues to pose a major threat to public health as approximately 292 million people worldwide are currently living with the chronic form of the disease, for which treatment is non-curative. Chronic HBV infections often progress to hepatocellular carcinoma (HCC) which is one of the world’s leading causes of cancer-related deaths. Although the process of hepatocarcinogenesis is multifaceted and has yet to be fully elucidated, several studies have implicated numerous long non-coding RNAs (lncRNAs) as contributors to the development of HCC. These host-derived lncRNAs, which are often dysregulated as a consequence of viral infection, have been shown to function as signals, decoys, guides, or scaffolds, to modulate gene expression at epigenetic, transcriptional, post-transcriptional and even post-translational levels. These lncRNAs mainly function to promote HBV replication and oncogene expression or downregulate tumor suppressors. Very few lncRNAs are known to suppress tumorigenesis and these are often downregulated in HCC. In this review, we describe the mechanisms by which lncRNA dysregulation in HBV-related HCC promotes tumorigenesis and cancer progression.
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Affiliation(s)
- Nazia Samudh
- Wits/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Creanne Shrilall
- Wits/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Patrick Arbuthnot
- Wits/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Kristie Bloom
- Wits/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Abdullah Ely
- Wits/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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32
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Tiegs G, Horst AK. TNF in the liver: targeting a central player in inflammation. Semin Immunopathol 2022; 44:445-459. [PMID: 35122118 PMCID: PMC9256556 DOI: 10.1007/s00281-022-00910-2] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/12/2022] [Indexed: 12/11/2022]
Abstract
Tumour necrosis factor-α (TNF) is a multifunctional cytokine. First recognized as an endogenous soluble factor that induces necrosis of solid tumours, TNF became increasingly important as pro-inflammatory cytokine being involved in the immunopathogenesis of several autoimmune diseases. In the liver, TNF induces numerous biological responses such as hepatocyte apoptosis and necroptosis, liver inflammation and regeneration, and autoimmunity, but also progression to hepatocellular carcinoma. Considering these multiple functions of TNF in the liver, we propose anti-TNF therapies that specifically target TNF signalling at the level of its specific receptors.
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Affiliation(s)
- Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. .,Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Andrea K Horst
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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33
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Xie X, Luo J, Zhu D, Zhou W, Yang X, Feng X, Lu M, Zheng X, Dittmer U, Yang D, Liu J. HBeAg Is Indispensable for Inducing Liver Sinusoidal Endothelial Cell Activation by Hepatitis B Virus. Front Cell Infect Microbiol 2022; 12:797915. [PMID: 35174107 PMCID: PMC8842949 DOI: 10.3389/fcimb.2022.797915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background and AimsLiver sinusoidal endothelial cells (LSECs) serve as sentinel cells to detect microbial infection and actively contribute to regulating immune responses for surveillance against intrahepatic pathogens. We recently reported that hepatitis B e antigen (HBeAg) stimulation could induce LSEC maturation and abrogate LSEC-mediated T cell suppression in a TNF-α and IL27 dependent manner. However, it remains unclear how HBeAg deficiency during HBV infection influences LSEC immunoregulation function and intrahepatic HBV-specific CD8 T cell responses.MethodsThe function of LSECs in regulating effector T cell response, intrahepatic HBV-specific CD8 T cell responses and HBV viremia were characterized in both HBeAg-deficient and -competent HBV hydrodynamic injection (HDI) mouse models.ResultsLSECs isolated from HBeAg-deficient HBV HDI mice showed a reduced capacity to promote T cell immunity in vitro compared with those isolated from wild-type HBV HDI mice. HBeAg expression replenishment in HBeAg-deficient HBV HDI mice restored the HBV-induced LSEC maturation, and resulted in potent intrahepatic anti-HBV CD8 T cell responses and efficient control of HBV replication. Moreover, in vivo TNF-α, but not IL27 blockade in HBV HDI mice impaired HBV-specific CD8 T cell immunity and delayed HBV clearance.ConclusionOur study underlines that HBeAg is indispensable for HBV-induced LSEC maturation to trigger intrahepatic HBV-specific T cell activation, and provides a new mechanism to elucidate the intrahepatic immune microenvironment regulation upon HBV exposure.
