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Li D, Ho V, Teng CF, Tsai HW, Liu Y, Bae S, Ajoyan H, Wettengel JM, Protzer U, Gloss BS, Rockett RJ, Al Asady R, Li J, So S, George J, Douglas MW, Tu T. Novel digital droplet inverse PCR assay shows that natural clearance of hepatitis B infection is associated with fewer viral integrations. Emerg Microbes Infect 2025; 14:2450025. [PMID: 39749570 PMCID: PMC11731057 DOI: 10.1080/22221751.2025.2450025] [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: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 01/04/2025]
Abstract
Hepatitis B virus (HBV) DNA integration into the host cell genome is reportedly a major cause of liver cancer, and a source of hepatitis B surface antigen (HBsAg). High HBsAg levels can alter immune responses which therefore contributes to the progression of HBV-related disease. However, to what extent integration leads to the persistent circulating HBsAg is unclear. Here, we aimed to determine if the extent of HBV DNA integration is associated with the persistence of circulating HBsAg in people exposed to HBV. We established a digital droplet quantitative inverse PCR (dd-qinvPCR) method to quantify integrated HBV DNA in patients who had been exposed to HBV (anti-HBc positive and HBeAg-negative). Total DNA extracts from both liver resections (n = 32; 14 HBsAg-negative and 18 HBsAg-positive) and fine-needle aspirates (FNA, n = 10; 2 HBsAg-negative and 8 HBsAg-positive) were analysed. Using defined in vitro samples for assay establishment, we showed that dd-qinvPCR could detect integrations within an input of <80 cells. The frequency of integrated HBV DNA in those who had undergone HBsAg loss (n = 14, mean ± SD of 1.514 × 10-3 ± 1.839 × 10-3 integrations per cell) was on average 9-fold lower than those with active HBV infection (n = 18, 1.16 × 10-2 ± 1.76 × 10-2 integrations per cell; p = 0.0179). In conclusion, we have developed and validated a highly precise, sensitive and quantitative PCR-based method for the quantification of HBV integrations in clinical samples. Natural clearance of HBV is associated with fewer viral integrations. Future studies are needed to determine if dynamics of integrated HBV DNA can inform the development of curative therapies.
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Affiliation(s)
- Dong Li
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Vikki Ho
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Chiao-Fang Teng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yuanyuan Liu
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Sarah Bae
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Harout Ajoyan
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Jochen M. Wettengel
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Brian S. Gloss
- Scientific Platforms, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
| | - Rebecca J. Rockett
- Centre for Infectious Diseases and Microbiology–Public Health, Westmead Hospital, Westmead, NSW, Australia
| | - Rafid Al Asady
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Jane Li
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Simon So
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Mark W. Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
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Jin C, Hu B, Liu H, Wang R, Jang J, Su M. Cystathionine gamma-lyase as an inflammatory factor and its link with immune inflammation in hepatitis B virus-related liver disease. Sci Rep 2025; 15:17777. [PMID: 40404804 PMCID: PMC12098708 DOI: 10.1038/s41598-025-98922-z] [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] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 04/15/2025] [Indexed: 05/24/2025] Open
Abstract
We aimed to explore the effectiveness of CTH as a serum inflammation biomarker for HCC. Enzyme-linked immunosorbent assay was used to detect serum levels of CTH, interleukin-6 (IL-6), C-reactive protein (CRP), and IL-10. The Scheuer scoring system was used to assess the liver inflammation grading (significant liver inflammation: ≥ G2 grade). CTH levels in the HCC group were significantly elevated (P < 0.0001). Of 146 patients, 58.22% exhibited significant liver inflammation. CTH levels in patients with significant liver inflammation were significantly higher than those in patients with no or mild liver inflammation (< G 2) (p < 0.0001). The area under the Receiver Operating Characteristic (ROC) curve for CTH in predicting significant hepatitis was 0.77 (sensitivity, 81.2%; specificity,62.3%). There was a significant positive correlation (r = 0.50, p < 0.05) between serum CTH levels and histopathological parameter G. The area under the ROC curve for CTH in predicting hepatocellular carcinoma was 0.83 (sensitivity, 64.6%; specificity, 83.3%). CTH and AFP improved the diagnostic accuracy of HCC. CTH levels significantly decreased 6 months post-operation (p < 0.05). The recurrence of HCC caused significant increases in CTH levels. Thus, CTH can serve as a serum inflammation marker for HCC.
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Affiliation(s)
- Chao Jin
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Bobin Hu
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Hongyu Liu
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Rongming Wang
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Jianning Jang
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Minghua Su
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China.
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Kakh M, Doroudchi M, Talepoor A. Induction of Regulatory T Cells After Virus Infection and Vaccination. Immunology 2025. [PMID: 40329764 DOI: 10.1111/imm.13927] [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: 09/24/2024] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 05/08/2025] Open
Abstract
Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.
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Affiliation(s)
- MansourehKarimi Kakh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - AtefeGhamar Talepoor
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Giovane RA, deWeber K, Sauceda U, Bianchi D. Blood-Borne Infection Prevention in Combat Sports: Position Statement of the Association of Ringside Physicians. Clin J Sport Med 2025:00042752-990000000-00320. [PMID: 40197438 DOI: 10.1097/jsm.0000000000001350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 02/22/2025] [Indexed: 04/10/2025]
Abstract
ABSTRACT The Association of Ringside Physicians (ARP) emphasizes the importance of screening combat sports athletes for blood-borne infections, including hepatitis B, HIV, and hepatitis C, to mitigate transmission risks and ensure participant safety. Although transmission of hepatitis B and C and HIV in combat sports is rare, protecting athletes is of utmost importance. It is the recommendation of the ARP that all fighters participating in combat sports, in which the presence of blood is a common occurrence and is allowed during competition, should undergo testing for HIV, hepatitis B (HBV), and hepatitis C (HCV). Testing should be conducted using serum samples, because rapid tests are not considered acceptable for accurate results. Testing for HBV, HCV, and HIV should optimally be done within 3 months of competition, but within 6 months is acceptable. Athletes whose tests suggest active HBV, HCV, or HIV infection should be disqualified from competition in sports where blood is common and allowed. Athletes with cured prior HCV infection may be cleared for competition in all combat sports. Athletes with prior HBV infection and no detectable HBV DNA in blood can be cleared for competition in all combat sports. Athletes with latent HBV infection with detectable HBV DNA in blood have a small risk of disease reactivation, so they should not be cleared.
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Affiliation(s)
- Richard A Giovane
- Department of Family Medicine, University of Alabama, Tuscaloosa, Alabama
| | - Kevin deWeber
- SW Washington Sports Medicine Fellowship, Vancouver, Washington
- Oregon Health and Science University, Portland, Oregon
| | - Uziel Sauceda
- RUHS/UCR Sports Medicine Fellowship, Moreno Valley California
- Riverside University Health System/University of California Riverside, Moreno Valley California
| | - Davide Bianchi
- Chief Medical Officer SwissBoxing, Verbandarzt SwissBoxing, Switzerland
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Huang SW, Long H, Huang JQ. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2024; 14:8. [PMID: 39860969 PMCID: PMC11768139 DOI: 10.3390/pathogens14010008] [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: 11/05/2024] [Revised: 12/25/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.
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Affiliation(s)
- Shuai-Wen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Hong Long
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
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Lu L, Cong D, Lv T, Wang H, Wang X. Novel NTCP ligand dimeric bile acid conjugated with ASO reduce hepatitis B virus surface antigen in vivo. Eur J Med Chem 2024; 280:116955. [PMID: 39426128 DOI: 10.1016/j.ejmech.2024.116955] [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: 09/04/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024]
Abstract
Hepatitis B virus (HBV) specifically infects hepatocytes and causes severe liver diseases. However, functional cure is rarely attainable by current treatment modalities. Anti-sense oligonucleotide (ASO), which targets pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication, has been studied as a novel treatment strategy for HBV cure and can be conjugated with N-acetylgalactosamine (GalNAc), thereby enhancing hepatocyte uptake via the asialoglycoprotein receptor (ASGPR). In comparison to GalNAc-ASO conjugation, clinical research indicates that unconjugated ASO is more effective in reducing hepatitis B virus surface antigen level. Recent studies have revealed that human sodium taurocholate co-transporting polypeptide (NTCP) is a functional cellular receptor for hepatitis B virus (HBV), and the bivalent bile acid structure may interact with multiple binding sites on NTCP, yielding much stronger interaction and substantially improved binding affinity. In this study, we synthesized NTCP ligand-antisense oligonucleotide (ASO) conjugation and evaluated the potential of antiviral therapy specifically reduction of HBV antigenemia in mice in vivo.
