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Wang X, Lai C, Li R, Lei J, Xie Y, Li Z, Tang Q, He Q, Zhang H, Zhang Z, Wang F. High HBsAg clearance rate and viral dynamics in HBeAg-positive, ALT-normal children and adolescents with chronic HBV infection: results from the prospective sprout project. Emerg Microbes Infect 2025; 14:2516173. [PMID: 40469009 DOI: 10.1080/22221751.2025.2516173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 04/22/2025] [Accepted: 05/30/2025] [Indexed: 06/28/2025]
Abstract
Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection in children and adolescents with normal alanine aminotransferase (ALT) levels constitutes a substantial population in China, yet the optimal timing for antiviral therapy remains unclear. This prospective, real-world study, conducted as the primary centre of the Sprout Project, evaluated the hepatitis B surface antigen (HBsAg) loss rate and viral-immune dynamics of pegylated interferon α (PEG-IFN-α) treatment in 85 chronic HBV patients aged 3-18 years over a 24-month period. A total of 27 HBeAg-positive, ALT-normal patients were selected for analysis. Patients were treated with a combination of PEG-IFN-α and entecavir. After 24 months, the overall HBsAg loss rate was 48.15%, with 47.37% in the immune-tolerant phase and 50% in the grey zone phase. Among those who cleared HBsAg, 84.62% had ALT elevation prior to anti-HBsAg antibody (HBsAb) seroconversion, which occurred 28-400 days before HBsAg loss. While HBsAg and HBV DNA were cleared by 24 months in the HBsAg loss group, 23.08% of children remained HBeAg-positive. Notably, 61.54% developed detectable HBsAb prior to HBsAg loss. Children aged 3-7 years had significantly higher clearance rates than those aged 8-18 years. These findings support the effectiveness of PEG-IFN-α combined with nucleos(t)ide analogs in achieving high HBsAg loss rates in young, HBeAg-positive, ALT-normal chronic HBV children and adolescents, with immune activation potentially preceding ALT elevation, and offers valuable insights into the viral-immune dynamics during treatment, highlighting the potential of antiviral therapy in this population.
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Affiliation(s)
- Xin Wang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, People's Republic of China
| | - Changxiang Lai
- Department of Liver Diseases, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, People's Republic of China
| | - Ruiling Li
- Department of Infectious Diseases, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Jia Lei
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, People's Republic of China
| | - Yuyin Xie
- School of Intelligent Medicine and Biotechnology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Zhiyu Li
- Department of Liver Diseases, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, People's Republic of China
| | - Qiyuan Tang
- Department of Liver Diseases, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, People's Republic of China
| | - Qing He
- Department of Liver Diseases, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, People's Republic of China
| | - Hongfei Zhang
- Beijing Chen Jumei Foundation, Beijing, People's Republic of China
| | - Zheng Zhang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, People's Republic of China
- Department of Infectious Diseases, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Fang Wang
- Department of Liver Diseases, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, People's Republic of China
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Chen CC, Chen SC. Letter: Advancing Serologic Classification in Indeterminate Chronic Hepatitis B Through Dynamic and Integrated Frameworks. Aliment Pharmacol Ther 2025. [PMID: 40569022 DOI: 10.1111/apt.70227] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2025] [Revised: 06/01/2025] [Accepted: 06/01/2025] [Indexed: 06/28/2025]
Affiliation(s)
- Chun-Chieh Chen
- Department of Family and Community Medicine, Chung Shan Medical University Hospital; School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shiuan-Chih Chen
- Department of Family and Community Medicine, Chung Shan Medical University Hospital; School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Li W, Huang R, Wang J, Zhang B, Wang Q, Feng J, Xing T. Development and validation of a new predictive model for the immune tolerance stage of chronic HBV infection based on the liver histopathological changes. BMC Gastroenterol 2025; 25:408. [PMID: 40426052 PMCID: PMC12107786 DOI: 10.1186/s12876-025-03999-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
OBJECTIVE To identify clinical and viral indicators for the development of a new model to accurately differentiate the stages of chronic hepatitis B virus (HBV) infection based on histopathological changes in the liver. METHODS Clinical and liver pathology data from chronic hepatitis B (CHB) patients who underwent liver biopsy were retrospectively collected. The patients were allocated into test and validation groups. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to idneitfy the optimal diagnostic value for differentiating the stages of chronic HBV infection. RESULTS A total of 118 patients and 73 patients who met the diagnostic and inclusion criteria were selected as the test group and validation group, respectively. Multivariate analysis revealed that HBeAg was independently correlated with the IT and IC stages. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 S/CO. The AUC values were 0.921 (95% confidence interval (CI): 0.836-0.971) and 0.846 (95% CI: 0.726-0.967) in the test and validation groups, respectively. A new prediction model of the IT stage was established by using three indicators, namely, HBeAg, HBsAg and HBV DNA. The AUC values were 0.923 (95% CI: 0.864-0.982, p < 0.001) and 0.89 (95% CI: 0.787-0.994, p < 0.01) in the test and validation groups, respectively, when this prediction model was used. For the new model, CMA guidelines (2019 version), EASL guidelines (2017 version) and AASLD guidelines (2018 version), the error rates in the test group were 4.65%, 11.62%, 23.26%, and 46.51%, respectively, while the errors rates in the validation group were 20.0%, 25.0%, 40.0%, and 45.0%, respectively. CONCLUSIONS High levels of HBeAg, rather than HBeAg positivity, may serve as a predictor of the IT stage. A predictive model for the immune tolerance stage was established by combining three indicators. Compared with the recommended standards from multiple current guidelines, the new prediction model has a significantly lower error rate.
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Affiliation(s)
- Wentao Li
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | - Rui Huang
- Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Jian Wang
- Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Binhao Zhang
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | | | - Jiang Feng
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | - Tongjing Xing
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China.
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Mon HC, Lee PC, Chi CT, Huang YH. Effect of immune checkpoint inhibitors on patients with hepatitis B virus infection. J Chin Med Assoc 2025; 88:93-97. [PMID: 39726106 DOI: 10.1097/jcma.0000000000001202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection is regarded as a major health concern worldwide. In patients with chronic HBV infection, exhausted virus-specific CD8+ T cells, resulting from the activation of the programmed cell death protein 1 and programmed death ligand 1 axis, play a key role in the chronicity of infection. Functional cure for HBV, defined as the seroclearance of hepatitis B surface antigen (HBsAg), is viewed as the optimal goal of chronic HBV infection treatment because HBsAg loss is associated with a low risk of hepatocellular carcinoma and a relatively favorable prognosis. Both interferon treatment and finite antiviral therapy are associated with positive HBV outcomes. Overall, combining immune checkpoint inhibitors with nucleos(t)ide analogs appears to be a promising approach for achieving HBsAg loss, particularly in patients with low HBsAg levels.
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Affiliation(s)
- Hsien-Chen Mon
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pei-Chang Lee
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chen-Ta Chi
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Xing T. Existing problems and new advice on stage criteria of natural history for chronic hepatitis B. BMC Infect Dis 2025; 25:17. [PMID: 39754052 PMCID: PMC11699759 DOI: 10.1186/s12879-024-10408-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025] Open
Abstract
The natural stages of chronic hepatitis B can be divided into four stages according to changes in virology, biochemistry, and pathology. However, there have been significant differences in the recommended stage criteria in the several major guidelines for chronic hepatitis B, especially regarding the immune tolerance phase. Inconsistent standards of indicators for different stages resulted in some problems, such as incorrect stage, uncertain stages and poor comparation of related studies. We propose suggestions for revisions to the stage criteria for CHB based on recent researches, including three stages: immune tolerance stage, immune clearance stage, and immune control stage. These revision suggestions rationalize some of the existing problems with the stage criteria for CHB and can significantly reduce the number of patients in the "uncertain stage" or "gray zone," which is particularly valuable in guiding clinical practice. However, further clinical studies with large samples are needed to confirm these suggestions.
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Affiliation(s)
- Tongjing Xing
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China.
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Tu T, McQuaid TJ, Jacobson IM. HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment. Liver Int 2025; 45:e16202. [PMID: 39720865 DOI: 10.1111/liv.16202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection. AIMS To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development. MATERIALS AND METHODS We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy. RESULTS We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention. CONCLUSION Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.
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Affiliation(s)
- Thomas Tu
- Storr Liver Centre, Westmead Clinical School, Centre for Infectious Diseases and Microbiology and Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
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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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8
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Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024; 31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV-host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.