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Affiliation(s)
- Xiaohong Xie
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinzhuo Luo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenqing Zhou
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jia Liu,
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34
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Dondeti MF, Abdelkhalek MS, El-Din Elezawy HM, Alsanie WF, Raafat BM, Gamal-Eldeen AM, Talaat RM. Association between interferon-gamma (IFN-γ) gene polymorphisms (+874A/T and +2109A/G), and susceptibility to hepatitis B viral infection (HBV). J Appl Biomed 2022; 20:37-43. [DOI: 10.32725/jab.2022.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
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35
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Zhao H, Han Q, Yang A, Wang Y, Wang G, Lin A, Wang X, Yin C, Zhang J. CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV. Int J Biol Sci 2022; 18:154-165. [PMID: 34975324 PMCID: PMC8692134 DOI: 10.7150/ijbs.62424] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic Hepatitis B virus (CHB) infection is a global public health problem. Oligodeoxynucleotides (ODNs) containing class C unmethylated cytosine-guanine dinucleotide (CpG-C) motifs may provide potential adjuvants for the immunotherapeutic strategy against CHB, since CpG-C ODNs stimulate both B cell and dendritic cell (DC) activation. However, the efficacy of CpG-C ODN as an anti-HBV vaccine adjuvant remains unclear. In this study, we demonstrated that CpG M362 (CpG-C ODN) as an adjuvant in anti-HBV vaccine (cHBV-vaccine) successfully and safely eliminated the virus in HBV-carrier mice. The cHBV-vaccine enhanced DC maturation both in vivo and in vitro, overcame immune tolerance, and recovered exhausted T cells in HBV-carrier mice. Furthermore, the cHBV-vaccine elicited robust hepatic HBV-specific CD8+ and CD4+ T cell responses, with increased cellular proliferation and IFN-γ secretion. Additionally, the cHBV-vaccine invoked a long-lasting follicular CXCR5+ CD8+ T cell response following HBV re-challenge. Taken together, CpG M362 in combination with rHBVvac cleared persistent HBV and achieved long-term virological control, making it a promising candidate for treating CHB.
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Affiliation(s)
- Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ailu Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yucan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Guan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ang Lin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiao Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
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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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Du Y, Broering R, Li X, Zhang X, Liu J, Yang D, Lu M. In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application. Front Immunol 2021; 12:766534. [PMID: 34777385 PMCID: PMC8586444 DOI: 10.3389/fimmu.2021.766534] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/14/2021] [Indexed: 12/19/2022] Open
Abstract
Despite the availability of effective vaccination, hepatitis B virus (HBV) infection continues to be a major challenge worldwide. Research efforts are ongoing to find an effective cure for the estimated 250 million people chronically infected by HBV in recent years. The exceptionally limited host spectrum of HBV has limited the research progress. Thus, different HBV mouse models have been developed and used for studies on infection, immune responses, pathogenesis, and antiviral therapies. However, these mouse models have great limitations as no spread of HBV infection occurs in the mouse liver and no or only very mild hepatitis is present. Thus, the suitability of these mouse models for a given issue and the interpretation of the results need to be critically assessed. This review summarizes the currently available mouse models for HBV research, including hydrodynamic injection, viral vector-mediated transfection, recombinant covalently closed circular DNA (rc-cccDNA), transgenic, and liver humanized mouse models. We systematically discuss the characteristics of each model, with the main focus on hydrodynamic injection mouse model. The usefulness and limitations of each mouse model are discussed based on the published studies. This review summarizes the facts for considerations of the use and suitability of mouse model in future HBV studies.
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Affiliation(s)
- Yanqin Du
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Xiaoran Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Bartoli A, Gabrielli F, Tassi A, Cursaro C, Pinelli A, Andreone P. Treatments for HBV: A Glimpse into the Future. Viruses 2021; 13:1767. [PMID: 34578347 PMCID: PMC8473442 DOI: 10.3390/v13091767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.