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Affiliation(s)
- Lei Lu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 S. Tianshui Rd., Lanzhou, 730000, PR China
| | - Dezi Cong
- SicaGene Biotechnology Co., Ltd, Buiding 16, No. 9 Yongteng North Road, Haidian District, Beijing, 100144, PR China
| | - Tinghong Lv
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 S. Tianshui Rd., Lanzhou, 730000, PR China
| | - Haisheng Wang
- SicaGene Biotechnology Co., Ltd, Buiding 16, No. 9 Yongteng North Road, Haidian District, Beijing, 100144, PR China
| | - Xiaolei Wang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 S. Tianshui Rd., Lanzhou, 730000, PR China; SicaGene Biotechnology Co., Ltd, Buiding 16, No. 9 Yongteng North Road, Haidian District, Beijing, 100144, PR China.
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Kar A, Mukherjee S, Mukherjee S, Biswas A. Ubiquitin: A double-edged sword in hepatitis B virus-induced hepatocellular carcinoma. Virology 2024; 599:110199. [PMID: 39116646 DOI: 10.1016/j.virol.2024.110199] [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: 06/28/2024] [Revised: 07/26/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024]
Abstract
Hepatitis B virus is one of the leading causes behind the neoplastic transformation of liver tissue and associated mortality. Despite the availability of many therapies and vaccines, the pathogenic landscape of the virus remains elusive; urging the development of novel strategies based on the fundamental infectious and transformative modalities of the virus-host interactome. Ubiquitination is a widely observed post-translational modification of several proteins, which either regulates the proteins' turnover or impacts their functionalities. In recent years, ample amount of literature has accumulated regarding the ubiquitination dynamics of the HBV proteins as well as the host proteins during HBV infection and carcinogenesis; with direct and detailed characterization of the involvement of HBV in these processes. Interestingly, while many of these ubiquitination events restrict HBV life cycle and carcinogenesis, several others promote the emergence of hepatocarcinoma by putting the virus in an advantageous position. This review sums up the snowballing literature on ubiquitination-mediated regulation of the host-HBV crosstalk, with special emphasis on its influence on the establishment and progression of hepatocellular carcinoma on a molecular level. With the advent of cutting-edge ubiquitination-targeted therapeutic approaches, the findings emanating from this review may potentiate the identification of novel anti-HBV targets for the formulation of novel anticancer strategies to control the HBV-induced hepato-carcinogenic process on a global scale.
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Affiliation(s)
- Arpita Kar
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Sandipan Mukherjee
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Soumyadeep Mukherjee
- Department of in Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India
| | - Avik Biswas
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India.
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Dong H, Liao Y, Shang M, Fu Y, Zhang H, Luo M, Hu B. Effects of co-infection with Clonorchis sinensis on T cell exhaustion levels in patients with chronic hepatitis B. J Helminthol 2024; 98:e13. [PMID: 38263743 DOI: 10.1017/s0022149x23000871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
To investigate the effects of co-infection with Clonorchis sinensis (C. sinensis) on T cell exhaustion levels in patients with chronic hepatitis B, we enrolled clinical cases in this study, including the patients with concomitant C. sinensis and HBV infection. In this study, we detected inhibitory receptors and cytokine expression in circulating CD4+ and CD8+ T cells by flow cytometry. PD-1 and TIM-3 expression levels were significantly higher on CD4+ T and CD8+ T cells from co-infected patients than on those from the HBV patients. In addition, CD4+ T cells and CD8+ T cells function were significantly inhibited by C. sinensis and HBV co-infection compared with HBV single infection, secreting lower levels of Interferon gamma (IFN-γ), Interleukin-2 (IL-2), and TNF-α. Our current results suggested that C. sinensis co-infection could exacerbate T cell exhaustion in patients with chronic hepatitis B. PD-1 and TIM-3 could be novel biomarkers for T cell exhaustion in patients with Clonorchis sinensis and chronic hepatitis B co-infection. Furthermore, it may be one possible reason for the weaker response to antiviral therapies and the chronicity of HBV infection in co-infected patients. We must realize the importance of C. sinensis treatment for HBV-infected patients. It might provide useful information for clinical doctors to choose the right treatment plans.
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Affiliation(s)
- Huimin Dong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuan Liao
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Mei Shang
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuechun Fu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hongbin Zhang
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Minqi Luo
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Tian R, Yang D, Xu B, Deng R, Xue B, Wang L, Li H, Liu Q, Wang X, Tang S, Wan M, Pei H, Zhu H. Establishment of cell culture model and humanized mouse model of chronic hepatitis B virus infection. Microbiol Spectr 2024; 12:e0274523. [PMID: 38018998 PMCID: PMC10783038 DOI: 10.1128/spectrum.02745-23] [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: 07/08/2023] [Accepted: 10/20/2023] [Indexed: 11/30/2023] Open
Abstract
IMPORTANCE Approximately 257 million people worldwide have been infected with hepatitis B virus (HBV), and HBV infection can cause chronic hepatitis, cirrhosis, and even liver cancer. The lack of suitable and effective infection models has greatly limited research in HBV-related fields for a long time, and it is still not possible to discover a method to completely and effectively remove the HBV genome. We have constructed a hepatocellular carcinoma cell line, HLCZ01, that can support the complete life cycle of HBV. This model can mimic the long-term stable infection of HBV in the natural state and can replace primary human hepatocytes for the development of human liver chimeric mice. This model will be a powerful tool for research in the field of HBV.
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Affiliation(s)
- Renyun Tian
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Di Yang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Biaoming Xu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Rilin Deng
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Binbin Xue
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Luoling Wang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Huiyi Li
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Qian Liu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Xiaohong Wang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Songqing Tang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Mengyu Wan
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
| | - Hua Pei
- Department of Pathogen Biology and Immunology, Department of Clinical Laboratory of the Second Affiliated Hospital, Key Laboratory of Tropical Translational Medicine of Ministry of Education,Institute of Pathogen Biology and Immunology,School of Basic Medicine and Life Science, The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Hainan, China
| | - Haizhen Zhu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China
- Department of Pathogen Biology and Immunology, Department of Clinical Laboratory of the Second Affiliated Hospital, Key Laboratory of Tropical Translational Medicine of Ministry of Education,Institute of Pathogen Biology and Immunology,School of Basic Medicine and Life Science, The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Hainan, China
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10
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Boni C, Rossi M, Montali I, Tiezzi C, Vecchi A, Penna A, Doselli S, Reverberi V, Ceccatelli Berti C, Montali A, Schivazappa S, Laccabue D, Missale G, Fisicaro P. What Is the Current Status of Hepatitis B Virus Viro-Immunology? Clin Liver Dis 2023; 27:819-836. [PMID: 37778772 DOI: 10.1016/j.cld.2023.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
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Affiliation(s)
- Carolina Boni
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Sara Doselli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valentina Reverberi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | - Anna Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Simona Schivazappa
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Gabriele Missale
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
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11
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Li Y, Yang Y, Li T, Wang Z, Gao C, Deng R, Ma F, Li X, Ma L, Tian R, Li H, Zhu H, Zeng L, Gao Y, Lv G, Niu J, Crispe IN, Tu Z. Activation of AIM2 by hepatitis B virus results in antiviral immunity that suppresses hepatitis C virus during coinfection. J Virol 2023; 97:e0109023. [PMID: 37787533 PMCID: PMC10617567 DOI: 10.1128/jvi.01090-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 08/28/2023] [Indexed: 10/04/2023] Open
Abstract
IMPORTANCE Clinical data suggest that Hepatitis C virus (HCV) levels are generally lower in Hepatitis B virus (HBV) co-infected patients, but the mechanism is unknown. Here, we show that HBV, but not HCV, activated absent in melanoma-2. This in turn results in inflammasome-mediated cleavage of pro-IL-18, leading to an innate immune activation cascade that results in increased interferon-γ, suppressing both viruses.