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Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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9
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Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association, Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association, National Clinical Research Center for Infectious Diseases (Beijing). Expert Consensus on the Prevention and Treatment of Chronic Hepatitis B in Children. INFECTIOUS DISEASES & IMMUNITY 2024; 4:106-120. [DOI: 10.1097/id9.0000000000000122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Abstract
The aim of this consensus is to standardize the prevention, diagnosis, and treatment of chronic hepatitis B in children and to achieve the goal of “eliminating viral hepatitis as a major public health threat by 2030” issued by the World Health Organization. Formulated by organized experts of the Chinese Society of Infectious Diseases and Chinese Society of Hepatology, Chinese Medical Association; Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association; and the National Clinical Research Center for Infectious Diseases (Beijing), the consensus provides the latest evidence and recommendations for the prevention, diagnosis, and treatment of chronic hepatitis B in children.
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Liu J, Yu Y, Zhao H, Guo L, Yang W, Yan Y, Lv J. Latest insights into the epidemiology, characteristics, and therapeutic strategies of chronic hepatitis B patients in indeterminate phase. Eur J Med Res 2024; 29:343. [PMID: 38902822 PMCID: PMC11191257 DOI: 10.1186/s40001-024-01942-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 06/17/2024] [Indexed: 06/22/2024] Open
Abstract
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
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Affiliation(s)
- Junye Liu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Heping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Wenjuan Yang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yuzhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China.
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Zong Q, Zhang H, Liu F, Li J, Liu Q, Duan Z, Duan W, Ruan M, Zhang J, Liu Y, Zhou Q, Wang Q. Activation of the cGAS-STING pathway by viral dsDNA leading to M1 polarization of macrophages mediates antiviral activity against hepatitis B virus. Immunobiology 2024; 229:152810. [PMID: 38772101 DOI: 10.1016/j.imbio.2024.152810] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 05/09/2024] [Accepted: 05/16/2024] [Indexed: 05/23/2024]
Abstract
BACKGROUND AND AIMS Activation of the cGAS-STING pathway induces the production of type I interferons, initiating the antiviral immune response, which contributes to the clearance of pathogens. Previous studies have shown that STING agonists promote hepatitis B virus (HBV) clearance; however, few studies have investigated the effect of activating the cGAS-STING pathway in macrophages on HBV. METHODS The polarization status of HBV particle-stimulated RAW264.7 macrophages was analyzed. After stimulation with HBV particles, the analysis focused on determining whether the DNA sensors in RAW264.7 macrophages recognized the viral double-stranded DNA (dsDNA) and evaluating the activation of the cGAS-STING pathway. Coculture of mouse macrophages and hepatocytes harboring HBV was used to study the antiviral activity of HBV-stimulated RAW264.7 macrophages. RESULTS After stimulation with HBV particles, HBV relaxed circular DNA (rcDNA) was detected in RAW264.7 macrophages, and the protein expression of phospho-STING, phospho-TBK1, and phospho-IRF3 in the STING pathway was increased, as shown by Western blot analysis, which revealed that M1 polarization of macrophages was caused by increased expression of CD86. RT-PCR analyses revealed elevated expression of M1 macrophage polarization-associated cytokines such as TNFα, IL-1β, iNOS, and IFNα/β. In the coculture experiment, both HBsAg and HBeAg expression levels were significantly decreased in AML12-HBV1.3 cells cocultured with the supernatants of HBV-stimulated RAW264.7 macrophages. CONCLUSION The results suggest that macrophages can endocytose HBV particles. Additionally, viral dsDNA can be recognized by DNA pattern recognition receptors, which in turn activate the cGAS-STING pathway, promoting the M1 polarization of macrophages, while no significant M2 polarization is observed. Macrophages stimulated with HBV particles exhibit enhanced antiviral activity against HBV.
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Affiliation(s)
- Qiyin Zong
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Zhang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Futing Liu
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianfei Li
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qian Liu
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi Duan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanlu Duan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mengqi Ruan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jingjing Zhang
- Department of Geriatric Cardiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yan Liu
- Department of Microbiology, School of Basic Medical, Anhui Medical University, Hefei, China
| | - Qiang Zhou
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Qin Wang
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
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Tang J, Zhang J, Zhang G, Peng W, Ling N, Zhou Y, Xu H, Ren H, Chen M. Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation. mBio 2024; 15:e0306823. [PMID: 38440978 PMCID: PMC11005361 DOI: 10.1128/mbio.03068-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 02/01/2024] [Indexed: 03/06/2024] Open
Abstract
The chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1β), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers. IMPORTANCE Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the "immune tolerance phase" will transition to the "immune activation phase" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers.
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Affiliation(s)
- Jinglin Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Transfusion Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jiaxuan Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Laboratory Medicine, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
| | - Gaoli Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenhui Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yingzhi Zhou
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hongmei Xu
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Nguwoh PS, Ngounouh CT, Essomba RG, Olinga PZ, Likeng JLN, Nguepidjo G, Douyong SCT, Tchoffo D, Nlend AEN, Assoumou MCO, Fokam J. Effect of hepatitis B vaccination on HBV-infection among school children in Yaounde; ten years after the introduction of HBV vaccine into routine Immunization Program in Cameroon. Pan Afr Med J 2024; 47:169. [PMID: 39036018 PMCID: PMC11260054 DOI: 10.11604/pamj.2024.47.169.40369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 02/08/2024] [Indexed: 07/23/2024] Open
Abstract
Introduction since the introduction of the anti-HBV vaccine into the Expanded Program on Immunization (EPI) in 2005 in Cameroon, vaccination coverage has reached 99.0%. This coverage would indicate an increase in the number of children immune to Hepatitis B Virus (HBV) and a decrease in susceptibility to HBV-infection. This study was conducted to evaluate the effect of the HBV vaccine on pediatric HBV-infection in Yaounde, Cameroon. Methods this school-based cross-sectional study was conducted from February to May 2016 among 180 children from Nkomo public school. The study population was stratified into two groups: vaccinated (n=95) versus (vs) unvaccinated (n=85). Screening for HBV biomarkers was done using a rapid panel test for detection (HBsAg, HBeAg and anti-HBc) and anti-HBs titer using enzyme linked immunosorbent assay (ELISA). Statistical analyses were done using SPSS v. 22 with p < 0.05 considered significant. Results the mean age was 9.65 years. HBsAg (p=0.019) and anti-HBc (p=0.001) rates were detected in children aged ≥10 years and children aged < 10 years (95.95% [71/74]) were vaccinated vs 22.64% (24/106) for those aged ≥10 years (OR: 80.86; 95% CI: 23.36%-279.87%, p < 0.0001). According to anti-HBV vaccination status, HBsAg rate varied from [9.41% (8/85) to 1.05% (1/95), p=0.025], HBeAg rate varied from [2.35% (2/85) to 0% (0/95), p= 0.42] and anti-HBc rate ranged from [12.94% (11/85) to 2.10% (2/95), p= 0.011]. Conclusion despite the variability of the anti-HBs titer, vaccination against HBV has a positive effect on the reduction of HBV-infection in children in tropical settings such as Cameroon.
