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Franzè MS, Saitta C, Lombardo D, Musolino C, Caccamo G, Filomia R, Pitrone C, Cacciola I, Pollicino T, Raimondo G. Long-term virological and clinical evaluation of chronic hepatitis B patients under nucleos(t)ide analogues therapy. Clin Res Hepatol Gastroenterol 2025; 49:102566. [PMID: 40043798 DOI: 10.1016/j.clinre.2025.102566] [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: 01/09/2025] [Accepted: 03/02/2025] [Indexed: 04/06/2025]
Abstract
INTRODUCTION AND OBJECTIVES Identifying hepatitis B virus (HBV) patients eligible for safe nucleos(t)ide analogues (NAs) discontinuation remains challenging. Discrepant data on combined HBV DNA and quantitative HBV surface antigen (qHBsAg) assessments are available. This study aimed to identify potential predictors for safe treatment discontinuation by evaluating clinical/virological outcomes in patients on long-term NA therapy. PATIENTS AND METHODS A retrospective cohort of 139 chronic hepatitis B (CHB) patients - who consecutively started Entecavir or Tenofovir from 2007 to 2011 - was evaluated. The study population was selected based on anti-HBe positivity, absence of prior antiviral treatment, absence of non-HBV-related liver diseases or hepatocellular carcinoma (HCC), and long-term clinical/ultrasonographic/laboratory evaluations post-NA initiation. Serum samples collected before starting NA (T0) and over ten years (T1-T10) were tested for HBV DNA and qHBsAg. RESULTS Twenty-two/139 (15.8 %) CHB patients (12 chronic hepatitis, 10 cirrhosis) met the inclusion criteria. All patients showed a significant decrease in liver stiffness values in the ten years of follow-up (p = 0.001), and no hepatic decompensation occurred. Three/22 (13.6 %) patients developed HCC. Ten/22 patients (45.5 %; group-A) had fluctuating HBV DNA, while other 10/22 (45.5 %; group-B) showed undetectable HBV DNA for 5-9 years with more significant qHBsAg decline (p = 0.04) than group-A. Two/22 (9.1 %) patients showed a critical qHBsAg decline up to seroconversion together with undetectable HBV DNA. CONCLUSIONS Persistent undetectable HBV DNA levels correlate with qHBsAg reduction and the potential HBsAg seroclearance, suggesting that long-term HBV DNA monitoring in NA-treated CHB patients might help identify candidates for treatment discontinuation.
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Affiliation(s)
- Maria Stella Franzè
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Cristina Musolino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Gaia Caccamo
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Roberto Filomia
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Concetta Pitrone
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Irene Cacciola
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy.
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Hao B, Liu Y, Wang B, Wu H, Chen Y, Zhang L. Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma. Exp Hematol Oncol 2025; 14:44. [PMID: 40141002 PMCID: PMC11938626 DOI: 10.1186/s40164-025-00642-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.
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Affiliation(s)
- Bingyan Hao
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bohan Wang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haofeng Wu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Chen
- Department of Paediatrics, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Tongji Hospital, Tongji Medical College, Shanxi Medical University, Huazhong University of Science and Technology, Taiyuan, 030032, China.
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Huang C, Zhang H, Wang J, Li J, Liu Q, Zong Q, Zhang Y, Wang Q, Zhou Q. Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway. Open Life Sci 2025; 20:20220951. [PMID: 39926475 PMCID: PMC11806202 DOI: 10.1515/biol-2022-0951] [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: 04/14/2024] [Revised: 07/04/2024] [Accepted: 07/30/2024] [Indexed: 02/11/2025] Open
Abstract
A growing body of evidence has shown that hepatitis B surface antigen (HBsAg) mutations can influence the occurrence of occult hepatitis B infection (OBI), particularly amino acid substitutions in small hepatitis B surface proteins (SHBs). The mechanistic basis for these results, however, remains unclear. This study was designed to explore the potential impact and mechanisms of OBI-related SHBs mutations on serum HBsAg. Huh7 and HepG2 cells were transfected with plasmids encoding wild-type (WT) or OBI-related SHB mutation-containing sequences, after which a chemiluminescence approach was used to detect HBsAg levels in cell culture supernatants. Western blotting was further used to assess HBsAg and endoplasmic reticulum stress (ERS)-related protein levels in lysates prepared from these cells, while the localization of HBsAg within cells was assessed via immunofluorescent staining. Cells transfected with OBI-related SHB mutation-encoding plasmids exhibited lower supernatant HBsAg levels than cells transfected with WT plasmids. Intracellular and extracellular HBsAg levels in these mutant plasmid-transfected cells were lower relative to those for WT plasmid-transfected cells, and HBsAg accumulation within the ER was detected via immunofluorescent staining in cells transfected with OBI-related SHB mutation-encoding plasmids, ERS-related protein content was also significantly increased in mutant plasmid-transfected cells as compared to those in the WT group. These results suggest that proteins harboring OBI-related mutations may tend to accumulate in the ER, thereby triggering an ERS response and impairing the transcription and translation of HBsAg via the activation of the unfolded protein response and ER-associated protein degradation pathway. These effects ultimately reduce the overall assembly of HBV virions in the ER and their associated secretion.