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Affiliation(s)
- Yongqi Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yang Yang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Tianyang Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhengmin Wang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunfeng Gao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Rilin Deng
- Hunan Provincial Key Laboratory of Medical Virology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, Hunan, China
| | - Faxiang Ma
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xinyang Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Licong Ma
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Renyun Tian
- Hunan Provincial Key Laboratory of Medical Virology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, Hunan, China
| | - Huiyi Li
- Hunan Provincial Key Laboratory of Medical Virology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, Hunan, China
| | - Haizhen Zhu
- Hunan Provincial Key Laboratory of Medical Virology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, Hunan, China
| | - Lei Zeng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhang Gao
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun , Jilin, China
| | - Guoyue Lv
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun , Jilin, China
| | - Junqi Niu
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun , Jilin, China
| | - Ian Nicholas Crispe
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Zhengkun Tu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun , Jilin, China
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12
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Olenginski LT, Attionu SK, Henninger EN, LeBlanc RM, Longhini AP, Dayie TK. Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target. Viruses 2023; 15:1913. [PMID: 37766319 PMCID: PMC10534774 DOI: 10.3390/v15091913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is ε, a cis-acting regulatory stem-loop RNA situated within the HBV pregenomic RNA (pgRNA). The binding of ε to the viral polymerase protein (P) is pivotal, as it triggers the packaging of pgRNA and P, as well as the reverse transcription of the viral genome. Consequently, small molecules capable of disrupting this interaction hold the potential to inhibit the early stages of HBV replication. The rational design of such ligands necessitates high-resolution structural information for the ε-P complex or its individual components. While these data are currently unavailable for P, our recent structural elucidation of ε through solution nuclear magnetic resonance spectroscopy marks a significant advancement in this area. In this review, we provide a brief overview of HBV replication and some of the therapeutic strategies to combat chronic HBV infection. These descriptions are intended to contextualize our recent experimental efforts to characterize ε and identify ε-targeting ligands, with the ultimate goal of developing novel anti-HBV therapeutics.
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Affiliation(s)
- Lukasz T. Olenginski
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Department of Biochemistry, University of Colorado, Boulder, CO 80309, USA
| | - Solomon K. Attionu
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Erica N. Henninger
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Regan M. LeBlanc
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Andrew P. Longhini
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
- Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Theodore K. Dayie
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
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13
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Adugna A. Antigen Recognition and Immune Response to Acute and Chronic Hepatitis B Virus Infection. J Inflamm Res 2023; 16:2159-2166. [PMID: 37223107 PMCID: PMC10202203 DOI: 10.2147/jir.s411492] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/02/2023] [Indexed: 05/25/2023] Open
Abstract
The antigen recognition and immune response to acute and chronic hepatitis B virus (HBV) infections are the result of both the innate and adaptive immune response. The innate immune response comprises Dendritic Cells (DCs), which served as professional antigen-presenting cells and a bridge between innate and adaptive immunity, Kupffer cells and inflammatory monocytes for the continuous inflammation of hepatocyte, neutrophils for hepatic tissue damage due to acute inflammation, type I interferons (IFN), which induce an antiviral state on infected cells, directs natural killer (NK) cells to kill virally infected cells, reduces the population of infected cells, and promotes the effective maturation and site recruitment of adaptive immunity through the production of pro-inflammatory cytokines and chemokines. Through stimulating B cells, T-helper, and cytotoxic T cells, the adaptive immune system also protects against hepatitis B infection. During HBV infection, a network of cell types that can either play protective or harmful functions creates the anti-viral adaptive immune response. These many elements, such as Cluster of differentiation four (CD4) T cells (traditionally known as helper T cells), are potent cytokine producers and necessary for the effective maturation of effector cytotoxic cluster of differentiation eight (CD8) T cells and B cell antibody production. By cytolytic and non-cytolytic processes, CD8 T cells are able to eliminate HBV-infected hepatocytes and directly detect virus-infected cells, and circulating CD4+ CD25+ regulatory T cells for the modulation of immune system. In order to avoid reinfection, B cells can produce antibodies that destroy free viral particles. Moreover, by presenting HBV antigens to helper T cells, B cells may also influence how well these cells operate.
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Affiliation(s)
- Adane Adugna
- Medical Microbiology, Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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14
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Svicher V, Salpini R, D’Anna S, Piermatteo L, Iannetta M, Malagnino V, Sarmati L. New insights into hepatitis B virus lymphotropism: Implications for HBV-related lymphomagenesis. Front Oncol 2023; 13:1143258. [PMID: 37007163 PMCID: PMC10050604 DOI: 10.3389/fonc.2023.1143258] [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: 01/12/2023] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
HBV is one of the most widespread hepatitis viruses worldwide, and a correlation between chronic infection and liver cancer has been clearly reported. The carcinogenic capacity of HBV has been reported for other solid tumors, but the largest number of studies focus on its possible lymphomagenic role. To update the correlation between HBV infection and the occurrence of lymphatic or hematologic malignancies, the most recent evidence from epidemiological and in vitro studies has been reported. In the context of hematological malignancies, the strongest epidemiological correlations are with the emergence of lymphomas, in particular non-Hodgkin's lymphoma (NHL) (HR 2.10 [95% CI 1.34-3.31], p=0.001) and, more specifically, all NHL B subtypes (HR 2.14 [95% CI 1.61-2.07], p<0.001). Questionable and unconfirmed associations are reported between HBV and NHL T subtypes (HR 1.11 [95% CI 0.88-1.40], p=0.40) and leukemia. The presence of HBV DNA in peripheral blood mononuclear cells has been reported by numerous studies, and its integration in the exonic regions of some genes is considered a possible source of carcinogenesis. Some in vitro studies have shown the ability of HBV to infect, albeit not productively, both lymphomonocytes and bone marrow stem cells, whose differentiation is halted by the virus. As demonstrated in animal models, HBV infection of blood cells and the persistence of HBV DNA in peripheral lymphomonocytes and bone marrow stem cells suggests that these cellular compartments may act as HBV reservoirs, allowing replication to resume later in the immunocompromised patients (such as liver transplant recipients) or in subjects discontinuing effective antiviral therapy. The pathogenetic mechanisms at the basis of HBV carcinogenic potential are not known, and more in-depth studies are needed, considering that a clear correlation between chronic HBV infection and hematological malignancies could benefit both antiviral drugs and vaccines.
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Affiliation(s)
- Valentina Svicher
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marco Iannetta
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Vincenzo Malagnino
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Loredana Sarmati
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
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15
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Wang Q, Qian H, Liu X, Jiang J, Hao Q. Plasma cytokine profile in occult HBV-infected blood donors. Future Virol 2023. [DOI: 10.2217/fvl-2022-0193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Aim: Cytokine profile in occult HBV infection (OBI) was systematically investigated to identify the immunopathogenesis of OBI. Materials & methods: A total of 46 OBI, ten asymptomatic hepatitis B surface antigen carriers, ten chronic hepatitis B and 12 healthy blood donors were recruited. A total of 21 plasma cytokines were detected. Results: Compared with healthy blood donors, elevated plasma Th1, Th2, Th17 and immune regulatory associated cytokines were observed in OBI. Almost no significant difference was found for these cytokines among OBI, asymptomatic hepatitis B surface antigen carriers and chronic hepatitis B. OBI displayed the predominance of type 2 and regulatory immunity. Conclusion: OBI displayed the general cytokine profile of chronic HBV infection, which might contribute to virus persistence and the presence of the liver microinflammatory environment. The clinical implications of OBI deserve more attention.