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Affiliation(s)
- Philippe Salomon Nguwoh
- National Public Health Laboratory, Ministry of Public Health, Yaounde, Cameroon
- Distant Production House University, Delaware, United State of America
- Higher Institute of Health Professions, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Higher Institute of Sciences and Techniques Applied to Health, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Faculty of Health Sciences, University of Lisala, Lisala, Mongala, Democratic Republic of Congo (DRC)
| | - Christian Taheu Ngounouh
- National Public Health Laboratory, Ministry of Public Health, Yaounde, Cameroon
- Distant Production House University, Delaware, United State of America
- Higher Institute of Health Professions, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Higher Institute of Sciences and Techniques Applied to Health, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Faculty of Health Sciences, University of Lisala, Lisala, Mongala, Democratic Republic of Congo (DRC)
| | - René Ghislain Essomba
- National Public Health Laboratory, Ministry of Public Health, Yaounde, Cameroon
- Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon
| | - Patrice Zanga Olinga
- Distant Production House University, Delaware, United State of America
- Higher Institute of Health Professions, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Faculty of Health Sciences, University of Lisala, Lisala, Mongala, Democratic Republic of Congo (DRC)
| | - Julienne Louise Ngo Likeng
- Higher Institute of Sciences and Techniques Applied to Health, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
- Faculty of Health Sciences, University of Lisala, Lisala, Mongala, Democratic Republic of Congo (DRC)
- School of Health Sciences, Catholic University of Central Africa, Yaounde, Cameroon
| | - Gilbert Nguepidjo
- Distant Production House University, Delaware, United State of America
- Higher Institute of Health Professions, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
| | - Sandrine Chimène Tonmeu Douyong
- National Public Health Laboratory, Ministry of Public Health, Yaounde, Cameroon
- Distant Production House University, Delaware, United State of America
| | - Désiré Tchoffo
- Distant Production House University, Delaware, United State of America
- Faculty of Health Sciences, University of Lisala, Lisala, Mongala, Democratic Republic of Congo (DRC)
- School of Health Sciences, Catholic University of Central Africa, Yaounde, Cameroon
| | - Anne Esther Njom Nlend
- Higher Institute of Medical Technology, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Yaounde, Cameroon
| | - Marie Claire Okomo Assoumou
- National Public Health Laboratory, Ministry of Public Health, Yaounde, Cameroon
- Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon
| | - Joseph Fokam
- Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon
- School of Health Sciences, Catholic University of Central Africa, Yaounde, Cameroon
- Faculty of Health Sciences, University of Buea, Buea, Cameroon
- Chantal BIYA International Reference Centre for Research on HIV/AIDS prevention and management, Yaounde, Cameroon
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14
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Lin HC, Jeng WJ, Liu J, Pan MH, Lee MH, Batrla-Utermann R, Lu SN, Chen CF, Yang HI, Chen CJ. Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients. Aliment Pharmacol Ther 2024; 59:993-1002. [PMID: 38410882 DOI: 10.1111/apt.17915] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/15/2023] [Accepted: 02/11/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.
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Affiliation(s)
- Hsin-Che Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Jessica Liu
- Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, School of Medicine, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California, USA
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | | | - Sheng-Nan Lu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chuen-Fei Chen
- Mackay Medical College Department of Medicine, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
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15
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Jiang B, Wang L, Liu H, Wang L, Su R, Xu L, Wei G, Li J, Lu F, Chen X. Association of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage in chronic HBV infection. J Med Virol 2024; 96:e29569. [PMID: 38549467 DOI: 10.1002/jmv.29569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 03/18/2024] [Indexed: 04/02/2024]
Abstract
The natural progression of chronic hepatitis B virus (HBV) infection is dynamic, but the longitudinal landscape of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage remains undetermined. To this issue, we studied the association of HBV serological markers with the severity of hepatic inflammatory damage and enumerated HBV-specific T cells using the cultured enzyme-linked immune absorbent spot (ELISpot). Five hundred and twenty-four treatment-naïve chronic HBV infection patients were enrolled. The Spearman correlation analysis revealed that in hepatitis B e antigen (HBeAg)-positive patients, all HBV virologic indicators negatively correlated with liver inflammatory damage and fibrosis (p < 0.01). Stronger correlations were accessed in the subgroup of HBeAg-positive patients with HBV DNA > 2 × 106 IU/mL (p < 0.01), whereas negative correlations disappeared in patients with HBV DNA ≤ 2 × 106 IU/mL. Surprisingly, in HBeAg-negative patients, the HBV DNA level was positively correlated with the hepatic inflammatory damage (p < 0.01). The relationship between type Ⅱ interferon genes expression and HBV DNA levels also revealed a direct shift from the initial negative to positive in HBeAg-positive patients with HBV DNA declined below 2 × 106 IU/mL. The number of HBV-specific T cells were identified by interferon γ ELISpot assays and showed a significant increase from HBeAg-positive to HBeAg-negative group. The host's anti-HBV immunity remains effective in HBeAg-positive patients with HBV DNA levels exceeding 2 × 106 IU/mL, as it efficiently eliminates infected hepatocytes and inhibits HBV replication. However, albeit the increasing number of HBV-specific T cells, the host antiviral immune response shifts towards dysfunctional when the HBV DNA load drops below this threshold, which causes more pathological damage and disease progression.
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Affiliation(s)
- Bei Jiang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Institute of hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Leijie Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Huan Liu
- Institute of hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Lin Wang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Shenzhen Blood Center, Shen Zhen, Guangdong, China
| | - Rui Su
- Institute of hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Liang Xu
- Institute of hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Guochao Wei
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Shenzhen Blood Center, Shen Zhen, Guangdong, China
| | - Jia Li
- Institute of hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Fengmin Lu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Shenzhen Blood Center, Shen Zhen, Guangdong, China
| | - Xiangmei Chen
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Shenzhen Blood Center, Shen Zhen, Guangdong, China
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Păcurar D, Dinulescu A, Jugulete G, Păsărică AS, Dijmărescu I. Hepatitis B in Pediatric Population: Observational Retrospective Study in Romania. Life (Basel) 2024; 14:348. [PMID: 38541675 PMCID: PMC10970939 DOI: 10.3390/life14030348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/21/2024] [Accepted: 03/05/2024] [Indexed: 09/29/2024] Open
Abstract
Hepatitis B virus (HBV) is a frequent cause of chronic hepatitis worldwide, with an estimated 5.6 million children under 5 years being infected. In Romania, there are no available epidemiology reports on large cohorts in children. We aimed to assess the profile of pediatric chronic HBV infection in southern Romania. We conducted an observational retrospective study on 506 HBV-infected children. Based on alaninaminotransferase (ALT), HBV serology and viremia, we identified four states of the disease. We correlated age, gender, household HBV infection, coinfection with other viruses and laboratory parameters. Most patients were in a positive HBV envelope antigen (HBeAg) immune-active state (65.4%). Age at diagnosis was significantly lower for those with household infection (p < 0.05). ALT values were not significantly different between positive or negative HBeAg patients in the immune-active state (p = 0.780). ALT values were higher in patients with hepatitis D virus (HDV)-associated infection (p < 0.001). Children with a household HBV infection had a high viraemia more frequently when compared to those with no infected relative (79.3% vs. 67.4%) (p < 0.001), but the ALT values were not significantly different (p = 0.21). Most of the patients are in an immune-active state (high ALT, high viremia). The percentages of HBV- and HDV-associated infections are high, but lower than the reported prevalence in Romania in the general population.
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Affiliation(s)
- Daniela Păcurar
- Department of Pediatrics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.P.); (I.D.)
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Children’s Hospital, 011743 Bucharest, Romania;
| | - Alexandru Dinulescu
- Department of Pediatrics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.P.); (I.D.)
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Children’s Hospital, 011743 Bucharest, Romania;
| | - Gheorghiță Jugulete
- Department of Infectious Diseases 3, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, 021105 Bucharest, Romania
| | - Alexandru-Sorin Păsărică
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Children’s Hospital, 011743 Bucharest, Romania;
| | - Irina Dijmărescu
- Department of Pediatrics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.P.); (I.D.)
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Children’s Hospital, 011743 Bucharest, Romania;
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17
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Liu YC, Jeng WJ. Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”? CURRENT HEPATOLOGY REPORTS 2024; 23:11-21. [DOI: 10.1007/s11901-024-00635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 01/04/2025]
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18
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Bailey JT, Moshkani S, Rexhouse C, Cimino JL, Robek MD. CD4 + T cells reverse surface antigen persistence in a mouse model of HBV replication. Microbiol Spectr 2023; 11:e0344723. [PMID: 37948314 PMCID: PMC10715182 DOI: 10.1128/spectrum.03447-23] [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: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 11/12/2023] Open
Abstract
IMPORTANCE Hepatitis B virus (HBV) is a leading causative agent of viral hepatitis. A preventative vaccine has existed for decades, but only limited treatment options are available for people living with chronic HBV. Animal models for studying HBV are constrained due to narrow viral tropism, impeding understanding of the natural immune response to the virus. Here, using a vector to overcome the narrow host range and establish HBV replication in mice, we identified the role of helper T cells in controlling HBV. We show that helper T cells promote the B cell's ability to generate antibodies that remove HBV and its associated surface antigen from the blood and that transfer of purified helper T cells from HBV-immunized mice can reverse the accumulation of virus and antigen, furthering our understanding of the immune response to HBV.