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Affiliation(s)
- Alessandra Bartoli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Filippo Gabrielli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Andrea Tassi
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
| | - Ambra Pinelli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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Boudewijns R, Ma J, Neyts J, Dallmeier K. A novel therapeutic HBV vaccine candidate induces strong polyfunctional cytotoxic T cell responses in mice. JHEP Rep 2021; 3:100295. [PMID: 34159304 PMCID: PMC8203848 DOI: 10.1016/j.jhepr.2021.100295] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/02/2021] [Accepted: 04/13/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND & AIMS Current standard-of-care suppresses HBV replication, but does not lead to a functional cure. Treatment aiming to cure chronic hepatitis B (CHB) is believed to require the induction of strong cellular immune responses, such as by therapeutic vaccination. METHODS We designed a therapeutic HBV vaccine candidate (YF17D/HBc-C) using yellow fever vaccine YF17D as a live-attenuated vector to express HBV core antigen (HBc). Its ability to induce potent cellular immune responses was assessed in a mouse model that supports flavivirus replication. RESULTS Following a HBc protein prime, a booster of YF17D/HBc-C was found to induce vigorous cytotoxic T cell responses. In a direct head-to-head comparison, these HBc-specific responses exceeded those elicited by adenovirus-vectored HBc. Target-specific T cells were not only more abundant, but also showed a higher degree of polyfunctionality, with HBc-specific CD8+ T cells producing interferon γ and tumour necrosis factor α in addition to granzyme B. This immune phenotype translated into a superior cytotoxic effector activity toward HBc-positive cells in YF17D/HBc-C vaccinated animals in vivo. CONCLUSIONS The results presented here show the potential of YF17D/HBc-C as a vaccine candidate to treat CHB, and warrant follow-up studies in preclinical animal models of HBV persistence in which other candidate vaccines have been unable to achieve a sustained virologic response. LAY SUMMARY Resolution of CHB requires the induction of strong cellular immune responses. We used the yellow fever vaccine as a vector for HBV antigens and show that it is capable of inducing high levels of HBV-specific T cells that produce multiple cytokines simultaneously and are cytotoxic in vivo.
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Key Words
- CAR-T, chimeric antigen receptor T cells
- CFSE, carboxy-fluorescein succinimidyl ester
- CHB, chronic hepatitis B
- CTL, cytotoxic T lymphocyte
- Chronic hepatitis B
- DCs, dendritic cells
- ELISPOT, enzyme-linked ImmunoSpot
- GzmB, granzyme B
- HBV
- HBc, HBV core antigen
- HBp, HBV polymerase antigen
- HBs, HBV surface antigen
- ICS, intracellular cytokine staining
- IFNγ, interferon γ
- MHC, major histocompatibility complex
- NanoLuc, nanoluciferase
- STAT2, signal transducer and activator of transcription 2
- TNFα, tumour necrosis factor α
- Therapeutic vaccination
- YF, yellow fever
- Yellow fever vaccine
- aa, amino acids
- cccDNA, covalently closed circular DNA
- ifnar, IFN-α/β receptor
- pfu, plaque-forming units
- rHBc, recombinant HBc
- t-SNE, t-stochastic neighbour embedding
- wt, wild-type
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Affiliation(s)
- Robbert Boudewijns
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Ji Ma
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Johan Neyts
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
| | - Kai Dallmeier
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium
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Zhao H, Wang H, Hu Y, Xu D, Yin C, Han Q, Zhang J. Chitosan Nanovaccines as Efficient Carrier Adjuvant System for IL-12 with Enhanced Protection Against HBV. Int J Nanomedicine 2021; 16:4913-4928. [PMID: 34321879 PMCID: PMC8312321 DOI: 10.2147/ijn.s317113] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
Purpose Alum adjuvant in HBV prophylactic vaccines is poor in inducing cellular immunity with the inhibition of IL-12 secretion, and approximately 5–10% of immunised individuals fail to clear HBV upon infection. IL-12 plasmids (pIL-12) as adjuvants enhance significant humoral and cellular immune response in vaccines. However, finding a novel delivery system to protect pIL-12 from enzymatic degradation and achieve efficient delivery remains a major challenge. Methods We prepared the chitosan nanovaccine-loaded IL-12 expression plasmid (termed as “Ng(-)pIL-12”) and analysed the physicochemical properties, encapsulation efficiency and safety. Then, we evaluated the efficiency of Ng(-)pIL-12 for prophylactic HBV vaccine. Serum samples were collected and analysed for IL-12, HBsAg, anti-HBs IgG, IgG1 and IgG2b. Liver tissues were collected and analysed for HBV DNA and RNA. BMDCs and lymphocytes were collected and analysed for HBV-specific immune responses. To further confirm the long-term protective immune response against HBV, these immunised mice were challenged with hydrodynamic injection of pAAV/HBV 1.2 plasmid on day 56 after the initiation of immunisation. Results Chitosan nanovaccine prepared with CS and γ-PGA could load pIL-12 effectively and safely, and IL-12 was efficiently produced in vivo. Interestingly, Ng(-)pIL-12 adjuvant combined with HBsAg induced higher levels of anti-HBs IgG, IgG1 and IgG2b, promoted maturation and presentation capacity of DCs, especially CD8α+/CD103+ DCs. Meanwhile, Ng(-)pIL-12 adjuvant generated robust HBV-specific CD8+ T and CD4+ T cell responses. More importantly, Ng(-)pIL-12 adjuvant triggered terminally differentiated effector memory responses with strong anti-HBV effects. Conclusion Chitosan nanovaccines as an efficient carrier adjuvant system for pIL-12 combined with HBsAg induced protective anti-HBs IgG and enhanced HBV-specific CD8+ T and CD4+ T cell responses, and achieved long-term memory response against HBV, making it a promising candidate for prophylactic HBV vaccines. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/RZZ_0Z5j7Yc