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Affiliation(s)
- Qinghui Wang
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Huizhong Qian
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Xiao Liu
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Jian Jiang
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Qingqin Hao
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
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16
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Zhang C, Li J, Cheng Y, Meng F, Song JW, Fan X, Fan H, Li J, Fu YL, Zhou MJ, Hu W, Wang SY, Fu YJ, Zhang JY, Xu RN, Shi M, Hu X, Zhang Z, Ren X, Wang FS. Single-cell RNA sequencing reveals intrahepatic and peripheral immune characteristics related to disease phases in HBV-infected patients. Gut 2023; 72:153-167. [PMID: 35361683 PMCID: PMC9763233 DOI: 10.1136/gutjnl-2021-325915] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 03/16/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVE A comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure. DESIGN We performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation. RESULTS Both IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell-cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores. CONCLUSION Our study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.
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Affiliation(s)
- Chao Zhang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiesheng Li
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China,Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
| | - Yongqian Cheng
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Fanping Meng
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jin-Wen Song
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xing Fan
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hongtao Fan
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China
| | - Jing Li
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yu-Long Fu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming-Ju Zhou
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wei Hu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Si-Yu Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yuan-Jie Fu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ji-Yuan Zhang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ruo-Nan Xu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming Shi
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xueda Hu
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China
| | - Zemin Zhang
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China .,Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
| | - Xianwen Ren
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China .,Changping Laboratory, Beijing, China
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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17
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Srivastava M, Copin R, Choy A, Zhou A, Olsen O, Wolf S, Shah D, Rye-Weller A, Chen L, Chan N, Coppola A, Lanza K, Negron N, Ni M, Atwal GS, Kyratsous CA, Olson W, Salzler R. Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues. Front Immunol 2022; 13:1032716. [PMID: 36582233 PMCID: PMC9793402 DOI: 10.3389/fimmu.2022.1032716] [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: 08/31/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.
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18
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Fisicaro P. Engineered IFN-α and anti-PDL1 containing compounds to target the liver and restore antiviral protection for HBV cure. Gut 2022; 72:gutjnl-2022-328902. [PMID: 36591618 DOI: 10.1136/gutjnl-2022-328902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 01/03/2023]
Affiliation(s)
- Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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19
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Hu Y, Sun F, Yuan Q, Du J, Hu L, Gu Z, Zhou Q, Du X, He S, Sun Y, Wang Q, Fan L, Wang L, Qin S, Chen S, Li J, Wu W, Mao J, Zhou Y, Zhou Q, Zhang G, Ding CZ. Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection. Bioorg Med Chem Lett 2022; 75:128977. [PMID: 36089112 DOI: 10.1016/j.bmcl.2022.128977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/25/2022] [Accepted: 09/04/2022] [Indexed: 11/09/2022]
Abstract
Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).
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Affiliation(s)
- Yanbin Hu
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Fei Sun
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Qiang Yuan
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Jinhua Du
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Lihong Hu
- WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
| | - Zhengxian Gu
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Qiong Zhou
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Xiaoting Du
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shibo He
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Ya Sun
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Qian Wang
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Lirong Fan
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Lina Wang
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shaohua Qin
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Shuhui Chen
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Jian Li
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
| | - Wenqiang Wu
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - John Mao
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Yixin Zhou
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Qiaoyun Zhou
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - George Zhang
- Fujian Akeylink Biotechnology Co.,Ltd, Fujian, China
| | - Charles Z Ding
- WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
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20
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Xie S, Yang L, Bi X, Deng W, Jiang T, Lin Y, Wang S, Zhang L, Liu R, Chang M, Wu S, Gao Y, Hao H, Shen G, Xu M, Chen X, Hu L, Lu Y, Song R, Xie Y, Li M. Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B. Front Immunol 2022; 13:1036612. [PMID: 36353632 PMCID: PMC9637985 DOI: 10.3389/fimmu.2022.1036612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/12/2022] [Indexed: 08/30/2023] Open
Abstract
OBJECTIVE We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV. METHODS This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg. RESULTS The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (β=-0.025, t=-2.613, P=0.014; β=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (β=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (β=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (β=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (β=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (β=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (β=-0.137, t=-3.273, P=0.003). CONCLUSIONS The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.
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Affiliation(s)
- Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Rui Song
- Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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21
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Xia Y, Gao B, Zhang X. Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC. Front Oncol 2022; 12:993437. [PMID: 36212470 PMCID: PMC9539266 DOI: 10.3389/fonc.2022.993437] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022] Open
Abstract
Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells’ metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.
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Affiliation(s)
- Yixue Xia
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai, China
| | - Binghong Gao
- School of Elite Sport, Shanghai University of Sport, Shanghai, China
- Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai, China
- *Correspondence: Binghong Gao, ; Xue Zhang,
| | - Xue Zhang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- School of Elite Sport, Shanghai University of Sport, Shanghai, China
- Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai, China
- *Correspondence: Binghong Gao, ; Xue Zhang,
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22
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Mohammadi H, Alavian SM, Sharafi H. Association of single nucleotide polymorphisms in immune-related genes with spontaneous HBsAg seroconversion: A systematic review and meta-analysis. Int Immunopharmacol 2022; 110:108982. [PMID: 35752129 DOI: 10.1016/j.intimp.2022.108982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 05/28/2022] [Accepted: 06/15/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Studies have reported that the immune system modulation genes are involved in the seroconversion during hepatitis B virus (HBV) infection. Here, a systematic review with meta-analysis is implemented on the association of polymorphisms in immune-related genes with the spontaneous hepatitis B surface antigen (HBsAg) seroconversion. METHODS A systematic literature search was conducted in the main electronic databases of Scopus, PubMed, and Web of Science before May 2022. Pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were used to evaluate the strength of the association between genetic polymorphisms and the chance of spontaneous HBsAg seroconversion. RESULTS A total of 40 studies finally included for meta-analysis of 2 HLA-DP SNPs, 2 HLA-DQ SNPs, 3 IFNL3/4 SNPs, 2 IL10 SNPs, and 5 TNF SNPs. Based on the overall pooled analysis, HLA-DP rs3077 A (OR = 1.47, 95%CI: 1.32-1.65), HLA-DP rs9277535 A (OR = 1.48, 95%CI: 1.32-1.66), HLA-DQ rs2856718 G (OR = 1.37, 95%CI: 1.18-1.59), HLA-DQ rs7453920 A (OR = 1.41, 95%CI: 1.04-1.93), IFNL3/4 rs12980275 G (OR = 1.26, 95%CI: 1.01-1.58), TNFA rs1799964 T (OR = 1.17, 95%CI: 1.02-1.35), and TNFA rs1800630 C (OR = 1.26, 95%CI: 1.03-1.55) increased significantly the chance of spontaneous HBsAg seroconversion. CONCLUSION This meta-analysis showed that the HLA-DP gene rs3077 and rs9277535 SNPs, HLA-DQ gene rs2856718 and rs7453920 SNPs, IFNL3/4 gene rs12980275 SNP, TNFA gene rs1799964 and rs1800630 SNPs are involved in the spontaneous HBsAg seroconversion.
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Affiliation(s)
- Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases (MELD) Center, Tehran, Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
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23
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Kayesh MEH, Hashem MA, Sanada T, Kitab B, Rashid MHO, Akter L, Ezzikouri S, Murakami S, Ogawa S, Tanaka Y, Kohara M, Tsukiyama-Kohara K. Characterization of innate immune response to hepatitis B virus genotype F acute infection in tree shrew (Tupaia belangeri) model. FRONTIERS IN VIROLOGY 2022; 2. [DOI: 10.3389/fviro.2022.926831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Hepatitis B virus (HBV) infection is a global public health problem. The clinical outcomes of HBV infections are influenced by host as well as viral factors, including viral genotypes and subgenotypes. The interplay between HBV and host innate immunity remains unclear because of the lack of a suitable small animal model. Tree shrews (Tupaia belangeri) have been utilized as a useful animal model for hepatitis viruses such as hepatitis B and C viruses. In this study, we characterized acute infections by HBV genotype F (HBV-F) wild type (Wt) and mutant type (Mt) viruses in adult tree shrews. Serum alanine aminotransferase levels were measured before and post- infection 7 and 14 dpi. Both HBV-F-Wt and Mt were detected in the HBV-F-infected tree shrew serum and liver tissue at 7 and 14 dpi. We examined the intrahepatic expression patterns of Toll-like receptors (TLRs) (TLR1–9 mRNAs), cGAS, several transcription factors such as STAT1, STAT2, IRF7, HNF4, PD-L1, and cytokines, including IFN-β, IFN-γ, IL-6, and TNF-α in HBV-F Wt/Mt-infected tree shrews. When compared with uninfected animal group, significant suppression of TLR8 in HBV-F-Wt infected animals and significant suppression of PD-L1 in both HBV-F-Wt and Mt infected animals were observed. Thus, tree shrew can be a useful animal model to characterize HBV-F pathogenesis.