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Affiliation(s)
- Jacob T. Bailey
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Safiehkhatoon Moshkani
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Catherine Rexhouse
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Jesse L. Cimino
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Michael D. Robek
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
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Rzymski P, Zarębska-Michaluk D, Flisiak R. Could chronic HBV infection explain Beethoven's hearing loss? Implications for patients currently living with hepatitis B. J Infect 2023; 87:171-176. [PMID: 37302659 DOI: 10.1016/j.jinf.2023.06.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/01/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
The cause of Ludwig van Beethoven's health deterioration, i.e., hearing loss and cirrhosis, have been subject to various studies. The genomic analysis of his hair indicates infection with the hepatitis B virus (HBV) at least 6 months prior to death. However, considering his first documented case of jaundice in the summer of 1821, second jaundice months prior to his death, and increased risk of hearing loss in HBV-infected patients, we offer an alternative hypothesis of chronic HBV infection as a cause of deafness and cirrhosis. According to it, HBV was acquired early, progressed from immune-tolerant to an immune-reactive phase, and triggered Beethoven's hearing issues when aged 28. Later, HBV infection entered the non-replication phase with at least two episodes of reactivation in the fifth decade of life accompanied by jaundice. More studies examining hearing loss in patients with chronic HBV infection are encouraged to better understand their potential otologic needs.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, 60-806 Poznań, Poland.
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, 25-317 Kielce, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-540 Białystok, Poland
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Nesina IM, Kryuchko TO, Poda OA, Tkachenko OY, Kuzmenko NV, Bubyr LM. A Current Management Strategy for Children with Chronic Viral Hepatitis B, Based on International and National Guidelines. JOURNAL OF MOTHER AND CHILD 2023; 27:134-141. [PMID: 37668440 PMCID: PMC10478681 DOI: 10.34763/jmotherandchild.20232701.d-23-00006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/23/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND Peculiarities of the course of chronic viral hepatitis B in children cause an important medical and social problem of health care, despite the implementation of modern treatment and prevention protocols. Pathogenetic mechanisms of the development and progression of viral hepatitis B infection, the presence of occult poorly diagnosed form, the impossibility of completely eliminating the virus and the specificity of the immune response in children are still not fully solved scientific problems. MATERIAL AND METHODS The aim of this review is to examine current strategies for the diagnosis and treatment of chronic hepatitis B in children, based on international and national guidelines. RESULTS A detailed analysis of modern guidelines on the course and pathogenesis of viral hepatitis B infection confirms the fact that chronic hepatitis B is characterised by a complex interaction between the immune system of the virus and the patient, whose dynamic balance is not only responsible for the various phases of chronic viral hepatitis B infection but also leads to the result of antiviral treatment. CONCLUSION Despite the introduction of vaccination of children against hepatitis B, the level of viral hepatitis B vaccination of children in Ukraine remains insufficient, which leads to the further spread of the infection. Currently available antiviral drugs can provide functional treatment of viral hepatitis B infection in a limited number of patients, but today's Ukrainian realities have caused a change in approach to the treatment and monitoring of patients, which may negatively affect the implementation of the key goals of the World Health Organization Global Strategy on the prevention, diagnosis and treatment of viral hepatitis.
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Affiliation(s)
- Inna M. Nesina
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
| | - Tetyana O. Kryuchko
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
| | - Olha A. Poda
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
| | - Olha Ya. Tkachenko
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
| | - Nataliia V. Kuzmenko
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
| | - Liudmyla M. Bubyr
- Department of Pediatrics No. 2, Poltava State Medical University, Poltava, Ukraine
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21
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Xu JQ, Su SB, Chen CY, Gao J, Cao ZM, Guan JL, Xiao LX, Zhao MM, Yu H, Hu YJ. Mechanisms of Ganweikang Tablets against Chronic Hepatitis B: A Comprehensive Study of Network Analysis, Molecular Docking, and Chemical Profiling. BIOMED RESEARCH INTERNATIONAL 2023; 2023:8782892. [PMID: 37197593 PMCID: PMC10185428 DOI: 10.1155/2023/8782892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 03/03/2023] [Accepted: 03/15/2023] [Indexed: 05/19/2023]
Abstract
The hepatitis B virus (HBV) is one of the major viral infection problems worldwide in public health. The exclusive proprietary Chinese medicine Ganweikang (GWK) tablet has been marketed for years in the treatment of chronic hepatitis B (CHB). However, the pharmacodynamic material basis and underlying mechanism of GWK are not completely clear. This study is aimed at investigating the pharmacological mechanism of the GWK tablet in the treatment of CHB. The chemical ingredient information was obtained from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP), Traditional Chinese Medicines Integrated Database (TCMID), and Shanghai Institute of Organic Chemistry of CAS. Ingredients and disease-related targets were defined by a combination of differentially expressed genes from CHB transcriptome data and open-source databases. Target-pathway-target (TPT) network analysis, molecular docking, and chemical composition analysis were adopted to further verify the key targets and corresponding active ingredients of GWK. Eight herbs of GWK were correlated to 330 compounds with positive oral bioavailability, and 199 correlated targets were identified. The TPT network was constructed based on the 146 enriched targets by KEGG pathway analysis, significantly associated with 95 pathways. Twenty-five nonvolatile components and 25 volatile components in GWK were identified in UPLC-QTOF/MS and GC-MS chromatograms. The key active ingredients of GWK include ferulic acid, oleanolic acid, ursolic acid, tormentic acid, 11-deoxyglycyrrhetic acid, dibenzoyl methane, anisaldehyde, wogonin, protocatechuic acid, psoralen, caffeate, dimethylcaffeic acid, vanillin, β-amyrenyl acetate, formonentin, aristololactam IIIa, and 7-methoxy-2-methyl isoflavone, associated with targets CA2, NFKB1, RELA, AKT1, JUN, CA1, CA6, IKBKG, FOS, EP300, CREB1, STAT1, MMP9, CDK2, ABCB1, and ABCG2.
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Affiliation(s)
- Jia-Qi Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao 999078, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - C. Y. Chen
- Jiaheng (Hengqin, Zhuhai) Pharmaceutical Technology Co., Ltd., Zhuhai, China
- National Engineering Research Center for Modernization of Traditional Chinese Medicine, Zhuhai, China
| | - J. Gao
- National Engineering Research Center for Modernization of Traditional Chinese Medicine, Zhuhai, China
| | - Z. M. Cao
- Jiaheng (Hengqin, Zhuhai) Pharmaceutical Technology Co., Ltd., Zhuhai, China
| | - J. L. Guan
- Henan Fusen Pharmaceutical Co., Ltd., Henan, China
| | - Lin-Xuan Xiao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Ming-Ming Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Hua Yu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Yuan-Jia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao 999078, China
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Djaogol T, Périères L, Marcellin F, Diouf A, Carrieri MP, Diallo A, Boyer S. Hepatitis B prevention and treatment needs in women in Senegal (ANRS 12356 AmBASS survey). BMC Public Health 2023; 23:825. [PMID: 37143029 PMCID: PMC10161542 DOI: 10.1186/s12889-023-15710-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 04/19/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Although mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is prevalent in West Africa, epidemiological data on HBV infection in women remain scarce. We studied i) hepatitis B surface antigen (HBsAg) prevalence and its correlates, ii) HBV screening history and serological status awareness, iii) MTCT risk and treatment needs in Senegalese women. METHODS A cross-sectional population-based serosurvey for HBsAg positivity was conducted in 2018-2019 in the rural area of Niakhar (Fatick region, Senegal). Participants were offered home-based HBV screening and answered face-to-face questionnaires. HBsAg-positive participants underwent clinical and biological assessments. Data were weighted and calibrated to be representative of the area's population. Logistic regression models helped identify factors associated with HBsAg-positivity in adult women (> 15 years old). RESULTS HBsAg prevalence in adult women was 9.2% [95% confidence interval: 7.0-11.4]. Factors associated with HBsAg-positivity were being 15-49 years old (ref: ≥ 50), living in a household with > 2 other HBsAg-positive members, and knowing someone with liver disease. Only 1.6% of women had already been tested for HBV; no one who tested HBsAg positive was already aware of their serological status. In women 15-49 years old, 5% risked MTCT and none were eligible for long-term antiviral treatment. CONCLUSIONS Adult women have a high HBsAg prevalence but a low MTCT risk. Low rates of HBV screening and serological status awareness argue for the adoption of systematic screening during pregnancy using free and rapid diagnostic tests. Additionally, screening household members of HBsAg-positive women may greatly improve the cascade of care in rural Senegal. TRIAL REGISTRATION ClinicalTrials.gov identifier (NCT number): NCT03215732.