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Affiliation(s)
- Chengrong Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Department of Clinical Laboratory, Anqing Municipal Hospital, Anqing, 246003, China
| | - Hao Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Jing Wang
- Department of Clinical Laboratory, Nanjing Jiangning Hospital, Nanjing, 211100, China
| | - Jianfei Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qian Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qiyin Zong
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yunyun Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qin Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
| | - Qiang Zhou
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
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Choi YM, Kim DH, Cho EJ, Kim Z, Jang J, Kim H, Yu SJ, Kim BJ. The sV184A Variant in HBsAg Specific to HBV Subgenotype C2 Leads to Enhanced Viral Replication and Apoptotic Cell Death Induced by PERK-eIF2α-CHOP-Mediated ER Stress. J Med Virol 2025; 97:e70253. [PMID: 39977392 DOI: 10.1002/jmv.70253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 01/15/2025] [Accepted: 02/05/2025] [Indexed: 02/22/2025]
Abstract
HBV genotype C, particularly subgenotype C2, is associated with an elevated risk of HCC and aggressive disease activity. We previously identified a nonsynonymous sV184A variant in the HBsAg region, predominantly in HBV subgenotype C2. This study investigates the mechanistic role of the sV184A variant in promoting liver disease progression. Analysis of 109 chronically HBV-infected patients revealed that the sV184A variant correlates with significantly elevated HBV DNA. Both patient data and public database indicated that sV184A is associated with high frequency of BCP mutations, however, the high HBV DNA in the sV184A group are independent of the presence of BCP mutations. In vitro and in vivo studies demonstrated that the sV184A variant enhances HBV replication and induces ER stress via the PERK-eIF2α-CHOP pathway, leading to apoptosis. HBV large surface (LHB)(LHB) protein was found to be a key factor, responsible for the strong ER stress, as the sV184A variant increases LHB protein stability. Pharmacological inhibition of PERK signaling or mutation of the LHB mitigated HBV proliferation and apoptosis induced by the sV184A variant. The sV184A variant specific to HBV subgenotype C2 significantly promotes HBV replication and apoptosis, serving as a driver of advanced liver disease and potentially increasing mutation rates in affected patients.
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Affiliation(s)
- Yu-Min Choi
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Seoul National University Medical Research Center (SNUMRC), Seoul, Republic of Korea
| | - Dong Hyun Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ziyun Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Junghwa Jang
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hyunsoo Kim
- Department of Convergent Bioscience and Informatics, Chungnam National University, Daejeon, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Seoul National University Medical Research Center (SNUMRC), Seoul, Republic of Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Liver Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea
- Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of Korea
- BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea
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Mo Y, Jin F, Li D, Zou W, Zhong J, Tong Z, Wang W, Qian F. Prevalence and molecular characteristics of occult hepatitis B virus infection among blood donors in Huzhou City, eastern China. Gene 2024; 927:148718. [PMID: 38914243 DOI: 10.1016/j.gene.2024.148718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/23/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Occult hepatitis B virus (HBV) infection (OBI) is a significant challenge for HBV prevention and control. We investigated the prevalence and surface (S) gene mutations of OBI among blood donors in Huzhou City, eastern China. The hepatitis B surface antigen (HBsAg) was routinely screened among 44,256 blood donors. HBV-DNA was detected using the Roche cobas®system. Serum samples that were HBsAg negative and HBV-DNA positive were selected, and the HBV S gene was amplified and sequenced. HBV genotype and S gene mutations were analyzed. The OBI rate in these blood donors was 0.070 % (31/44,256). Among the blood donors with OBI, only two cases (2/31, 6.5 %) were anti-HBc negative. The S gene sequences of 28 samples were successfully obtained, and we found that HBV genotype C (21/28, 70 %) was predominant among blood donors with OBI. Most S gene mutations were associated with OBI, and the high frequency mutations included N40S, G44E, Q51R/P, T113A/S,T118K/M, P120Q/S/T, and Y161F/S. Notably, amino acid substitutions at some sites differed from those reported previously, such as Y72F, G102V, P127L, Q129P, and S143T. Additionally, six novel mutations (S31I/N/R, P46L, S58C, C76Y, Y200F/C, and I208T) that may be associated with OBI were found. OBI was detected in a certain proportion of blood donors in Huzhou City. S gene mutations play an important role in OBI development. Further research is required to explore the functions of novel S gene mutants in OBI pathogenesis. The findings of this study may provide important insights to prevent HBV transmission through blood transfusions.
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Affiliation(s)
- Yanping Mo
- Huzhou Center Blood Station, 577 Fenghuang Road, Huzhou, Zhejiang 313000, China
| | - Fang Jin
- Departmentof Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China
| | - Dongli Li
- Departmentof Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China
| | - Weihua Zou
- Department of Laboratory Medicine, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China
| | - Jianfeng Zhong
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China; Department of Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China
| | - Zhaowei Tong
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China; Department of Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China
| | - Weihong Wang
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China; Department of Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China
| | - Fuchu Qian
- Departmentof Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital, Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China.
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6
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Kozuka R, Enomoto M, Yukawa-Muto Y, Odagiri N, Kotani K, Motoyama H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Kawada N. Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy. Hepatol Res 2024; 54:615-626. [PMID: 38323994 DOI: 10.1111/hepr.14016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 02/08/2024]
Abstract
AIM A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown. METHODS A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy. RESULTS Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53 log IU/mL; p = 0.047), HBsAgGi/HBsAg ratio (≥1.10; p = 0.035), and HBV DNA (≤6.3 log copies/mL; p = 0.012) at baseline and HBsAg (≤3.19 log IU/mL; p = 0.033) and HBsAgGi/HBsAg ratio (≥1.09; p = 0.003) at 48 weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88 × 103/mm3 (p = 0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48 weeks after NA therapy ≥1.09 (p = 0.040; HR, 10.099) were independently and significantly associated with the development of HCC. CONCLUSIONS Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yoshimi Yukawa-Muto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kohei Kotani
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Li G, Liu X, Lu F. What is the real sword of HBV precore and basal core promoter mutations piercing the hepatocyte homeostasis: HBcAg or HBsAg? J Med Virol 2024; 96:e29745. [PMID: 38884414 DOI: 10.1002/jmv.29745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/24/2024] [Accepted: 06/08/2024] [Indexed: 06/18/2024]
Affiliation(s)
- Guixin Li
- Peking University People's Hospital, Peking University Hepatology Institute, Infectious Disease and Hepatology Center of Peking University People's Hospital，Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xin Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Fengmin Lu
- Peking University People's Hospital, Peking University Hepatology Institute, Infectious Disease and Hepatology Center of Peking University People's Hospital，Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
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Lago BV, Portilho MM, Mello VM, De Sousa PSF, Angelice GP, Marques BCL, da Silva Andrade LT, Marques VA, Lewis-Ximenez LL, Mello FCDA, Villar LM. Genetic variability of hepatitis B virus in acute and in different phases of chronic infection in Brazil. Sci Rep 2024; 14:10742. [PMID: 38730249 PMCID: PMC11087654 DOI: 10.1038/s41598-024-60900-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/29/2024] [Indexed: 05/12/2024] Open
Abstract
The selection pressure imposed by the host immune system impacts on hepatitis B virus (HBV) variability. This study evaluates HBV genetic diversity, nucleos(t)ide analogs resistance and HBsAg escape mutations in HBV patients under distinct selective pressures. One hundred and thirteen individuals in different phases of HBV infection were included: 13 HBeAg-positive chronic infection, 9 HBeAg-positive chronic hepatitis, 47 HBeAg-negative chronic infection (ENI), 29 HBeAg-negative chronic hepatitis (ENH) and 15 acute infected individuals. Samples were PCR amplified, sequenced and genetically analyzed for the overlapping POL/S genes. Most HBV carriers presented genotype A (84/113; 74.3%), subgenotype A1 (67/84; 79.7%), irrespective of group, followed by genotypes D (20/113; 17.7%), F (8/113; 7.1%) and E (1/113; 0.9%). Clinically relevant mutations in polymerase (tL180M/M204V) and in the Major Hydrophilic Region of HBsAg (sY100C, T118A/M, sM133T, sD144A and sG145R) were observed. Our findings, however, indicated that most polymorphic sites were located in the cytosolic loops (CYL1-2) and transmembrane domain 4 (TMD4) of HBsAg. Lower viral loads and higher HBV genetic diversity were observed in ENI and ENH groups (p < 0.001), suggesting that these groups are subjected to a higher selective pressure. Our results provide information on the molecular characteristics of HBV in a diverse clinical setting, and may guide future studies on the balance of HBV quasispecies at different stages of infection.