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24
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Erken R, Loukachov V, van Dort K, van den Hurk A, Takkenberg RB, de Niet A, Jansen L, Willemse S, Reesink H, Kootstra N. Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B. Hepatology 2022; 76:196-206. [PMID: 35073596 PMCID: PMC9305117 DOI: 10.1002/hep.32352] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/20/2021] [Accepted: 01/07/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes. APPROACH AND RESULTS We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up. CONCLUSIONS Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB.
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Affiliation(s)
- Robin Erken
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands,Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Vladimir Loukachov
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - Karel van Dort
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - Anne van den Hurk
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
| | - R. Bart Takkenberg
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Anniki de Niet
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Louis Jansen
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Sophie Willemse
- Department of Gastroenterology and HepatologyAmsterdam Gastroenterology Endocrinology MetabolismAmsterdam UMC, location AMCAmsterdamthe Netherlands
| | - Henk Reesink
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeidenthe Netherlands
| | - Neeltje Kootstra
- Department of Experimental ImmunologyAmsterdam UMC, location AMCAmsterdam Infection & Immunity InstituteUniversity of AmsterdamAmsterdamthe Netherlands
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25
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Ahmed Z, Shetty A, Victor DW, Kodali S. Viral hepatitis: A narrative review of hepatitis A–E. World J Meta-Anal 2022; 10:99-121. [DOI: 10.13105/wjma.v10.i3.99] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/27/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis continues to be a major health concern leading to hepatic decompensation ranging from acute hepatitis to cirrhosis and hepatocellular carcinoma. The hepatic and extrahepatic manifestations are not only debilitating but also associated with a significant economic burden. Over the last two decades, the field of virology has made significant breakthroughs leading to a better understanding of the pathophysiology of viral hepatitis, which in turn has led to new therapeutic options. The advent of direct-acting antiviral agents changed the landscape of hepatitis C virus (HCV) therapy, and new drugs are in the pipeline for chronic hepatitis B virus (HBV) treatment. There has also been a significant emphasis on screening and surveillance programs, widespread availability of vaccines, and linkage of care. Despite these efforts, significant gaps persist in care, and there is a pressing need for increased collaboration and teamwork across the globe to achieve a reduction of disease burden and elimination of HBV and HCV.
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Affiliation(s)
- Zunirah Ahmed
- Division of Gastroenterology and Hepatology, Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, TX 77030, United States
| | - Akshay Shetty
- Department of Gastroenterology and Hepatology, University of California, Los Angeles, CA 90095, United States
| | - David W Victor
- Department of Hepatology, J C Walter Jr Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Weill Cornell Medical College, Houston, TX 77030, United States
| | - Sudha Kodali
- Department of Hepatology, J C Walter Jr Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Weill Cornell Medical College, Houston, TX 77030, United States
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26
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Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022; 13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [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: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open
Abstract
Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.
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Affiliation(s)
- Steffen Wildum
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kyle E Korolowicz
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Guido Steiner
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Lue Dai
- Roche Pharma, Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China
| | - Bin Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Changsuek Yon
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | | | | | - Xu Huang
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xupeng Hong
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - John A T Young
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
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27
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Khanam A, Tang LSY, Kottilil S. Programmed death 1 expressing CD8 + CXCR5 + follicular T cells constitute effector rather than exhaustive phenotype in patients with chronic hepatitis B. Hepatology 2022; 75:690-708. [PMID: 34689344 DOI: 10.1002/hep.32210] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/29/2021] [Accepted: 10/19/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B (CHB) infection. Recently, a subset of CD8 T cells expressing C-X-C chemokine receptor type 5 (CXCR5) and exhibiting features of TFH cells has been identified during chronic viral infections. However, in CHB, knowledge of their roles is limited. APPROACH AND RESULTS We characterized circulating CD8+ CXCR5+/- cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8+ CXCR5+ cells whereas CD8+ CXCR5- cells were increased. However, among CHB, CD8+ CXCR5+ cells were higher in patients with low HBsAg and HBV-DNA levels, patients who were HBeAg negative and had high fibrosis scores, and these cells exhibited a significant association with HBsAg and HBV-DNA reduction. Contrarily, CD8+ CXCR5- cells were expanded and positively correlated with patients having high HBsAg, HBV-DNA, and alanine aminotransferase levels. CD8+ CXCR5+ cells express costimulatory molecules ICOS, OX40, CD40 ligand, inhibitory molecule programmed death 1, transcription factors B-cell lymphoma (BCL)-2, BCL-6, and signal transducer and activator of transcription 3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature given that they constitute different subsets of cytotoxic follicular T cells (TCF), including TCF1, TCF2, TCF17, and TCF22. Despite expressing high PD-1, CD8+ CXCR5+ cells are activated, proliferating, secreting more IFN-γ, IL-21, and IL-22, and have better cytolytic potential than CD8+ CXCR5- cells, which were inhibited after PD-1/PD-L1 blockade. CD8+ CXCR5+ cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. CONCLUSIONS In conclusion, CD8+ CXCR5+ cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1, and are associated with HBsAg and HBV-DNA reduction. These cells competently support B-cell function, required for viral clearance, which may serve as potential therapeutic targets for CHB.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Lydia S Y Tang
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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28
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Wang X, Xie Q. Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) and Viral Hepatitis. J Clin Transl Hepatol 2022; 10:128-133. [PMID: 35233381 PMCID: PMC8845159 DOI: 10.14218/jcth.2021.00200] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 12/04/2022] Open
Abstract
A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.
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Affiliation(s)
- Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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29
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A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients. J Clin Exp Hepatol 2022; 12:735-744. [PMID: 35677522 PMCID: PMC9168707 DOI: 10.1016/j.jceh.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. METHODS HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. RESULTS Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. CONCLUSIONS This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
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Key Words
- ADV, Adefovir dipivoxil
- ALT, Alanine aminotransferase
- CHB, Chronic hepatitis B
- EOT, End of treatment
- GZ, Grey zone
- HBeAg, Hepatitis B e antigen
- HBsAg, Hepatitis B surface antigen
- HCC, Hepatocellular Carcinoma
- HNCH, HBeAg-negative chronic infection
- NA, Nucleot(s)ide analogue
- ROC, Receiver operating characteristic
- TAF, Tenofovir alafenamide fumarateor
- TDF, Tenofovir disoproxil fumarate
- ULN, Upper limit of normal
- UMC, University Medical Centers
- combination therapy
- functional cure
- hepatitis B virus
- inactive carrier
- low viral load
- peg-IFN, Pegylated-interferon
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30
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Salpini R, D’Anna S, Benedetti L, Piermatteo L, Gill U, Svicher V, Kennedy PTF. Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure. Front Microbiol 2022; 13:972687. [PMID: 36118192 PMCID: PMC9478028 DOI: 10.3389/fmicb.2022.972687] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic infection with Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality worldwide. HBV-DNA integration into the human genome is recognized as a frequent event occurring during the early phases of HBV infection and characterizing the entire course of HBV natural history. The development of refined molecular biology technologies sheds new light on the functional implications of HBV-DNA integration into the human genome, including its role in the progression of HBV-related pathogenesis and in triggering the establishment of pro-oncogenic mechanisms, promoting the development of hepatocellular carcinoma. The present review provides an updated and comprehensive overview of the current body of knowledge on HBV-DNA integration, focusing on the molecular mechanisms underlying HBV-DNA integration and its occurrence throughout the different phases characterizing the natural history of HBV infection. Furthermore, here we discuss the main clinical implications of HBV integration as a biomarker of HBV-related pathogenesis, particularly in reference to hepatocarcinogenesis, and how integration may act as a barrier to the achievement of HBV cure with current and novel antiviral therapies. Overall, a more refined insight into the mechanisms and functionality of HBV integration is paramount, since it can potentially inform the design of ad hoc diagnostic tools with the ability to reveal HBV integration events perturbating relevant intracellular pathways and for identifying novel therapeutic strategies targeting alterations directly related to HBV integration.