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Affiliation(s)
- Tchadine Djaogol
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, ISSPAM, Marseille, France
- Univ. Bordeaux, INSERM, Institut Bergonié, BPH, U1219, CIC-P 1401, F-33000, Bordeaux, France
| | - Lauren Périères
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, ISSPAM, Marseille, France
- VITROME, Campus IRD-UCAD, Dakar, Senegal
| | - Fabienne Marcellin
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, ISSPAM, Marseille, France
| | | | - Maria Patrizia Carrieri
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, ISSPAM, Marseille, France
| | | | - Sylvie Boyer
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, ISSPAM, Marseille, France.
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23
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Transcriptomic Analysis of Hepatitis B Infected Liver for Prediction of Hepatocellular Carcinoma. BIOLOGY 2023; 12:biology12020188. [PMID: 36829466 PMCID: PMC9952979 DOI: 10.3390/biology12020188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023]
Abstract
Hepatocellular cancer (HCC) is a leading cause of cancer-related mortality worldwide, and chronic hepatitis B virus infection (CHB) has been a major risk factor for HCC development. The pathogenesis of HBV-related HCC has been a major focus revealing the interplay of a multitude of intracellular signaling pathways, yet the precise mechanisms and their implementations to clinical practice remain to be elucidated. This study utilizes publicly available transcriptomic data from the livers of CHB patients in order to identify a population with a higher risk of malignant transformation. We report the identification of a novel list of genes (PCM1) which can generate clear transcriptomic sub-groups among HBV-infected livers. PCM1 includes genes related to cell cycle activity and liver cancer development. In addition, markers of inflammation, M1 macrophages and gamma delta T cell infiltration are present within the signature. Genes within PCM1 are also able to differentiate HCC from normal liver, and some genes within the signature are associated with poor prognosis of HCC at the mRNA level. The analysis of the immunohistochemical stainings validated that proteins coded by a group of PCM1 genes were overexpressed in liver cancer, while minimal or no expression was detected in normal liver. Altogether, our findings suggest that PCM1 can be developed into a clinically applicable method to identify CHB patients with a higher risk of HCC development.
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24
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Choi WM, Choi J, Lim YS. Hepatitis B: epidemiology, natural history, and diagnosis. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:183-203. [DOI: 10.1016/b978-0-323-98368-6.00007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Contribution of T- and B-cell intrinsic toll-like receptors to the adaptive immune response in viral infectious diseases. Cell Mol Life Sci 2022; 79:547. [PMID: 36224474 PMCID: PMC9555683 DOI: 10.1007/s00018-022-04582-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/03/2022]
Abstract
Toll-like receptors (TLRs) comprise a class of highly conserved molecules that recognize pathogen-associated molecular patterns and play a vital role in host defense against multiple viral infectious diseases. Although TLRs are highly expressed on innate immune cells and play indirect roles in regulating antiviral adaptive immune responses, intrinsic expression of TLRs in adaptive immune cells, including T cells and B cells, cannot be ignored. TLRs expressed in CD4 + and CD8 + T cells play roles in enhancing TCR signal-induced T-cell activation, proliferation, function, and survival, serving as costimulatory molecules. Gene knockout of TLR signaling molecules has been shown to diminish antiviral adaptive immune responses and affect viral clearance in multiple viral infectious animal models. These results have highlighted the critical role of TLRs in the long-term immunological control of viral infection. This review summarizes the expression and function of TLR signaling pathways in T and B cells, focusing on the in vitro and vivo mechanisms and effects of intrinsic TLR signaling in regulating T- and B-cell responses during viral infection. The potential clinical use of TLR-based immune regulatory drugs for viral infectious diseases is also explored.
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26
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Lei B, Song H, Xu F, Wei Q, Wang F, Tan G, Ma H. When does hepatitis B virus meet long-stranded noncoding RNAs? Front Microbiol 2022; 13:962186. [PMID: 36118202 PMCID: PMC9479684 DOI: 10.3389/fmicb.2022.962186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/22/2022] [Indexed: 01/16/2023] Open
Abstract
Hepatitis B virus (HBV) infection in humans and its associated diseases are long-standing problems. HBV can produce a large number of non-self-molecules during its life cycle, which acts as targets for innate immune recognition and initiation. Among these, interferon and its large number of downstream interferon-stimulated gene molecules are important early antiviral factors. However, the development of an effective antiviral immune response is not simple and depends not only on the delicate regulation of the immune response but also on the various mechanisms of virus-related immune escape and immune tolerance. Therefore, despite there being a relatively well-established consensus on the major pathways of the antiviral response and their component molecules, the complete clearance of HBV remains a challenge in both basic and clinical research. Long-noncoding RNAs (lncRNAs) are generally >200 bp in length and perform different functions in the RNA strand encoding the protein. As an important part of the IFN-inducible genes, interferon-stimulated lncRNAs are involved in the regulation of several HBV infection-related pathways. This review traces the basic elements of such pathways and characterizes the various recent targets of lncRNAs, which not only complement the regulatory mechanisms of pathways related to chronic HBV infection, fibrosis, and cancer promotion but also present with new potential therapeutic targets for controlling HBV infection and the malignant transformation of hepatocytes.
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Affiliation(s)
- Bingxin Lei
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiao Song
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengchao Xu
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qi Wei
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fei Wang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guangyun Tan
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Guangyun Tan,
| | - Haichun Ma
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
- Haichun Ma,
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27
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Bonino F, Colombatto P, Brunetto MR. HBeAg-Negative/Anti-HBe-Positive Chronic Hepatitis B: A 40-Year-Old History. Viruses 2022; 14:1691. [PMID: 36016312 PMCID: PMC9416321 DOI: 10.3390/v14081691] [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: 07/12/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 12/03/2022] Open
Abstract
Hepatitis B "e" antigen (HBeAg) negative chronic hepatitis B (CHB), 40 years since discovery in the Mediterranean area, has become the most prevalent form of HBV-induced liver disease worldwide and a major health care burden caused by HBV infection. A great deal of knowledge accumulated over the last decades provides consistent evidence on the bimodal dynamics of the expression of structural and non-structural forms of the viral core proteins which associate with different virologic and clinic-pathologic outcomes of HBV infection. In absence of serum HBeAg, the presence and persistence of HBV replication causes and maintains virus-related liver injury. Thus, in clinical practice it is mandatory to screen HBV carriers with HBeAg-negative infection for the early diagnosis of HBeAg-negative CHB since antiviral therapy can cure HBV-induced liver disease when started at early stages.
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Affiliation(s)
- Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
| | - Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy;
| | - Maurizia R. Brunetto
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy;
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28
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Gherlan GS. Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus. World J Clin Cases 2022; 10:5518-5530. [PMID: 35979101 PMCID: PMC9258381 DOI: 10.12998/wjcc.v10.i17.5518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.
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Affiliation(s)
- George Sebastian Gherlan
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy, Bucharest 030303, Romania
- Department of Infectious Diseases, “Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Bucharest 030303, Romania
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29
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Ashouri S, Khor SS, Hitomi Y, Sawai H, Nishida N, Sugiyama M, Kawai Y, Posuwan N, Tangkijvanich P, Komolmit P, Tsuiji M, Shotelersuk V, Poovorawan Y, Mizokami M, Tokunaga K. Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population. Front Genet 2022; 13:887121. [PMID: 35769989 PMCID: PMC9234442 DOI: 10.3389/fgene.2022.887121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
Abstract
To identify novel host genetic variants that predispose to hepatitis B virus (HBV) persistence, we performed the first genome-wide association study in the Thai population involving 318 cases of chronic hepatitis B and 309 healthy controls after quality control measures. We detected the genome-wide significant association of the HLA class II region (HLA-DPA1/DPB1, rs7770370, p-value = 7.71 × 10-10, OR = 0.49) with HBV chronicity. Subsequent HLA allele imputation revealed HLA-DPA1*01:03 (Pc = 1.21 × 10-6, OR = 0.53), HLA-DPB1*02:01 (Pc = 2.17 × 10-3, OR = 0.50), and HLA-DQB1*06:09 (Pc = 2.17 × 10-2, OR = 0.07) as protective alleles, and HLA-DPA1*02:02 (Pc = 6.32 × 10-5, OR = 1.63), HLA-DPB1*05:01 (Pc = 1.13 × 10-4, OR = 1.72), HLA-DPB1*13:01 (Pc = 4.68 × 10-2, OR = 1.60), and HLA-DQB1*03:03 (Pc = 1.11 × 10-3, OR = 1.84) as risk alleles for HBV persistence. We also detected suggestive associations in the PLSCR1 (rs35766154), PDLIM5 (rs62321986), SGPL1 (rs144998273), and MGST1 (rs1828682) loci. Among single-nucleotide polymorphisms in the PLSCR1 locus, rs1061307 was identified as the primary functional variant by in silico/in vitro functional analysis. In addition to replicating the association of the HLA class II region, we detected novel candidate loci that provide new insights into the pathophysiology of chronic hepatitis B.