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Affiliation(s)
- Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Haigang Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Yifei Hu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Dongqing Xu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Chunlai Yin
- Department of Immunology, Dalian Medical University, Dalian, People's Republic of China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
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Hepatocellular cancer therapy in patients with HIV infection: Disparities in cancer care, trials enrolment, and cancer-related research. Transl Oncol 2021; 14:101153. [PMID: 34144349 PMCID: PMC8220238 DOI: 10.1016/j.tranon.2021.101153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
In the highly active antiretroviral therapy (HAART) era, hepatocellular carcinoma (HCC) is arising as a common late complication of human immunodeficiency virus (HIV) infection, with a great impact on morbidity and mortality. Though HIV infection alone may not be sufficient to promote hepatocarcinogenesis, the complex interaction of HIV with hepatitis is a main aspect influencing HCC morbidity and mortality. Data about sorafenib effectiveness and safety in HIV-infected patients are limited, particularly for patients who are on HAART. However, in properly selected subgroups, outcomes may be comparable to those of HIV-uninfected patients. Scarce data are available for those other systemic treatments, either tyrosine kinase inhibitors, as well as immune checkpoint inhibitors (ICIs), which have been added to our therapeutic armamentarium. This review examines the influence of HIV infection on HCC development and natural history, summarizes main data on systemic therapies, offers some insight into possible mechanisms of T cell exhaustion and reversal of HIV latency with ICIs and issues about clinical trials enrollment. Nowadays, routine exclusion of HIV-infected patients from clinical trial participation is totally inappropriate, since it leaves a number of patients deprived of life-prolonging therapies.
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Inoue J, Sato K, Ninomiya M, Masamune A. Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis. Viruses 2021; 13:1124. [PMID: 34208172 PMCID: PMC8230773 DOI: 10.3390/v13061124] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/15/2022] Open
Abstract
The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; (K.S.); (M.N.); (A.M.)
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Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression. Sci Rep 2021; 11:7772. [PMID: 33833369 PMCID: PMC8032722 DOI: 10.1038/s41598-021-87537-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/27/2021] [Indexed: 02/07/2023] Open
Abstract
The inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.
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A putative amphipathic alpha helix in hepatitis B virus small envelope protein plays a critical role in the morphogenesis of subviral particles. J Virol 2021; 95:JVI.02399-20. [PMID: 33536177 PMCID: PMC8103704 DOI: 10.1128/jvi.02399-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) small (S) envelope protein has the intrinsic ability to direct the formation of small spherical subviral particles (SVPs) in eukaryotic cells. However, the molecular mechanism underlying the morphogenesis of SVPs from the monomeric S protein initially synthesized at the endoplasmic reticulum (ER) membrane remains largely elusive. Structure prediction and extensive mutagenesis analysis suggested that the amino acid residues spanning W156 to R169 of S protein form an amphipathic alpha helix and play essential roles in SVP production and S protein metabolic stability. Further biochemical analyses showed that the putative amphipathic alpha helix was not required for the disulfide-linked S protein oligomerization, but was essential for SVP morphogenesis. Pharmacological disruption of vesicle trafficking between the ER and Golgi complex in SVP producing cells supported the hypothesis that S protein-directed SVP morphogenesis takes place at the ER-Golgi intermediate compartment (ERGIC). Moreover, it was demonstrated that S protein is degraded in hepatocytes via a 20S proteasome-dependent, but ubiquitination-independent non-classic ER-associated degradation (ERAD) pathway. Taken together, the results reported herein favor a model in which the amphipathic alpha helix at the antigenic loop of S protein attaches to the lumen leaflet to facilitate SVP budding from the ERGIC compartment, whereas the failure of budding process may result in S protein degradation by 20S proteasome in an ubiquitination-independent manner.Importance Subviral particles are the predominant viral product produced by HBV-infected hepatocytes. Their levels exceed the virion particles by 10,000 to 100,000-fold in the blood of HBV infected individuals. The high levels of SVPs, or HBV surface antigen (HBsAg), in the circulation induces immune tolerance and contributes to the establishment of persistent HBV infection. The loss of HBsAg, often accompanied by appearance of anti-HBs antibodies, is the hallmark of durable immune control of HBV infection. Therapeutic induction of HBsAg loss is, therefore, considered to be essential for the restoration of host antiviral immune response and functional cure of chronic hepatitis B. Our findings on the mechanism of SVP morphogenesis and S protein metabolism will facilitate the rational discovery and development of antiviral drugs to achieve this therapeutic goal.