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Affiliation(s)
- Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Livia Benedetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Upkar Gill
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Valentina Svicher
- Department of Biology, University of Rome Tor Vergata, Roma, Italy
- *Correspondence: Valentina Svicher,
| | - Patrick T. F. Kennedy
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
- Patrick T. F. Kennedy,
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31
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Li C, Yu T, Shi X, Yu J. Interleukin-33 Reinvigorates Antiviral Function of Viral-Specific CD8 + T Cells in Chronic Hepatitis B Virus Infection. Viral Immunol 2021; 35:41-49. [PMID: 34818081 DOI: 10.1089/vim.2021.0140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Restoration of exhausted hepatitis B virus (HBV)-specific CD8+ T cells is one of the important strategies for inhibition of viral replication. The role of interleukin (IL)-33 to recovery of CD8+ T cell activity is not fully elucidated. We investigated the effect of IL-33 on viral-specific CD8+ T cell responses in chronic hepatitis B (CHB) patients in vitro by both phenotypic and functional analysis. Plasma IL-33 was downregulated in CHB patients, while effective antiviral therapy rescued IL-33 expression. There was no significant difference of IL-33 receptor mRNA relative level in CD8+ T cells between CHB patients and controls. IL-33 induced the proliferation of HBV-specific CD8+ T cells, and reduced programmed death-1 expression on HBV-specific CD8+ T cells. IL-33 promoted the direct cytolytic activity of CD8+ T cells against HepG2.2.15 cells through boosting perforin and granzyme B production. Furthermore, IL-33 administration increased HBV-specific CD8+ T cell-mediated HBV replication and HBV antigen secretion mainly via enhancement of interferon-γ and tumor necrosis factor-α. IL-33 reinvigorated antiviral activity of HBV-specific CD8+ T cells, revealing that IL-33 might contribute to viral clearance in persistent HBV infection.
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Affiliation(s)
- Chao Li
- The First Operating Room, First Hospital of Jilin University, Changchun, China
| | - Tao Yu
- Neurosurgical Intensive Care Unit, First Hospital of Jilin University, Changchun, China
| | - Xiaoju Shi
- Hepatobiliary Pancreatic Department, First Hospital of Jilin University, Changchun, China
| | - Jing Yu
- The First Operating Room, First Hospital of Jilin University, Changchun, China
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32
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Molecular Epidemiology of Hepatitis B Virus Genotypes and Subgenotypes in Ethnic Minority Populations, Yunnan Province, China. Epidemiol Infect 2021; 150:e11. [PMID: 34784995 PMCID: PMC8753486 DOI: 10.1017/s0950268821002326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The aim of our study was to determine the distribution of hepatitis B virus (HBV) genotypes and subgenotypes in ethnic minorities in Yunnan province to provide evidence supporting the theoretical basis for hepatitis B prevention and control. We obtained serum samples and demographic data from 765 individuals reported by Yunnan province who had either acute or chronic HBV infection and were from one of 20 ethnic minority populations: Achang, Bai, Brown, Tibetan, Dai, Deang, Dulong, Hani, Hui, Jingpo, Lahu, Yi, Lisu Miao, Naxi, Nu, Pumi, Wa, Yao, or Zhuang people. We sequenced the HBV DNA and determined the genotypes and subgenotypes of the isolated HBVs. We mapped the genotype and subgenotype distribution by ethnic minority population and conducted descriptive analyses. There were four genotypes among the 20 ethnic groups: genotype B (21.3% of samples), C (76.6%), D (1.8%) and I (0.3%). The most common subgenotype was C1. There were no genotype differences by gender (P = 0.954) or age (P = 0.274), but there were differences by region (P < 0.001). There were differences in genotype distribution (P < 0.001) and subgenotype distribution (P = 0.011) by ethnic group. Genotype D was most prominent in Tibet and most HBV isolates were C/D recombinant viruses. The only two genotype I virus isolates were in Zhuang people. Susceptibility and geographic patterns may influence HBV prevalence in different ethnic populations, but additional research is needed for such a determination.
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33
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Jin X, Yan ZH, Lu L, Lu S, Zhang G, Lin W. Peripheral Immune Cells Exhaustion and Functional Impairment in Patients With Chronic Hepatitis B. Front Med (Lausanne) 2021; 8:759292. [PMID: 34782855 PMCID: PMC8589627 DOI: 10.3389/fmed.2021.759292] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/17/2021] [Indexed: 12/30/2022] Open
Abstract
After infection of hepatitis B virus (HBV), the virus induces a variety of immune disorders in the host, leading to immune escape and, finally, the chronicity of the disease. This study investigated immune cell defects and functional impairment in patients with chronic hepatitis B (CHB). We analyzed the percentage, function, and phenotypes of various immune cell subpopulations in the peripheral blood along with the concentrations of cytokines in the plasma. We compared the results between patients with CHB and healthy individuals. It was found that in patients with CHB, the cell function was impaired and, there was increased expression of inhibitory receptors, such as NKG2A and PD-1 in both NK and T cells. The impairment of function was mainly in cytokine secretion, and the cytotoxicity was not significantly diminished. We also found that the proportion of dendritic cells (DC) decreased and regulatory B cells (Breg) increased in CHB. In addition, the Breg cells were negatively correlated with T cell cytokine and positively correlated with ALT and HBV viral load. Taken together, various disorders and functional impairments were found in the immune cells of peripheral blood in CHB patients, especially NK and T cells. These cells showed exhaustion and the increase of regulatory B cells may be one of the reasons for this phenomenon.
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Affiliation(s)
- Xin Jin
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Zhi-Han Yan
- Department of Hepatology, Wuxi Fifth People's Hospital, Wuxi, China
| | - Lingna Lu
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shengjia Lu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Guoping Zhang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Lin
- Department of Otolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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34
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de Almeida NAA, de Paula VS. Occult Hepatitis B virus (HBV) infection and challenges for hepatitis elimination: A literature review. J Appl Microbiol 2021; 132:1616-1635. [PMID: 34724308 DOI: 10.1111/jam.15351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum or liver but negativity for hepatitis B surface antigen. OBI, which is thought to be maintained by host, immunological, viral and/or epigenetic factors, is one of the most challenging clinical features in the study of viral hepatitis. Currently, there is no validated detection test for OBI. It is believed that OBI is widely distributed throughout the world, with a higher prevalence in populations at high-risk HBV, but the detailed worldwide prevalence patterns are unknown. We conducted a survey of recently published studies on OBI rates across all continents. High prevalence rates of OBI are observed in some specific groups, including patients with hepatitis C virus, human immunodeficiency virus co-infection or hepatocellular carcinoma. In 2016, the World Health Organization adopted strategies to eliminate viral hepatitis by 2030, but the difficulties in detecting and treating OBI currently challenge this goal. Subjects with OBI can transmit HBV, and episodes of reactivation can occur. Further studies to understanding the mechanisms that drive the development of OBI are needed and can contribute to efforts at eliminating viral hepatitis.