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Affiliation(s)
- Saeideh Ashouri
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuki Hitomi
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nawarat Posuwan
- Chulabhorn International College of Medicine, Thammasat University, Rangsit Campus, Pathum Thani, Thailand
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Liver Fibrosis and Cirrhosis Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Makoto Tsuiji
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Vorasuk Shotelersuk
- Department of Pediatrics, Center of Excellence for Medical Genomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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30
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Lee DH, Chung SW, Lee JH, Kim HY, Chung GE, Kim MS, Yang BR, Nam JY, Lee YB, Kim YJ, Yoon JH. Association of Chronic Hepatitis B Infection and Antiviral Treatment With the Development of the Extrahepatic Malignancies: A Nationwide Cohort Study. J Clin Oncol 2022; 40:3394-3405. [PMID: 35561284 DOI: 10.1200/jco.21.01285] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Epidemiologic studies suggest that chronic hepatitis B (CHB) is a risk factor for various primary extrahepatic malignancies. Our aim was to evaluate the associations of CHB and nucleos(t)ide analog (NA) treatment with the risk of the development of extrahepatic malignancies. PATIENTS AND METHODS We conducted an 18-month landmark analysis using nationwide claims data from the National Health Insurance Service of South Korea. Patients newly diagnosed with CHB in 2012-2014 (n = 90,944) and matched-controls (n = 685,436) were included. Patients with CHB were further classified as the NA-treated (CHB+/NA+, n = 6,539) or the NA-untreated (CHB+/NA-, n = 84,405) group. Inverse probability of treatment weighting analysis was applied to balance the treatment groups. Time-varying Cox analysis was performed to evaluate time-varying effect of NA treatment. The primary outcome was the development of any primary extrahepatic malignancy. Development of intrahepatic malignancy and death were considered as competing events. RESULTS During the study period (median = 47.4 months), 30,413 patients (3.9%) developed any extrahepatic malignancy. The CHB+/NA- group had a higher overall risk of extrahepatic malignancy than the CHB+/NA+ group (adjusted subdistribution hazard ratio [aSHR] = 1.28; 95% CI, 1.12 to 1.45; P < .001) or controls (aSHR = 1.22; 95% CI, 1.18 to 1.26; P < .001). There was no difference in the risk of extrahepatic malignancy between the CHB+/NA+ group and the controls (CHB+/NA+ v control: aSHR = 0.96; 95% CI, 0.84 to 1.08; P = .48). In time-varying Cox analysis, the CHB+/NA- patients were associated with a higher risk of extrahepatic malignancy than the CHB+/NA+ patients (aSHR = 1.37; 95% CI, 1.23 to 1.52; P < .001). CONCLUSION Patients with CHB have an elevated risk of developing primary extrahepatic malignancy. Long-term NA treatment was associated with a lower risk of extrahepatic malignancy development among patients with CHB.
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Affiliation(s)
- Dong Hyeon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Sung Won Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hwi Young Kim
- Department of Internal Medicine, Ewha Womans University Medical Center, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Goh Eun Chung
- Department of Internal Medicine, Healthcare System Gangnam Center Seoul National University Hospital, Seoul, South Korea
| | - Mi-Sook Kim
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea
| | - Bo Ram Yang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea.,College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Joon Yeul Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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31
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Wang L, Fan Y. Current Advances of Innate and Adaptive Immunity in Acute-on-Chronic Hepatitis B Liver Failure. INFECTIOUS DISEASES & IMMUNITY 2022; 2:113-121. [DOI: 10.1097/id9.0000000000000051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Indexed: 01/03/2025]
Abstract
Abstract
Acute-on-chronic hepatitis B liver failure (ACHBLF) is a term used to define the acute deterioration of liver function that occurs in patients with chronic hepatitis B virus infection or hepatitis B virus-related liver cirrhosis. The specific pathogenesis of ACHBLF is still not completely understood. Current research has shown that an intense systemic inflammation is involved in the development of acute-on-chronic liver failure (ACLF). Meanwhile, a subsequent immune paresis over the course of ACLF favors the development of infection and sepsis. Deregulation in both the innate and adaptive immunity is the notable feature of ACLF. The dysregulated immune responses play a crucial role in disease progression and potentially drive organ failure and mortality in ACHBLF. In this review, we highlight the current knowledge of innate and adaptive immune cells in ACHBLF.
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Affiliation(s)
- Liyuan Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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32
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Song HF, Chen XJ, Tang PJ, Xu P, Huang ZY, Wang XF. Clinical Significance of BTLA and HVEM Expression on Circulating CD4 + T and CD8 + T Cells in Chronic Hepatitis B Virus Infection. Viral Immunol 2022; 35:291-302. [PMID: 35196150 DOI: 10.1089/vim.2021.0134] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In this study, B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) expression on the surface of circulating CD4+ T and CD8+ T cells of patients with chronic hepatitis B (CHB) was investigated to explore their relationship with hepatitis B virus (HBV) clinical parameters. Both BTLA and HVEM were significantly upregulated on CD4+ T and CD8+ T cells of CHB patients compared with healthy controls (p < 0.01). Intriguingly, in CHB patients, the percentage of BTLA expression was positively correlated with that of HVEM (CD4+ T cells: r = 0.5461, p < 0.001 and CD8+ T cells: r = 0.4206, p < 0.01). Moreover, the percentage of BTLA expression was positively correlated with the levels of aspartate aminotransferase (AST) (CD4+ T cells: r = 0.3136, p < 0.05 and CD8+ T cells: r = 0.3159, p < 0.05) and alanine aminotransaminase (ALT) (CD4+ T cells: r = 0.3177, p < 0.05 and CD8+ T cells: r = 0.3311, p < 0.05). At the same time, the percentage of HVEM expression was also positively correlated with AST levels (CD4+ T cells: r = 0.3721, p < 0.05 and CD8+ T cells: r = 0.3325, p < 0.05) and ALT (CD4+ T cells: r = 0.3689, p < 0.05 and CD8+ T cells: r = 0.3476, p < 0.05). However, the percentage of BTLA and HVEM expression did not show significant relevance to HBV viral load. Further study demonstrated that BTLA inhibitory signaling could significantly inhibit T cell proliferation, activation, and cytokine production under optimal T cell receptor signaling (p < 0.05). Thereby, our findings indicate that the increased BTLA and HVEM expression on the surface of CD4+ and CD8+ T cells might represent a certain clinical significance and be involved in CHB progression during T cell exhaustion.
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Affiliation(s)
- Hua-Feng Song
- Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.,Central Lab, The Affiliated Infectious Hospital of Soochow University, Suzhou, China
| | - Xiao-Juan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Pei-Jun Tang
- Central Lab, The Affiliated Infectious Hospital of Soochow University, Suzhou, China
| | - Ping Xu
- Central Lab, The Affiliated Infectious Hospital of Soochow University, Suzhou, China
| | - Zi-Yi Huang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xue-Feng Wang
- Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
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33
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Zhao H, Han Q, Yang A, Wang Y, Wang G, Lin A, Wang X, Yin C, Zhang J. CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV. Int J Biol Sci 2022; 18:154-165. [PMID: 34975324 PMCID: PMC8692134 DOI: 10.7150/ijbs.62424] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic Hepatitis B virus (CHB) infection is a global public health problem. Oligodeoxynucleotides (ODNs) containing class C unmethylated cytosine-guanine dinucleotide (CpG-C) motifs may provide potential adjuvants for the immunotherapeutic strategy against CHB, since CpG-C ODNs stimulate both B cell and dendritic cell (DC) activation. However, the efficacy of CpG-C ODN as an anti-HBV vaccine adjuvant remains unclear. In this study, we demonstrated that CpG M362 (CpG-C ODN) as an adjuvant in anti-HBV vaccine (cHBV-vaccine) successfully and safely eliminated the virus in HBV-carrier mice. The cHBV-vaccine enhanced DC maturation both in vivo and in vitro, overcame immune tolerance, and recovered exhausted T cells in HBV-carrier mice. Furthermore, the cHBV-vaccine elicited robust hepatic HBV-specific CD8+ and CD4+ T cell responses, with increased cellular proliferation and IFN-γ secretion. Additionally, the cHBV-vaccine invoked a long-lasting follicular CXCR5+ CD8+ T cell response following HBV re-challenge. Taken together, CpG M362 in combination with rHBVvac cleared persistent HBV and achieved long-term virological control, making it a promising candidate for treating CHB.