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Affiliation(s)
- Barbara Vieira Lago
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil.
- Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fiocruz, Rio de Janeiro, Brazil.
| | - Moyra Machado Portilho
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Vinicius Motta Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil.
| | - Paulo Sergio Fonseca De Sousa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Giovana Paula Angelice
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Bianca Cristina Leires Marques
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Larissa Tropiano da Silva Andrade
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Vanessa Alves Marques
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Lia Laura Lewis-Ximenez
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Francisco Campello do Amaral Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
| | - Livia Melo Villar
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fiocruz, Hélio and Peggy Pereira Pavillion, Ground Floor, Office B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, 210360-040, Brazil
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Hepatitis B Surface Antigen Isoforms: Their Clinical Implications, Utilisation in Diagnosis, Prevention and New Antiviral Strategies. Pathogens 2024; 13:46. [PMID: 38251353 PMCID: PMC10818932 DOI: 10.3390/pathogens13010046] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
The hepatitis B surface antigen (HBsAg) is a multifunctional glycoprotein composed of large (LHB), middle (MHB), and small (SHB) subunits. HBsAg isoforms have numerous biological functions during HBV infection-from initial and specific viral attachment to the hepatocytes to initiating chronic infection with their immunomodulatory properties. The genetic variability of HBsAg isoforms may play a role in several HBV-related liver phases and clinical manifestations, from occult hepatitis and viral reactivation upon immunosuppression to fulminant hepatitis and hepatocellular carcinoma (HCC). Their immunogenic properties make them a major target for developing HBV vaccines, and in recent years they have been recognised as valuable targets for new therapeutic approaches. Initial research has already shown promising results in utilising HBsAg isoforms instead of quantitative HBsAg for correctly evaluating chronic infection phases and predicting functional cures. The ratio between surface components was shown to indicate specific outcomes of HBV and HDV infections. Thus, besides traditional HBsAg detection and quantitation, HBsAg isoform quantitation can become a useful non-invasive biomarker for assessing chronically infected patients. This review summarises the current knowledge of HBsAg isoforms, their potential usefulness and aspects deserving further research.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.B.); (D.M.); (M.C.)
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Yi L, Wu J, Yang Z, Li Y, Lian J, Yao T, Feng S, Wang B, Feng Y, Wang S. Maternal A90V mutation in the PreS1 gene of sub-genotype C2 hepatitis B virus is associated with intrauterine transmission. Rev Inst Med Trop Sao Paulo 2023; 65:e46. [PMID: 37703117 PMCID: PMC10495115 DOI: 10.1590/s1678-9946202365046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/17/2023] [Indexed: 09/15/2023] Open
Abstract
PreS/S gene mutations could impact virus secretion, infection and immune evasion. However, the relationship between PreS/S mutations and intrauterine transmission has not yet been clarified. Thus, we aimed to explore the associations between PreS/S gene mutations of HBV isolated from mothers and intrauterine transmission. We analyzed the mutations of PreS/S regions of the HBV genome in mothers with HBV DNA levels ≥ 106 IU/mL whose neonates experienced HBV intrauterine transmission (transmission group, GT) and those whose neonates did not experience intrauterine transmission (control group, GC) analyzed using clone-based sequencing. In total, 206 sequences were successfully amplified, including 98 sequences (from 21 mothers) from GT and 108 sequences (from 20 mothers) from GC of genotype C for mutational analysis. Among the 1203 nucleotides of PreS/S regions, there were 219 (18.20%) base substitutions, of which 103 (47.03%) base mutations caused amino acid changes. F80S, A90V and I68T were mutation hotspots. Mothers in GT had a higher mutation rate of A90V in the PreS1 gene than mothers in GC. The A90V mutation increased the risk of HBV intrauterine transmission after adjusting the maternal age and the mode of delivery (OR = 6.23, 95% CI: 1.18-32.97). Moreover, the area under the ROC curve (AUC) for intrauterine transmission due to A90V and a combination of A90V with the mode of delivery were 0.723 (95% CI: 0.575 to 0.891, P = 0.011) and 0.848 (95% CI: 0.723 to 0.972, P < 0.001), respectively. Mothers with the A90V mutation in the PreS1 gene may be a potential risk factor for HBV intrauterine transmission.