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D’Arienzo V, Magri A, Harris JM, Wing PAC, Ko C, Rubio CO, Revill PA, Protzer U, Balfe P, McKeating JA. A PCR assay to quantify patterns of HBV transcription. J Gen Virol 2021; 102:001373. [PMID: 31846416 PMCID: PMC7610515 DOI: 10.1099/jgv.0.001373] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) is the prototype member of the family Hepadnaviridae and replicates via episomal copies of a covalently closed circular DNA (cccDNA) genome of approximately 3.2 kb. The chromatinization of this small viral genome, with overlapping open reading frames and regulatory elements, suggests an important role for epigenetic pathways to regulate HBV transcription. However, the host pathways that regulate HBV transcription and the temporal nature of promoter usage in infected cells are not well understood, in part due to the compact genome structure and overlapping open reading frames. To address this we developed a simple and cost-effective PCR assay to quantify the major viral RNAs and validated this technique using current state-of-art de novo HBV infection model systems. Our PCR method is three orders of magnitude more sensitive than Northern blot and requires relatively small amounts of starting material, making this an attractive tool for assessing HBV transcription.
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Affiliation(s)
- Valentina D’Arienzo
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
| | - Andrea Magri
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
| | - James M. Harris
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
| | - Peter A. C. Wing
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
| | - Chunkyu Ko
- Institute of Virology, Technische Universität, München/Helmholtz Zentrum München, Germany
| | - Claudia Orbegozo Rubio
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
| | - Peter A. Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute of Infection and Immunity, Melbourne, Australia
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
| | - Ulrike Protzer
- Institute of Virology, Technische Universität, München/Helmholtz Zentrum München, Germany
- German Center for Infection Research (DZIF), Munich partner site, Munich, Germany
| | - Peter Balfe
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Jane A. McKeating
- Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
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Wu ZQ, Tan L, Gan WQ, Mo ZS, Chen DB, Wang PP, Zhao QY, Xie DY, Gao ZL. The relationship between the clearance of HBsAg and the remodeling of B cell subsets in CHB patients treated with Peg-IFN-α. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:414. [PMID: 33842635 PMCID: PMC8033293 DOI: 10.21037/atm-21-409] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background The seroconversion of the hepatitis B antigen is the ideal outcome for long-acting interferon-pegylated interferon-α (Peg-IFN-α) treatment among patients with chronic hepatitis B (CHB). B-cell response plays an important role in the process of hepatitis B antigen clearance, but the specific mechanism by which B-cell improve hepatitis B virus (HBV) is still unclear. Methods A total of 103 CHB patients participated in this study. The patients received 24 weeks of Peg-IFN-α treatment. Flow cytometry was used to detect B-cell surface markers’ cluster of differentiation cluster of differentiation CD19, CD24, and CD27 in the peripheral blood mononuclear cells (PBMCs) of CHB patients before and after 24 weeks of Peg-IFN-α treatment. Results After 24 weeks of Peg-IFN-α treatment, the content of memory B cells (CD19+CD27+) and effector B cells (CD19+CD38+) increased significantly. Further analysis showed that the clearance of the hepatitis B antigen was correlated with the change value, ΔT, of plasma cells before and after treatment. The B-cell subsets (CD19+CD24+; CD19+CD40+; CD19+CD40+; CD19+CD80+), was also tested and the results showed that CD19+CD24+ and CD19+CD80+ content also increased significantly after treatment. Conclusions After Peg-IFN-α treatment, the B-cell subsets of CHB patients are remodeled. Thus, Peg-IFN-α treatment appears to play an important role in the remodeling of B cell subsets and the clearance of HBV antigens. The results of this study provide a theoretical basis and guidance for the clinical treatment of CHB.