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Affiliation(s)
- Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ailu Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yucan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Guan Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Ang Lin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiao Wang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
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Abstract
Patients with chronic hepatitis B (CHB) represent a living and permanent reservoir of hepatitis B virus (HBV). Millions of these CHB patients will eventually develop complications such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma if they are not treated properly. Accordingly, several antiviral drugs have been developed for the treatment of CHB, but these drugs can neither eradicate all forms of HBV nor contain the progression of complications in most patients with CHB. Thus, the development of new and novel therapeutics for CHB remains a pressing need. The molecular and cellular mechanisms underlying the pathogenesis of CHB indicate that immune dysregulations may be responsible for HBV persistence and progressive liver damage in CHB. This provided the scientific and ethical basis for the immune therapy of CHB patients. Around 30 years have passed since the initiation of immune therapies for CHB in the early 1990s, and hundreds of clinical trials have been accomplished to substantiate this immune treatment. Despite these approaches, an acceptable regimen of immune therapy is yet to be realized. However, most immune therapeutic agents are safe for human usage, and many of these protocols have inspired considerable optimism. In this review, the pros and cons of different immune therapies, observed in patients with CHB during the last 30 years, will be discussed to derive insights into the development of an evidence-based, effective, and patient-friendly regimen of immune therapy for the treatment of CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan.
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon City, Ehime, 791-0295, Japan
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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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Abstract
Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver - and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis - profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.
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Ma H, Lim TH, Leerapun A, Weltman M, Jia J, Lim YS, Tangkijvanich P, Sukeepaisarnjaroen W, Ji Y, Le Bert N, Li D, Zhang Y, Hamatake R, Tan N, Li C, Strasser SI, Ding H, Yoon JH, Stace NH, Ahmed T, Anderson DE, Yan L, Bertoletti A, Zhu Q, Yuen MF. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study. JHEP Rep 2021; 3:100361. [PMID: 34661089 PMCID: PMC8502773 DOI: 10.1016/j.jhepr.2021.100361] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/02/2021] [Accepted: 08/25/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND & AIMS Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS Both 20 μg and 40 μg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER ACTRN12619001210167. LAY SUMMARY BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.
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Key Words
- AE, adverse event
- ALT, alanine aminotransferase
- Anti-HBs, hepatitis B surface antibody
- BMI, body mass index
- BRII-179
- CHB
- CHB, chronic hepatitis B
- ELISpot, enzyme-linked immune absorbent spot
- HBV, hepatitis B virus
- HBV-specific immune response
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- IFN-alpha
- IFN-α, interferon-α
- IM, intramuscular
- IU, international units
- NA, nucleos(t)ide analogue
- PBMCs, peripheral blood mononuclear cells
- PEG-IFN-α, pegylated interferon-α
- SAE, serious adverse events
- Th1, T helper type 1
- immunotherapy
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Affiliation(s)
- Haiyan Ma
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | | | | | | | - Jidong Jia
- Beijing Friendship Hospital, Beijing, China
| | - Young-suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Yun Ji
- Brii Biosciences Inc. Durham, NC, USA
| | - Nina Le Bert
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Dong Li
- Brii Biosciences Inc. Beijing, PR China
| | - Yao Zhang
- Brii Biosciences Inc. Beijing, PR China
| | | | - Nicole Tan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | | | | | - Huiguo Ding
- Beijing You 'an Hospital affiliated to Capital Medical University, Beijing, China
| | | | - Nigel H. Stace
- Capital & Coast District Health Board, Wellington, New Zealand
| | | | | | - Li Yan
- Brii Biosciences Inc. Durham, NC, USA
| | - Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Qing Zhu
- Brii Biosciences Inc. Durham, NC, USA
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Shenge JA, Osiowy C. Rapid Diagnostics for Hepatitis B and C Viruses in Low- and Middle-Income Countries. FRONTIERS IN VIROLOGY 2021; 1. [DOI: 10.3389/fviro.2021.742722] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
The global health challenge posed by hepatitis B virus (HBV) and hepatitis C virus (HCV) persists, especially in low-and-middle-income countries (LMICs), where underdiagnosis of these viral infections remains a barrier to the elimination target of 2030. HBV and HCV infections are responsible for most liver-related mortality worldwide. Infected individuals are often unaware of their condition and as a result, continue to transmit these viruses. Although conventional diagnostic tests exist, in LMIC they are largely inaccessible due to high costs or a lack of trained personnel, resulting in poor linkage to care and increased infections. Timely and accurate diagnosis is needed to achieve elimination of hepatitis B and C by the year 2030 as set out by the World Health Organization Global Health Sector Strategy. In this review rapid diagnostic tests allowing for quick and cost-effective screening and diagnosis of HBV and HCV, are discussed, as are their features, including suitability, reliability, and applicability in LMIC, particularly those within Africa.
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Jeng WJ, Lok AS. Should Treatment Indications for Chronic Hepatitis B Be Expanded? Clin Gastroenterol Hepatol 2021; 19:2006-2014. [PMID: 32434068 DOI: 10.1016/j.cgh.2020.04.091] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/20/2020] [Accepted: 04/24/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIM Antiviral therapy has greatly improved the outcomes of patients with chronic hepatitis B virus (HBV) infection and active liver disease or advanced fibrosis/cirrhosis. However, current treatment does not eradicate HBV and long-term treatment is needed in most patients to maintain clinical benefit. Thus, professional society guidelines do not recommend treatment of all patients with chronic HBV infection. This review article will examine evidence for and against expansion of treatment to patients in whom treatment is not recommended based on current guidelines. RESULTS Available data support expanding treatment to immune tolerant patients and patients in the grey zones who have evidence of active/advanced liver disease based on liver biopsy or non-invasive tests and those who remain in the immune tolerant phase after age 40. Evidence supporting treatment expansion to confirmed inactive carriers and other immune tolerant patients is lacking. CONCLUSIONS HBV treatment indications can be more liberal when new therapies that can achieve HBsAg loss safely in a high percentage of patients after a finite course of treatment are available.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taiwan; Chang Gung University College of Medicine, Taiwan
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
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Hirschenberger M, Hunszinger V, Sparrer KMJ. Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections. Cells 2021; 10:2134. [PMID: 34440903 PMCID: PMC8391718 DOI: 10.3390/cells10082134] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/12/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.
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Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression. Int J Mol Sci 2021; 22:ijms22115497. [PMID: 34071064 PMCID: PMC8197097 DOI: 10.3390/ijms22115497] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 02/07/2023] Open
Abstract
More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients.
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Identification of novel hepatitis B virus therapeutic vaccine candidates derived from polymerase protein. Aging (Albany NY) 2021; 13:14372-14384. [PMID: 34016795 PMCID: PMC8202855 DOI: 10.18632/aging.203053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 04/28/2021] [Indexed: 01/05/2023]
Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem with high morbidity and mortality rates. The therapeutic vaccine is a promising method of treatment, and HBV polymerase plays a vital role in viral replication. Therefore, a therapeutic vaccine that binds to HBV DNA polymerase may control HBV infection. We predicted and selected epitopes of polymerase using online databases and analysis software. We then performed molecular docking and peptide binding assays to evaluate the binding energies and affinities between polymerase epitopes and the HLA-A0201 molecule. Finally, we induced T cells from the peripheral blood mononuclear cells (PBMCs) of healthy donors using each epitope and quantified the functions of epitope-specific T cells by IFN-γELISPOT assay, T2 cell cytotoxicity assay, HepG2.2.15 cell cytotoxicity assay and HBV gene expression assays. Four epitopes (RVTGGVFLV, GLLGFAAPF, LLDDEAGPL and YMDDVVLGA) had low binding energy and two epitopes (RVTGGVFLV and GLLGFAAPF) had a high binding affinity. The T cells stimulated by two epitopes (GLLGFAAPF and HLYSHPIIL) had a greater ability to induce immune response and suppress HBV. The HBV DNA polymerase epitopes identified in this study are promising targets for designing an epitope-based therapeutic vaccine against HBV.