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Affiliation(s)
- Linzhu Yi
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Jiaxin Wu
- Shanxi Provincial Center for Disease Control and Prevention, Taiyuan, Shanxi, China
| | - Zhiqing Yang
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Yandi Li
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Jia Lian
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Tian Yao
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Shuying Feng
- Third People’s Hospital, Department of Obstetrics and Gynaecology, Taiyuan, Shanxi, China
| | - Bo Wang
- Third People’s Hospital, Department of Obstetrics and Gynaecology, Taiyuan, Shanxi, China
| | - Yongliang Feng
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
| | - Suping Wang
- Shanxi Medical University, Department of Epidemiology, Taiyuan, Shanxi, China
- Shanxi Medical University, Center of Clinical Epidemiology and Evidence Based Medicine, Taiyuan, Shanxi, China
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Liu X, Chen SX, Liu H, Lou JL. Host immunity and HBV S gene mutation in HBsAg-negative HBV-infected patients. Front Immunol 2023; 14:1211980. [PMID: 37646026 PMCID: PMC10461097 DOI: 10.3389/fimmu.2023.1211980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/20/2023] [Indexed: 09/01/2023] Open
Abstract
Background Clinically, some patients whose HBsAg becomes negative owing to antiviral therapy or spontaneously still show a low level of HBV DNA persistence in serum. T-lymphocyte subsets, cytokine levels and HBV S gene sequences were analyzed in this study. Methods A total of 52 HBsAg-negative and HBV DNA-positive patients(HBsAg-/HBV DNA+ patients), 52 persistently HBsAg-positive patients(HBsAg+/HBV DNA+ patients) and 16 healthy people were evaluated. T-lymphocyte subsets of these patients were detected by flow cytometry, serum cytokines and chemokines were detected by the Luminex technique, and the HBV S region was evaluated by Sanger sequencing. T%, T-lymphocyte, CD8+ and CD4+T lymphocyte were lower in the HBsAg-negative group than in the HC group. Compared with the HBsAg-positive group, the HBsAg-negative group had lower levels in T lymphocyte %, CD8+T lymphocyte %, CD8+T lymphocyte and CD4/CD8. These difference were statistically significant (P<0.05). Serum IFN-γ, IFN-α and FLT-3L levels were significantly higher in the HBsAg-negative group than in the HBsAg-positive group (P<0.05). However, levels of many cytokines related to inflammation (i.e., IL-6, IL-8, IL10, IL-12, IL-17A) were lower in the HBsAg-negative group. Fifty-two HBsAg-negative samples were sequenced, revealing high-frequency amino acid substitution sites in the HBV S protein, including immune escape mutations (i.e., Y100C, S114T, C124Y, P127L, G130R, T131N, M133T, C137S, G145A) and TMD region substitutions (i.e., E2K/R/D, G7D/R, G10D, A17R, F20L/S, L21V, L22V). Conclusions According to the results of T-lymphocyte subsets and serum cytokines, it can be deduced that the cellular immune function of HBsAg-negative patients is superior to that of HBsAg-positive patients, with attenuation of liver inflammation. HBsAg-negative patients may show a variety of mutations and amino acid replacement sites at high frequency in the HBV S region, and these mutations may lead to undetectable HBsAg, HBsAg antigenic changes or secretion inhibition.
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Affiliation(s)
| | | | | | - Jin-li Lou
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Han JJ, Hu YA, Nan Y, Chen Y, Yang YL. Decreased expression of HBV surface antigen (HBsAg) with sK122R and sV96A co-mutation is associated with an ineffective antibody response in a chronic hepatitis B patient. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2023; 111:105431. [PMID: 37015318 DOI: 10.1016/j.meegid.2023.105431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 02/01/2023] [Accepted: 03/29/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND Emergence and predominance of hepatitis B virus (HBV) variants carrying S gene mutations frequently occur in HBV-infected individuals. Here, coexistent serum anti-HBsAg antibody (HBsAb) and HBV surface antigen (HBsAg) were detected in a chronic HBV patient. The patient's HBsAg proteins possessed amino acid substitutions sK122R and sV96A. We reported this case and conducted relevant studies to investigate differences in expression levels and antibody neutralization of HBsAg proteins bearing sK122R and sV96A amino acid substitutions to explore causes of antigen-antibody coexistence in a chronic hepatitis B patient. STUDY DESIGN We first sequenced the S gene from HBV present within the patient's serum. Based on the S gene sequence, we cloned wild-type and mutated S gene sequences via site-directed mutagenesis to construct expression plasmids pJW4303-WT (wild-type), pJW4303-sV96A, pJW4303-sK122R, and pJW4303-sV96A-sK122R. Plasmids were transfected into HEK 293 T cells then culture supernatants and cells were collected. Collected cells and supernatants were next subjected to a series of quantitative and functional tests to assess expression and neutralization characteristics of wild-type and mutant HBsAg proteins. RESULTS Based on quantification of HBsAg expression in cells transfected with the four plasmids, HBsAg-sK122R-sV96A was more intracellularly retained and less secreted than HBsAg-sV96A single-mutant protein and WT. Neutralization ability of serum from chronic HBV patient against culture supernatants containing recombinant HBsAg proteins were ranked from highest to lowest as HBsAg-sV96A, HBsAg-sV96A-sK122R, and HBsAg-sK122R. However, no significant differences of neutralization efficiency by high-potency antibodies from HBV-vaccinees against these three mutant proteins were observed. CONCLUSIONS The levels of HBsAg proteins with amino acid substitutions sV96A-sK122R were greatly reduced in culture supernatants but were apparently increased in the intracellular fraction. This may account for the higher levels of HBV replication in patients. HBsAg neutralization by HBsAb in this patient may have been compromised by the HBsAg sK122R amino acid substitution, suggesting that antibodies produced by the patient had lost their HBV-neutralizing effect.
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Affiliation(s)
- Jing-Jing Han
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yu-An Hu
- Basic Medical Laboratory, Institute of Clinical Laboratory Science, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi Province, China
| | - Yu Chen
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yong-Lin Yang
- Department of Infectious Disease, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China.