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Affiliation(s)
- Ze-Qian Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Lei Tan
- Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei-Qiang Gan
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Zhi-Shuo Mo
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Da-Biao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Pei-Pei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Qi-Yi Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Dong-Ying Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
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Hepatitis B core-based virus-like particles: A platform for vaccine development in plants. ACTA ACUST UNITED AC 2021; 29:e00605. [PMID: 33732633 PMCID: PMC7937989 DOI: 10.1016/j.btre.2021.e00605] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/17/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
Virus-like particles (VLPs) are a class of structures formed by the self-assembly of viral capsid protein subunits and contain no infective viral genetic material. The Hepatitis B core (HBc) antigen is capable of assembling into VLPs that can elicit strong immune responses and has been licensed as a commercial vaccine against Hepatitis B. The HBc VLPs have also been employed as a platform for the presentation of foreign epitopes to the immune system and have been used to develop vaccines against, for example, influenza A and Foot-and-mouth disease. Plant expression systems are rapid, scalable and safe, and are capable of providing correct post-translational modifications and reducing upstream production costs. The production of HBc-based virus-like particles in plants would thus greatly increase the efficiency of vaccine production. This review investigates the application of plant-based HBc VLP as a platform for vaccine production.
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Ciupe SM, Vaidya NK, Forde JE. Early events in hepatitis B infection: the role of inoculum dose. Proc Biol Sci 2021; 288:20202715. [PMID: 33563115 DOI: 10.1098/rspb.2020.2715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The relationship between the inoculum dose and the ability of the pathogen to invade the host is poorly understood. Experimental studies in non-human primates infected with different inoculum doses of hepatitis B virus have shown a non-monotonic relationship between dose magnitude and infection outcome, with high and low doses leading to 100% liver infection and intermediate doses leading to less than 0.1% liver infection, corresponding to CD4 T-cell priming. Since hepatitis B clearance is CD8 T-cell mediated, the question of whether the inoculum dose influences CD8 T-cell dynamics arises. To help answer this question, we developed a mathematical model of virus-host interaction following hepatitis B virus infection. Our model explains the experimental data well, and predicts that the inoculum dose affects both the timing of the CD8 T-cell expansion and the quality of its response, especially the non-cytotoxic function. We find that a low-dose challenge leads to slow CD8 T-cell expansion, weak non-cytotoxic functions, and virus persistence; high- and medium-dose challenges lead to fast CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance; while a super-low-dose challenge leads to delayed CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance. These results are useful for designing immune cell-based interventions.
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Affiliation(s)
- Stanca M Ciupe
- Department of Mathematics, Virginia Tech, Blacksburg, 24060 VA, USA
| | - Naveen K Vaidya
- Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA.,Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA.,Viral Information Institute, San Diego State University, San Diego, CA 92182, USA
| | - Jonathan E Forde
- Department of Mathematics and Computer Science, Hobart and William Smith Colleges, Geneva, New York 14456, USA
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Rong X, Ailing F, Xiaodong L, Jie H, Min L. Monitoring hepatitis B by using point-of-care testing: biomarkers, current technologies, and perspectives. Expert Rev Mol Diagn 2021; 21:195-211. [PMID: 33467927 DOI: 10.1080/14737159.2021.1876565] [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: 01/05/2023]
Abstract
Introduction: Liver diseases caused by hepatitis B virus (HBV) are pandemic infectious diseases that seriously endanger human health, conventional diagnosis methods can not meet the requirements in resource-limited areas. The point of acre detection methods can easily resolve those problems. Herein, we review the most recent advances in POC-based hepatitis B detection methods and present some recommendations for future development. It aims to provide ideas for future research.Areas covered: Epidemiological data on Hepatitis B, conventional diagnostic methods for hepatitis B detection, some latest point of care detection methods for hepatitis B detection and list out the recommendations for future development.Expert opinion: This manuscript summarized traditional biomarkers of different hepatitis B stages and recent-developed POCT platforms (including microfluidic platforms and lateral-flow strips) and discuss the challenges associated with their use. Some emerging biomarkers that can be used in hepatitis B diagnosis are also listed. This manuscript has certain guiding significance to the development of hepatitis B detection.
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Affiliation(s)
- Xu Rong
- Institute of Physics & Optoelectronics Technology, Baoji University of Arts and Sciences, Baoji, China
| | - Feng Ailing
- Institute of Physics & Optoelectronics Technology, Baoji University of Arts and Sciences, Baoji, China
| | - Li Xiaodong
- Institute of Physics & Optoelectronics Technology, Baoji University of Arts and Sciences, Baoji, China
| | - Hu Jie
- Suzhou DiYinAn Biotech Co., Ltd. & Suzhou Innovation Center for Life Science and Technology, Suzhou, China
| | - Lin Min
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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