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Abstract
Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.
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Affiliation(s)
- Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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44
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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45
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Kinfe H, Sendo EG, Gebremedhin KB. Prevalence of Hepatitis B Virus Infection and Factors Associated with Hepatitis B Virus Infection Among Pregnant Women Presented to Antenatal Care Clinics at Adigrat General Hospital in Northern Ethiopia. Int J Womens Health 2021; 13:119-127. [PMID: 33519245 PMCID: PMC7837579 DOI: 10.2147/ijwh.s280806] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/28/2020] [Indexed: 12/25/2022] Open
Abstract
Background Hepatitis B infection is among the most common public health concerns globally, particularly in low- and middle-income countries. The prevalence of hepatitis B infection is more common among most vulnerable populations, including pregnant women. However, there are limited studies on hepatitis B virus infection among pregnant women in low-income countries, including Ethiopia, and the previous studies focused on the general population rather than the pregnant women. The purpose of this study was to estimate the prevalence and examine factors associated with hepatitis B virus infection among pregnant women in the Northern Ethiopia. Methods nstitution-based cross-sectional study design and a structured face-to-face interview were used to collect data from the study participants. Simple random sampling method was used to select eligible study participants. Data were entered using EpiData version 3.1, and SPSS version 20 was used for the data analysis. We analyzed the data to examine factors associated with hepatitis B virus infection using binary and multivariable logistic regression models. Results The overall prevalence of hepatitis B virus infection among the study participants was 9.2%. The majority (46.7%) of the study participants infected by hepatitis B were in the age group 25-34 years. The study found that married study participants were more likely to be infected by hepatitis B when compared to the unmarried study participants. Having history of abortion [OR = 0.12 (95% CI: 0.03, 0.47), P < 0.01] and having history of tattooing [OR = 0.21 (95% CI: 0.07, 0.62), P < 0.01] were found to be statistically significantly associated with the prevalence of hepatitis B virus infection among pregnant women. Conclusion A significant number of pregnant women participating in the study were infected by the hepatitis B virus which needs efficient intervention to reduce the infection rate. Further, educational status, having history of surgery, dental procedure, ear piercing, abortion and tattooing were found statistically to be significant before controlling for confounders. But, after controlling for confounders, only having history of tattooing and having history of abortion were found to be independent factors affecting the prevalence of the infection.
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Affiliation(s)
| | - Endalew Gemechu Sendo
- School of Nursing and Midwifery, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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Zhang Z, Trippler M, Real CI, Werner M, Luo X, Schefczyk S, Kemper T, Anastasiou OE, Ladiges Y, Treckmann J, Paul A, Baba HA, Allweiss L, Dandri M, Gerken G, Wedemeyer H, Schlaak JF, Lu M, Broering R. Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes. Hepatology 2020; 72:829-844. [PMID: 31925967 DOI: 10.1002/hep.31112] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/17/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. APPROACH AND RESULTS The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen. CONCLUSIONS PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.
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Affiliation(s)
- Zhenhua Zhang
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Martin Trippler
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Catherine I Real
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Melanie Werner
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Xufeng Luo
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Stefan Schefczyk
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Thekla Kemper
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Olympia E Anastasiou
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Yvonne Ladiges
- Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Juergen Treckmann
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Andreas Paul
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Hideo A Baba
- Department of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lena Allweiss
- Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maura Dandri
- Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Joerg F Schlaak
- Department of Internal medicine, Evangelisches Klinikum Niederrhein GmbH, Duisburg, Germany
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Le Bert N, Gill US, Hong M, Kunasegaran K, Tan DZM, Ahmad R, Cheng Y, Dutertre CA, Heinecke A, Rivino L, Tan A, Hansi NK, Zhang M, Xi S, Chong Y, Pflanz S, Newell EW, Kennedy PTF, Bertoletti A. Effects of Hepatitis B Surface Antigen on Virus-Specific and Global T Cells in Patients With Chronic Hepatitis B Virus infection. Gastroenterology 2020; 159:652-664. [PMID: 32302614 DOI: 10.1053/j.gastro.2020.04.019] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/03/2020] [Accepted: 04/06/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen [HBsAg]) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations. METHODS We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, hepatitis B e antigen, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMCs). In PBMCs from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer and T cells by mass cytometry. PBMCs from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry. We used multivariate linear regression and performed variable selection using the Akaike information criterion to identify covariates associated with HBV-specific responses of T cells. RESULTS Although T- and natural killer cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r = 0.3367; P < .00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P = .000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decreased to 7.14% in patients older than 30 years. CONCLUSIONS In an analysis of immune cells from patients with chronic HBV infection, we found that the duration of HBsAg exposure, rather than the quantity of HBsAg, was associated with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for the clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should be considered in patients younger than 30 years.
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Affiliation(s)
- Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Upkar S Gill
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Michelle Hong
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Kamini Kunasegaran
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Damien Z M Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Raidah Ahmad
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Yang Cheng
- Singapore Immunology Network, A∗STAR, Singapore
| | - Charles-A Dutertre
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A∗STAR, Singapore
| | | | - Laura Rivino
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; School of Cellular and Molecular Medicine, University of Bristol, United Kingdom
| | - Anthony Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Navjyot K Hansi
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Min Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sujuan Xi
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Stefan Pflanz
- Gilead Sciences, Inc, Department of Biology, Foster City, California
| | | | - Patrick T F Kennedy
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A∗STAR, Singapore.
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48
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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49
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Broering R, Luo X, Liu J, Lu M. Controversial: Early Innate Responses to Hepatitis B Virus Infection, an Explanation for Viral Persistence? Virol Sin 2020; 36:163-166. [PMID: 32632817 PMCID: PMC7973328 DOI: 10.1007/s12250-020-00235-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/03/2020] [Indexed: 12/22/2022] Open
Affiliation(s)
- Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany.
| | - Xufeng Luo
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
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50
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Wu J, Niu Q, Yuan J, Xu X, Cao L. lncRNA-CD160 decreases the immunity of CD8 + T cells through epigenetic mechanisms in hepatitis B virus infection. Oncol Lett 2020; 20:235-247. [PMID: 32565950 PMCID: PMC7286002 DOI: 10.3892/ol.2020.11534] [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] [Received: 08/15/2017] [Accepted: 01/07/2020] [Indexed: 02/06/2023] Open
Abstract
The transfer and development of chronic hepatitis B virus (HBV) infection is associated with the T cell immune response, therefore investigating the key regulators of cell immune response is needed to improve chronic HBV treatment. Blood samples from patients with chronic HBV infection were used to confirm the correlation between HBV infection stage and CD160 receptor expression levels in CD8+ T cells, the CD8+ T cells are used to research the mechanism of T cell immune response modulation, moreover, C3H/HeN mice with reduced CD160 expression levels were used to investigate the association between long non-coding (lnc)RNA-CD160 and HBV infection. Long non-coding (lnc)RNA-CD160 and histone-modification enzyme gene histone deacetylase 11 (HDAC11) expression levels were negatively associated with CD160 expression. lncRNA-CD160 can inhibit the secretion of IFN-γ and TNF-α through HDAC11 recruitment and bind to HDAC11 to form a complex on the promoters of IFN-γ and TNF-α. The HDAC11, IFN-γ and TNF-α form a complex and enhance the methylation of H3K9Me1, chromatin changes into the heterochromatin and the transcription of IFN-γ and TNF-α is blocked; moreover, the HDAC11/IFN-γ/TNF-α complex can also inhibit the secretion of IFN-γ and TNF-α in CD160- CD8+ T cells and suppresses the function of CD8+ T cells. Furthermore, small interfering RNA targeting lncRNA-CD160 can block HBV infection progression. lncRNA-CD160 acts as an immune suppressive factor and is expressed at a high level in peripheral blood CD8+ T cells of HBV infected patients. Furthermore, high expression levels of lncRNA-CD160 can contribute to the inhibition of IFN-γ and TNF-α secretion in CD8+ T cells and decrease the immune response of CD8+ T cells. Therefore, lncRNA-CD160 may become a new target for immunotherapy of chronic HBV infection in the future and may provide a new therapeutic strategy for the treatment of HBV infection.
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Affiliation(s)
- Jiansong Wu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Qiang Niu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Jie Yuan
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Xiaodan Xu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Liuxia Cao
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
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