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Hsu HY, Chen HL, Chiang CL, Lai MW, Mu SC, Wen WH, Cheng SW, Hu JJ, Chang KC, Lee CN, Liu CJ, Wu JF, Ni YH, Chang MH. Characterization of Hepatitis B Virus in Tenofovir-Treated and Untreated Chronically Infected Mothers and Their Immunoprophylaxis Failure Infants. Clin Infect Dis 2023; 76:e783-e790. [PMID: 35789261 DOI: 10.1093/cid/ciac539] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Maternal tenofovir disoproxil fumarate (TDF) therapy during late pregnancy can reduce mother-to-infant transmission of hepatitis B virus (HBV). We investigated HBV mutations associated with maternal TDF therapy and their role in infant immunonophylaxis failure (IPF). METHODS Serum samples from untreated (n = 89) and TDF-treated (n = 68), highly viremic, chronically infected mothers and their infants were analyzed for HBV DNA by nested polymerase chain reaction (PCR) and direct sequencing. RESULTS At delivery, compared with untreated mothers, TDF-treated mothers had a lower HBV DNA titer and a higher frequency of basal core promoter (BCP) gene mutations, but they had similar frequencies in pre-S/S and pre-core/core mutations. The 14 mothers harboring surface "a" determinant mutants did not transmit the mutants to their immunized infants. Such mutants were found in 3 of 13 IPF infants; the 13 mothers had wild-type hepatitis B surface antigen (HBsAg). In univariable analysis, maternal HBV DNA titer (odds ratio [OR]: 1.54; 95% confidence intervals [CI]: 1.02-2.33; P = .039), genotype C (OR: 4.18; 95% CI: 1.28-13.62; P = .018) and pre-S1 wild-type sequence (OR: 6.33; 95% CI: 1.85-21.68; P = .003) at delivery were associated with infant IPF. Multivariable analyses showed that maternal genotype C (OR: 3.71; 95% CI: 1.11-12.36; P = .033) and pre-S1 wild-type (OR: 6.34; 95% CI: 1.79-22.44; P = .004) were associated with infant IPF independently of maternal viremia. CONCLUSIONS Along with high maternal HBV DNA titer at delivery, maternal genotype C and pre-S1 wild-type sequence were potential risk factors for infant IPF, although BCP mutations were not. The offspring of pregnant women harboring "a" determinant mutants as major strains seemed to be protected by immunoprophylaxis. CLINICAL TRIALS REGISTRATION NCT01312012.
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Affiliation(s)
- Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department and Graduate Institute of Medical Education and Bioethics National Taiwan University College of Medicine, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department and Graduate Institute of Medical Education and Bioethics National Taiwan University College of Medicine, Taipei, Taiwan
| | - Cheng-Lun Chiang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department and Graduate Institute of Medical Education and Bioethics National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Shu-Chi Mu
- Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Wan-Hsin Wen
- Department of Pediatrics, Cardinal Tien Hospital, and School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Shao-Wen Cheng
- Department of Pediatrics, Chang Gung Memorial Hospital, Taipei Branch, Taiwan
| | - Jen-Jan Hu
- Department of Pediatrics, Taiwan Adventist Hospital, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Chien-Nan Lee
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Shui LP, Zhu Y, Duan XQ, Chen YT, Yang L, Tang XQ, Zhang HB, Xiao Q, Wang L, Liu L, Luo XH. HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) predicts a high risk of hepatitis B reactivation in patients with B-cell lymphoma receiving rituximab based immunochemotherapy. J Med Virol 2023; 95:e28549. [PMID: 36734081 DOI: 10.1002/jmv.28549] [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: 08/13/2022] [Revised: 12/30/2022] [Accepted: 01/24/2023] [Indexed: 02/04/2023]
Abstract
Patterns of hepatitis B virus reactivation (HBV-R) in HBsAg (-)/HBcAb (+) patients with B-cell non-Hodgkin lymphoma (NHL) receiving rituximab based immunochemotherapy have not been well described. The retrospective study included 222 HBsAg (-)/HBcAb (+) NHL patients as training cohort and 127 cases as validation cohort. The incidence of HBV-R in HBsAg (-)/HBcAb (+) B-cell NHL patients was 6.3% (14/222), of which that in HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was 23.7% (9/38). Multivariate analysis showed that HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) correlated with a high risk of HBV-R in B-cell lymphoma patients (training phase hazard ratio [HR], 10.123; 95% confidence interval [CI], 3.389-30.239; p < 0.001; validation phase HR, 18.619; 95% CI, 1.684-205.906; p = 0.017; combined HR, 12.264; 95% CI, 4.529-33.207; p < 0.001). In the training cohort, the mortality rate of HBsAg (-)/HBcAb (+) B-cell NHL caused by HBV-R was 14.3% (2/14) while that for HBV reactivated HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was up to 44.4% (4/9). As a high incidence of HBV-R and high mortality after HBV-R was found in HBsAg (-)/HBsAb (-)/HBcAb (+)/HBeAg (-)/HBeAb (+) patients with B-cell NHL receiving rituximab based immunochemotherapy, prophylactic antiviral therapy is recommended for these patients.