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35
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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36
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Akbar SMF, Al Mahtab M, Cesar Aguilar J, Uddin MH, Khan MSI, Yoshida O, Penton E, Gerardo GN, Hiasa Y. Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/03/2021] [Indexed: 01/02/2025] Open
Abstract
With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 1000, Bangladesh
| | - Julio Cesar Aguilar
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Md. Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Eduardo Penton
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
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37
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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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38
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Suresh M, Menne S. Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer. World J Gastrointest Oncol 2021; 13:509-535. [PMID: 34163570 PMCID: PMC8204361 DOI: 10.4251/wjgo.v13.i6.509] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/02/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
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39
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Buschow SI, Jansen DTSL. CD4 + T Cells in Chronic Hepatitis B and T Cell-Directed Immunotherapy. Cells 2021; 10:cells10051114. [PMID: 34066322 PMCID: PMC8148211 DOI: 10.3390/cells10051114] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/23/2021] [Accepted: 04/29/2021] [Indexed: 12/17/2022] Open
Abstract
The impaired T cell responses observed in chronic hepatitis B (HBV) patients are considered to contribute to the chronicity of the infection. Research on this impairment has been focused on CD8+ T cells because of their cytotoxic effector function; however, CD4+ T cells are crucial in the proper development of these long-lasting effector CD8+ T cells. In this review, we summarize what is known about CD4+ T cells in chronic HBV infection and discuss the importance and opportunities of including CD4+ T cells in T cell-directed immunotherapeutic strategies to cure chronic HBV.
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40
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Xu D, Tian Y, Xia Q, Ke B. The cGAS-STING Pathway: Novel Perspectives in Liver Diseases. Front Immunol 2021; 12:682736. [PMID: 33995425 PMCID: PMC8117096 DOI: 10.3389/fimmu.2021.682736] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/19/2021] [Indexed: 12/18/2022] Open
Abstract
Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.
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Affiliation(s)
- Dongwei Xu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yizhu Tian
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bibo Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
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41
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Narayanan S, Au VB, Khakpoor A, Yan C, Ahl PJ, Kaliaperumal N, Lee B, Xiang WW, Wang J, Lee C, Tay A, Lim SG, Connolly JE. Bayesian analysis of cytokines and chemokine identifies immune pathways of HBsAg loss during chronic hepatitis B treatment. Sci Rep 2021; 11:7455. [PMID: 33811250 PMCID: PMC8018960 DOI: 10.1038/s41598-021-86836-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022] Open
Abstract
Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other.
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Affiliation(s)
- Sriram Narayanan
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Veonice Bijin Au
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Atefeh Khakpoor
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng Yan
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Patricia J Ahl
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Nivashini Kaliaperumal
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Bernett Lee
- Singapore Immunology Network, A*STAR REs, Singapore, Singapore
| | - Wen Wei Xiang
- IMCB, Tessa Therapeutics Pvt Ltd, Singapore, Singapore
| | - Juling Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chris Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Amy Tay
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Seng Gee Lim
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.,Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John E Connolly
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore. .,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Institute of Biomedical Studies, Baylor University, Waco, TX, USA.
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Liu R, Zhao L, Cheng X, Han H, Li C, Li D, Liu A, Gao G, Zhou F, Liu F, Jiang Y, Zhu C, Xia Y. Clinical characteristics of COVID-19 patients with hepatitis B virus infection - a retrospective study. Liver Int 2021; 41:720-730. [PMID: 33351265 DOI: 10.1111/liv.14774] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 12/07/2020] [Accepted: 12/19/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The outbreak of coronavirus disease 2019 (COVID-19) has been declared a pandemic. Although COVID-19 is caused by infection in the respiratory tract, extrapulmonary manifestations including dysregulation of the immune system and hepatic injury have been observed. Given the high prevalence of hepatitis B virus (HBV) infection in China, we sought to study the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HBV coinfection in patients. METHODS Blood samples of 50 SARS-CoV-2 and HBV coinfected patients, 56 SARS-CoV-2 mono-infected patients, 57 HBeAg-negative chronic HBV patient controls and 57 healthy controls admitted to Renmin Hospital of Wuhan University were collected in this study. Complete blood count and serum biochemistry panels including markers indicative of liver functions were performed. Cytokines including IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-10 were evaluated. T cell, B cell and NK cell counts were measured using flow cytometry. RESULTS SARS-CoV-2 and HBV coinfection did not significantly affect the outcome of the COVID-19. However, at the onset of COVID-19, SARS-CoV-2 and HBV coinfected patients showed more severe monocytopenia and thrombocytopenia as well as more disturbed hepatic function in albumin production and lipid metabolism. Most of the disarrangement could be reversed after recovery from COVID-19. CONCLUSIONS While chronic HBV infection did not predispose COVID-19 patients to more severe outcomes, our data suggest SARS-CoV-2 and HBV coinfection poses a higher extent of dysregulation of host functions at the onset of COVID-19. Thus, caution needs to be taken with the management of SARS-CoV-2 and HBV coinfected patients.
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Affiliation(s)
- Rui Liu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xiaoming Cheng
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Huan Han
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Cong Li
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Dong Li
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Andrew Liu
- Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT, USA
| | - Guosheng Gao
- Department of Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Feng Zhou
- Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal Diseases, Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fang Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital, Wuhan University, Wuhan, China
| | - Chengliang Zhu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
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Zhan MR, Gao XZ, Wang C, Peng F, Wang XM, Xu HQ, Niu JQ. Elevated soluble 4-1BB is associated with serum markers of hepatitis B virus in patients with chronic hepatitis B. World J Clin Cases 2021; 9:1619-1630. [PMID: 33728305 PMCID: PMC7942032 DOI: 10.12998/wjcc.v9.i7.1619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/13/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous studies have suggested that the costimulatory molecule 4-1BB plays pivotal roles in regulating immunity during chronic viral infection. However, up to now, there are few studies about 4-1BB in chronic hepatitis B (CHB).
AIM To clarify this issue, we report our comprehensive study results on the expression levels of 4-1BB in patients with CHB.
METHODS From September 2018 to June 2019, a total of 64 patients with CHB were recruited from the Department of Hepatology, The First Hospital of Jilin University. Peripheral blood samples were collected from 52 treatment-naïve and 12 entecavir-treated patients with CHB as well as 37 healthy donors (including 24 healthy adults and 13 healthy children). The levels of soluble 4-1BB (s4-1BB) in plasma were measured by ELISA. 4-1BB mRNA expression in peripheral blood mononuclear cells was detected by real-time quantitative PCR.
RESULTS The s4-1BB levels in the plasma of patients with CHB were significantly higher than those in healthy adults (94.390 ± 7.393 ng/mL vs 8.875 ± 0.914 ng/mL, P < 0.001). In addition, the s4-1BB level in plasma was significantly increased in patients with a higher viral load and a disease flare up. However, there were no significant differences between treatment-naïve and entecavir-treated patients. Interestingly, among treatment-naïve patients with CHB, the levels of s4-1BB in plasma had a significant positive correlation with hepatitis B surface antigen, hepatitis B virus DNA, hepatitis B e antigen, and triglyceride levels (r = 0.748, P < 0.001; r = 0.406, P = 0.004; r = 0.356, P = 0.019 and r = -0.469, P = 0.007, respectively). The 4-1BB mRNA expression was higher in the peripheral blood mononuclear cells of patients with CHB than in the peripheral blood mononuclear cells of healthy adults, but the difference was not statistically significant.
CONCLUSION These results suggest that the levels of s4-1BB may be associated with pathogenesis of hepatitis B virus and therefore may be a promising biomarker for disease progression.
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Affiliation(s)
- Meng-Ru Zhan
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiu-Zhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Fei Peng
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Mei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qin Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jun-Qi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Hou W, Wu X. Diverse Functions of γδ T Cells in the Progression of Hepatitis B Virus and Hepatitis C Virus Infection. Front Immunol 2021; 11:619872. [PMID: 33597951 PMCID: PMC7882476 DOI: 10.3389/fimmu.2020.619872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/17/2020] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are primary risk factors for a wide spectrum of liver diseases that severely affect human health. The liver is an immunological organ that has an abundance of immune cells. Thus, various innate or adaptive immune cells are involved in the progression of HBV or HCV infection. Among those cells, a unique kind of immune cell, the γδ T cell, contributes to promoting or inhibiting the progression of liver diseases. To reveal the diverse roles of γδ T cells in HBV or HCV infection, the properties and functions of these cells in human and mouse models are analyzed. Here, we briefly describe the characteristics and functions of γδ T cells subsets in liver diseases. Then, we fully discuss the diverse roles of γδ T cells in the progression of HBV or HCV infection, including stages of acute infection, chronic infection, liver cirrhosis, and hepatocellular carcinoma. Finally, the functions and existing problems of γδ T cells in HBV or HCV infection are summarized. A better understanding of the function of γδ T cells during the progression of HBV and HCV infection will be helpful for the treatment of virus infection.