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Affiliation(s)
- Li-Ping Shui
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Zhu
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiao-Qin Duan
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Ting Chen
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Yang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Qiong Tang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong-Bin Zhang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing Xiao
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Liu
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Hua Luo
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Sun H, Chang L, Yan Y, Ji H, Jiang X, Song S, Xiao Y, Lu Z, Wang L. Naturally occurring pre-S mutations promote occult HBV infection by affecting pre-S2/S promoter activity. Antiviral Res 2022; 208:105448. [DOI: 10.1016/j.antiviral.2022.105448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/08/2022] [Accepted: 10/12/2022] [Indexed: 11/15/2022]
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Chang KC, Lin MT, Wang JH, Hung CH, Chen CH, Chiu SYH, Hu TH. HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral. Viruses 2022; 14:v14122671. [PMID: 36560675 PMCID: PMC9782149 DOI: 10.3390/v14122671] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4-4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Sherry Yueh-Hsia Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Health Care Management, College of Management, and Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
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Yan Y, Sun H, Chang L, Ji H, Jiang X, Song S, Xiao Y, Feng K, Nuermaimaiti A, Lu Z, Wang L. Circulating immune complexes and mutations of HBsAg are associated with the undetectable HBsAg in anti-HBs and HBeAg positive occult hepatitis B virus infection. Front Microbiol 2022; 13:1063616. [DOI: 10.3389/fmicb.2022.1063616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/14/2022] [Indexed: 11/30/2022] Open
Abstract
IntroductionOccult hepatitis B virus infection (OBI) is an HBsAg negative state in HBV infection with usually inactive HBV replication. However, there were a minority of individuals with positive HBeAg and anti-HBs among OBI blood donors and few studies have focused on this unusual serological pattern.Methods2022 plasma of blood donors that preliminary screened reactive for HBV DNA and non-reactive for HBsAg were collected from 16 provinces in China from 2015 to 2018. HBV DNA and HBsAg in these samples were retested using the Cobas TaqScreen MPX test and ARCHITECT HBsAg Quantitative II assay. Lumipulse HBsAg-HQ assay and polyethylene glycol (PEG)-double precipitation following HCl and trypsin digestion were performed to detect HBsAg from HBsAg-anti-HBs circulating immune complexes (CICs).Results1487 of 2022 samples were positive for Cobas HBV DNA test and non-reactive for ARCHITECT HBsAg assay, while 404 of them were positive using Lumipulse HBsAg-HQ assay. 10 HBsAg-/anti-HBs+/HBeAg+ OBI blood donor samples were further dissociated and HBsAg-CICs were detected in 7 samples. Sequencing analysis showed that D44N, N98T, G73S, Del 56-116, and I161T occurred in the pre-S region, and immune escape mutations such as P127T, F134L, G145R, V168A, and I126T/S in the S region were found.DiscussionIn conclusion, there were a minority of HBsAg-/anti-HBs+/HBeAg+ individuals in OBI blood donors. The undetectable HBsAg in these individuals was mainly due to HBsAg-CICs. Immune escape-associated mutations also happened under the host’s selective pressure. HBsAg dissociation methods or Lumipulse HBsAg-HQ assay is recommended to distinguish these individuals.
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Endoplasmic Reticulum Stress in Hepatitis B Virus and Hepatitis C Virus Infection. Viruses 2022; 14:v14122630. [PMID: 36560634 PMCID: PMC9780809 DOI: 10.3390/v14122630] [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: 09/30/2022] [Revised: 11/20/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Endoplasmic reticulum (ER) stress, a type of cellular stress, always occurs when unfolded or misfolded proteins accumulating in the ER exceed the protein folding capacity. Because of the demand for rapid viral protein synthesis after viral infection, viral infections become a risk factor for ER stress. The hepatocyte is a cell with large and well-developed ER, and hepatitis virus infection is widespread in the population, indicating the interaction between hepatitis viruses and ER stress may have significance for managing liver diseases. In this paper, we review the process that is initiated by the hepatocyte through ER stress against HBV and HCV infection and explain how this information can be helpful in the treatment of HBV/HCV-related diseases.
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Yu Y, Zhang Y, Dai Y, Sun Q, Jiang C, Xu X, Mei C, Cheng J. Analysis of S gene characteristic sequences and changes in properties of protein expression in HBV ASCs with low-level HBsAg. Front Med (Lausanne) 2022; 9:948842. [PMID: 36186824 PMCID: PMC9516100 DOI: 10.3389/fmed.2022.948842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/26/2022] Open
Abstract
Objective We detected the serum HBsAg immune complex (HBsAg-CIC) and sequenced the HBV S gene in these patients to reveal the association between sustained low-level expression of HBsAg and mutated S gene sequence characteristics, protein function changes, and HBsAg immune complex formation. Methods A total of 204 samples were collected and divided into high-level (n = 60, HBsAg level >10 IU/ml) and low-level (n = 144, HBsAg level ≤ 10 IU/ml) HBsAg groups. The clinical and epidemiological data of the two groups were statistically compared. According to different serological patterns and genotypes, the HBsAg-CIC results of the high-level and low-level HBsAg groups were divided into different subgroups, and then the HBsAg-CIC positive rates among different subgroups were compared. We sequenced the S gene of HBV from the two groups and identified the relevant mutations in the MHR of the S gene. In addition, we compared the changes in HBsAg protein properties and functions after hot spot mutation in the MHR of the S gene. Results Comparing the positive rates of HBsAg-CIC under different serological patterns and genotypes in the two groups, the HBsAg-CIC positive rate was higher in the low-level HBsAg group. Moreover, there was weak correlation between HBsAg-CIC and HBsAg or HBV DNA in both groups (r = 0.32, 0.27, 0.41, 0.48; P < 0.05). Sequencing of S gene in the two groups, showed that the hot-spot mutations were T126A, M133L/T/S, and F134L/T/I in MHR of S gene of genotype B, and hot-spot mutations were Q101R and I126S/T in MHR of S gene of genotype C. Additionally, the positive rate of MHR mutation in the S gene from HBsAg-CIC positive patients was higher in the low-level HBsAg group. Conclusion The host immune process of clearing HBV seems to have multiple site mutations in MHR, which changes the physicochemical properties and functions of HBsAg and intensifies the formation of HBsAg-CIC, thus avoiding the effective recognition of HBsAg by the host and resulting in immune tolerance between the host and HBV, which may be one of the formation mechanisms of sustained low-level expression of HBsAg in the serum of HBV-infected persons.
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Affiliation(s)
- Yu Yu
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
- Department of Clinical Research, The 903rd Hospital of PLA, Hangzhou, China
| | - Yingqiang Zhang
- Department of Clinical Research, The 903rd Hospital of PLA, Hangzhou, China
| | - Yuzhu Dai
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
- Department of Clinical Research, The 903rd Hospital of PLA, Hangzhou, China
| | - Qingyang Sun
- Department of Clinical Research, The 903rd Hospital of PLA, Hangzhou, China
| | - Chun Jiang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Xujian Xu
- Department of Biotechnology, The University of Tokyo, Tokyo, Japan
| | - Chuanzhong Mei
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
- Chuanzhong Mei
| | - Jun Cheng
- School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
- Department of Clinical Research, The 903rd Hospital of PLA, Hangzhou, China
- Faculty of Graduate Studies, Jiangsu University, Zhenjiang, China
- *Correspondence: Jun Cheng
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20
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Lok J, Dusheiko G, Carey I, Agarwal K. Review article: novel biomarkers in hepatitis B infection. Aliment Pharmacol Ther 2022; 56:760-776. [PMID: 35770458 DOI: 10.1111/apt.17105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.