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Affiliation(s)
- Wen Hou
- Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin First Central Hospital, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Xiaoli Wu
- School of Life Sciences, Tianjin University, Tianjin, China
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45
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Jeng WJ, Lok ASF. Is Cure of Hepatitis B Infection a Mission Possible? HEPATITIS B VIRUS AND LIVER DISEASE 2021:475-495. [DOI: 10.1007/978-981-16-3615-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Gu Y, Li X, Gu L, Lian Y, Wang K, Chen Y, Lai J, Mei Y, Liu J, Huang Z, Zhang M, Chen L, Huang Y. An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B. Aging (Albany NY) 2020; 12:26063-26079. [PMID: 33401245 PMCID: PMC7803537 DOI: 10.18632/aging.202274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 11/13/2020] [Indexed: 12/20/2022]
Abstract
We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.
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Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoyan Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ke Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Youming Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Lai
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yongyu Mei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Min Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Jiaming Z, Pinzhu H, Xiaoyan G, Shuyun T, Rongwan L, Huanmiao Z, Xiaofeng W, Yuanlv X, Mingzhe H, Hongen Y, Meijin H, Jianping W. HBV infection may reduce the risk of metachronous liver metastasis in postoperative pathological stage 2 colorectal cancer. Int J Colorectal Dis 2020; 35:2205-2217. [PMID: 32728919 DOI: 10.1007/s00384-020-03712-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/23/2020] [Indexed: 05/13/2025]
Abstract
PURPOSE To analyze whether HBV infection can reduce the risk of colorectal liver metastasis (CRLM) in stage 2 colorectal cancer (CRC). METHODS The data of postoperative pathological stage 2 CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University between 2013 and 2015 were analyzed. The patients were divided into an infection group (group A) and a non-infection group (group B). The correlations between HBV infection and CRLM, 5-year liver disease-free survival, and 5-year overall survival were compared. RESULTS A total of 884 patients who met the inclusion criteria were included in the study. Group A included 297 patients (33.60%), and 5 patients (1.68%) had CRLM. Group B included 587 patients (66.40%), and 31 patients (5.28%) had CRLM. The results of correlation analysis and logistic regression analysis showed that HBV infection (P = 0.013, HR = 0.29, 95% CI 0.11-0.77) was a protective factor for CRLM, while CEA > 5 ng/ml (P = 0.002, HR = 3.12, 95% CI 1.51-6.47) and hypertension (P = 0.010, HR = 3.50, 95% CI 1.34-9.09) were risk factors for CRLM. Group A had a significantly better 5-year liver disease-free survival than group B (P = 0.011, HR = 0.31, 95% CI 0.16-0.63), but there was no significant difference in the 5-year overall survival (P = 0.433). CONCLUSION HBV infection may reduce the risk of metachronous liver metastasis in stage 2 colorectal cancer.
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Affiliation(s)
- Zhou Jiaming
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huang Pinzhu
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Guo Xiaoyan
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tan Shuyun
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lin Rongwan
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhan Huanmiao
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wu Xiaofeng
- Department of Medical Records Management, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao Yuanlv
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huang Mingzhe
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yu Hongen
- Department of Chemotherapy, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huang Meijin
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Wang Jianping
- Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
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Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees. mBio 2020; 11:mBio.02580-20. [PMID: 33203756 PMCID: PMC7683399 DOI: 10.1128/mbio.02580-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1β. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic.IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.
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Chen H, He G, Chen Y, Zhang X. Hepatitis B Virus Might Be Sensed by STING-Dependent DNA Sensors and Attenuates the Response of STING-Dependent DNA Sensing Pathway in Humans with Acute and Chronic Hepatitis B Virus Infection. Viral Immunol 2020; 33:642-651. [PMID: 33170089 DOI: 10.1089/vim.2020.0096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
DNA-dependent activator of interferon regulatory factors (DAIs), interferon gamma inducible protein 16 (IFI16), DEAD-box polypeptide 41 (DDX41), DNA-dependent protein kinase (DNA-PK), meiotic recombination 11 homolog A (MRE11), and cyclic GMP-AMP synthase (cGAS) have been identified as intracellular STING-dependent DNA sensors in recent years. Studies have shown that the DNA sensor-STING-interferon (IFN)-β pathway plays an important role in the defense against intracellular invasion of many DNA viruses. However, the intracellular recognition of hepatitis B virus (HBV) DNA by DNA sensors is still largely unclear. In this study, we aimed to determine whether the DNA sensor-STING pathway in peripheral blood mononuclear cells (PBMCs) can be activated by acute and chronic HBV infections in humans. We first evaluated the expression of these DNA sensors in PBMCs of acute and chronic HBV-infected patients by quantitative real-time polymerase chain reaction. We next compared the expression of the upregulated DNA sensor between monocytes and nonmonocytes to find its cellular source. Finally, by in vitro stimulation, we analyzed the IFN-β response of the DNA sensor-STING pathway in PBMCs and monocytes from chronic HBV-infected patients. The results showed that IFI16, DDX41, MRE11, and the adaptor STING were upregulated in chronic HBV-infected patients, whereas only IFI16 was upregulated in acute HBV-infected patients. However, IFN-β expression was not changed in PBMCs from acute and chronic HBV-infected patients. We next found IFI16 was mainly expressed in monocytes of acute and chronic hepatitis B patients. Finally, by stimulation of monocytes with VACV ds 70mer, a ligand for IFI16, we confirmed the attenuated response of the IFI16-STING pathway. Taken together, our results suggest that HBV might be sensed by DNA sensors in PBMCs of acute and chronic HBV-infected patients, and meanwhile HBV infection attenuates the response of the DNA sensor-STING pathway in PBMCs and monocytes, which may facilitate the persistence of HBV infection.
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Affiliation(s)
- Hongtao Chen
- 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.,Department of Infectious Diseases, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China.,Key Laboratory of Pathogenic Microorganisms of Shenzhen, Shenzhen Institute of Respiratory Diseases, Shenzhen, China
| | - Guirong He
- Department of Clinical Laboratory, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China
| | - Yue Chen
- Department of Clinical Laboratory, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, 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
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Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats. PLoS One 2020; 15:e0238810. [PMID: 32915856 PMCID: PMC7485842 DOI: 10.1371/journal.pone.0238810] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 08/23/2020] [Indexed: 01/17/2023] Open
Abstract
Previous studies reported that sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae, HRP) exhibits hepatoprotective effects via its anti-inflammatory and antioxidant properties as well as its inhibitory effects on collagen synthesis. However, it is unclear whether this hepatoprotective effect is also achieved by regulating liver drug metabolism enzyme pathways. Herein, we examined the regulatory effect of HRP on cytochrome P450 3A (CYP3A) in rats with immune liver injury, and explored the molecular mechanism of its hepatoprotective effect. Rat models of immunological liver injury were induced by intravenous injections of Bacillus Calmette-Guerin (BCG; 125 mg kg-1; 2 wks). Specific protein levels were detected by ELISA or western blot, and CYP3A mRNA expression was detected by RT-PCR. High-performance liquid chromatography (HPLC) detected relative changes in CYP3A metabolic activity based on the rates of 1-hydroxylation of the probe drug midazolam (MDZ). BCG pretreatment (125 mg kg-1) significantly down-regulated liver CYP3A protein expression compared with the control, metabolic activity, and transcription levels while up-regulating liver NF-κB, IL-1β, TNF-α and iNOS. HRP intervention (ED50: 78 mg kg-1) moderately reversed NF-κB, inflammatory cytokines, and iNOS activation in a dose-dependent manner (P < 0.05), and suppressed CYP3A down-regulation (P < 0.05); thereby partially alleviating liver injury. During immune liver injury, HRP may reverse CYP3A down-regulation by inhibiting NF-κB signal transduction, and protect liver function, which involves regulation of enzymes transcriptionally, translationally and post-translationally. The discovery that NF-κB is a molecular target of HRP may initiate the development and optimization of a clinical therapeutic approach to mitigate hepatitis B and other immunity-related liver diseases.
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