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Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
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21
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Liu W, Cai S, Pu R, Li Z, Liu D, Zhou X, Yin J, Chen X, Chen L, Wu J, Tan X, Wang X, Cao G. HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling. Cancers (Basel) 2022; 14:cancers14133274. [PMID: 35805045 PMCID: PMC9265300 DOI: 10.3390/cancers14133274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Viral mutations at the preS region of hepatitis B virus (HBV) significantly increase the risk of developing hepatocellular carcinoma (HCC). Compared to HBV preS deletion, the oncogenic effect of preS combo mutation has rarely been investigated. With a cohort including 2114 subjects, we demonstrated that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased the risk of HCC in patients without antiviral treatment, whereas preS2 deletion significantly increased the risk of HCC in patients with antiviral treatment. The prevalence of C3116T/T31C (43.61%) was higher than preS2 deletion (7.16%). By using Sleeping Beauty mouse models and in vitro experiments, we found G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promoted hepatocarcinogenesis by increasing levels of inflammatory cytokines, activating STAT3 pathway, enhancing endoplasmic reticulum stress, and altering gene expression profiles in inflammation- and metabolism-related pathways. These results suggest that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C had similar oncogenic effects of preS2 deletion and should also be monitored. Abstract This study aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The effect of the preS mutations on hepatocellular carcinoma (HCC) occurrence was evaluated using a prospective cohort study with 2114 HBV-infected patients, of whom 612 received antiviral treatments. The oncogenic functions of HBV preS mutations were investigated using cancer cell lines and Sleeping Beauty (SB) mouse models. RNA-sequencing and microarray were applied to identify key molecules involved in the mutant-induced carcinogenesis. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas the preS2 deletion significantly increased HCC risk in patients with antiviral treatment. In SB mice, the preS1/preS2/S mutants induced a higher rate of tumor and higher serum levels of inflammatory cytokines than did wild-type counterpart. The preS1/preS2/S mutants induced altered gene expression profiles in the inflammation- and metabolism-related pathways, activated pathways of endoplasmic reticulum (ER) stress, affected the response to hypoxia, and upregulated the protein level of STAT3. Inhibiting the STAT3 pathway attenuated the effects of the preS1/preS2/S mutants on cell proliferation. G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism alteration, and STAT3 pathways, which might be translated into HCC prophylaxis.
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Affiliation(s)
- Wenbin Liu
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Shiliang Cai
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Rui Pu
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Zixiong Li
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Donghong Liu
- Department of Liver Cancer Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai 200433, China;
| | - Xinyu Zhou
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Xi Chen
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Liping Chen
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Jianfeng Wu
- Department of Pathology, Xijing Hospital, Xi’an 710032, China;
| | - Xiaojie Tan
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Xin Wang
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200433, China;
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
- Correspondence: ; Tel.: +86-21-8187-1060
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22
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Cheng B, Wang Q, Wei Z, He Y, Li R, Liu G, Zeng S, Meng Z. MHBSt 167 induced autophagy promote cell proliferation and EMT by activating the immune response in L02 cells. Virol J 2022; 19:110. [PMID: 35761331 PMCID: PMC9235077 DOI: 10.1186/s12985-022-01840-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 06/03/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Hepatitis B virus can induce hepatocellular carcinoma (HCC) by inducing a host immune response against infected hepatocytes. C-terminally truncated middle surface protein (MHBSt) has been reported to contribute to HCC through transcriptional activation in epidemiology studies, while the underlying mechanism of MHBSt-induced HCC is unknown. METHODS In this study, a premature stop at codon 167 in MHBS (MHBSt167) was investigated into eukaryotic expression plasmid pcDNA3.1(-). MHBSt167 expressed plasmid was transfected into the L02 cell line, cell proliferation was analyzed by CCK-8 and high-content screening assays, the cell cycle was analyzed by flow cytometry, and epithelial-to-mesenchymal transition and autophagy were analyzed by immunoblotting and immunofluorescence. NF-κB activation and the MHBSt167-induced immune response were analyzed by immunoblotting and immunofluorescence. IFN-α, IFN-β and IL-1α expression were analyzed by qPCR. Autophagy inhibitors were used to analyze the relationship between the immune response and autophagy. RESULTS The results showed that MHBSt167 promoted L02 cell proliferation, accelerated cell cycle progression from the S to G2 phase and promoted epithelial-to-mesenchymal transition through ER-stress, leading to autophagy and NF-κB activation and increased immune-related factor expression. The MHBSt167-induced acceleration of cell proliferation and the cell cycle was abolished by autophagy or NF-κB inhibitors. CONCLUSION In summary, MHBSt167 could promote cell proliferation, accelerate cell cycle progression, induce EMT and activate autophagy through ER-stress to induce the host immune response, supporting a potential role of MHBSt167 in contributing to carcinogenesis.
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Affiliation(s)
- Bin Cheng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Qiong Wang
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Zhiqiang Wei
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Yulin He
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Ruiming Li
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Guohua Liu
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China
| | - Shaobo Zeng
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, Hubei, China.
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23
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Association of Pre-S/S and Polymerase Mutations with Acute and Chronic Hepatitis B Virus Infections in Patients from Rio de Janeiro, Brazil. Viruses 2022; 14:v14071375. [PMID: 35891356 PMCID: PMC9315576 DOI: 10.3390/v14071375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 06/10/2022] [Accepted: 06/16/2022] [Indexed: 02/01/2023] Open
Abstract
Several hepatitis B virus (HBV)-related factors, including the viral load, genotype, and genomic mutations, have been linked to the development of liver diseases. Therefore, in this study we aimed to investigate the influence of HBV genetic variability during acute and chronic infection phases. A real-time nested PCR was used to detect HBV DNA in all samples (acute, n = 22; chronic, n = 49). All samples were sequenced for phylogenetic and mutation analyses. Genotype A, sub-genotype A1, was the most common genotype in the study population. A total of 190 mutations were found in the pre-S/S gene area and the acute profile revealed a greater number of nucleotide mutations (p < 0.05). However, both profiles contained nucleotide mutations linked to immune escape and an increased risk of hepatocellular carcinomas (acute, A7T; chronic, A7Q). Furthermore, 17 amino acid substitutions were identified in the viral polymerase region, including the drug resistance mutations lamivudine and entecavir (rtL180M), with statistically significant differences between the mutant and wild type strains. Owing to the natural occurrence of these mutations, it is important to screen for resistance mutations before beginning therapy.
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24
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Molecular characteristics of the full-length genome of occult hepatitis B virus from blood donors in China. Sci Rep 2022; 12:8194. [PMID: 35581341 PMCID: PMC9114411 DOI: 10.1038/s41598-022-12288-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/06/2022] [Indexed: 11/22/2022] Open
Abstract
The characteristics of a large sample size of the full-length genome of occult hepatitis B virus (HBV) infection (OBI) have not been extensively explored in China. Voluntary blood donors who were HBsAg-negative/HBV NAT-positive (HBsAg−/HBV NAT+) were identified by blood screening and recruited. Blood samples were tested for HBV serologic markers, viral loads, and PCR to identify OBI. HBV full-length genomes were obtained by amplifying two fragments using nested PCR. The characterization of OBI strains was based on sequence analyses compared with HBsAg+ strains obtained from the same donor population. Of the 50 full-length genomes of 172 identified OBI strains, 33 were classified as genotype B (OBIB) and 17 strains as genotype C (OBIC). Significantly higher nucleotide variabilities were observed in the Pre-S2/S promoter region (SP2) and core upstream regulatory sequence (CURS) in OBIB than in their HBsAg+ controls (P < 0.05). Both OBIB and OBIC showed higher amino acid (aa) variabilities in Pol and Pre-S/S regions than their controls (P < 0.05). In addition, 19 novel OBI-related mutations were found spanning the four open reading frames (ORFs) of the HBV genome. Four novel deletions and one novel insertion were also found in OBIC strains. Several novel OBI-related mutations spanning the four ORFs of the virus were identified by characterizing a large sample size of the full-length OBI genome, which may affect the production of HBsAg and contribute to the occult infection of HBV.
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25
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Pley C, Lourenço J, McNaughton AL, Matthews PC. Spacer Domain in Hepatitis B Virus Polymerase: Plugging a Hole or Performing a Role? J Virol 2022; 96:e0005122. [PMID: 35412348 PMCID: PMC9093120 DOI: 10.1128/jvi.00051-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatitis B virus (HBV) polymerase is divided into terminal protein, spacer, reverse transcriptase, and RNase domains. Spacer has previously been considered dispensable, merely acting as a tether between other domains or providing plasticity to accommodate deletions and mutations. We explore evidence for the role of spacer sequence, structure, and function in HBV evolution and lineage, consider its associations with escape from drugs, vaccines, and immune responses, and review its potential impacts on disease outcomes.
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Affiliation(s)
- Caitlin Pley
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
| | - José Lourenço
- Department of Zoology, University of Oxford, Oxford, United Kingdom
- Biosystems and Integrative Sciences Institute, University of Lisbon, Lisbon, Portugal
| | - Anna L. McNaughton
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Nuffield Department of Medicine, University of Oxford Medawar Building, Oxford, United Kingdom
| | - Philippa C. Matthews
- Nuffield Department of Medicine, University of Oxford Medawar Building, Oxford, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
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26
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Research Progress on the Mechanism of Persistent Low-Level HBsAg Expression in the Serum of Patients with Chronic HBV Infection. J Immunol Res 2022; 2022:1372705. [PMID: 35465353 PMCID: PMC9020929 DOI: 10.1155/2022/1372705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
Among HBV-infected persons, there is a group of people with hepatitis B surface antigen (HBsAg) showing persistently low levels of expression. The production of low-level HBsAg does not mean a good outcome of chronic HBV infection. Patients still have virus replication and sustained liver damage, and they have the potential to transmit the infection. This risk poses a challenge to clinical diagnosis and blood transfusion safety and is a major concern of experts. However, the mechanism behind persistent low-level HBsAg expression in serum is not completely clear, and complete virus clearance by the host is vital. In this review, we summarize the research progress on the mechanism behind low-level expression of HBsAg in patients with chronic HBV infection in recent years.
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27
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Thi Cam Huong N, Trung NQ, Luong BA, Tram DB, Vu HA, Bui HH, Pham Thi Le H. Mutations in the HBV PreS/S gene related to hepatocellular carcinoma in Vietnamese chronic HBV-infected patients. PLoS One 2022; 17:e0266134. [PMID: 35390033 PMCID: PMC8989215 DOI: 10.1371/journal.pone.0266134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 03/15/2022] [Indexed: 12/23/2022] Open
Abstract
Background Chronic hepatitis B virus (CHB) infection is a major health problem and leading cause of hepatocellular carcinoma (HCC) worldwide. Several point and deletion mutations on the PreS/S gene have been intensively considered associated with HCC. This study aimed to describe the characteristics of HBV PreS/S mutations in Vietnamese CHB-infected patients and their association with HCC. Methods This cross-sectional study was conducted from 02/2020 to 03/2021, recruited Vietnamese CHB-infected patients with HBV-DNA >3 log10-copies/mL and successful PreS/S gene sequencing. Mutations were detected by direct Sanger sequencing. Results 247 CHB-infected patients were recruited, characterized by 68.8% males, 54.7% HBV genotype B, 57.5% HBeAg positive, 23.1% fibrosis score ≥F3 and 19.8% HCC. 61.8% amino acid replacements were detected throughout the PreS1/PreS2/S genes. The most common point-mutations included N/H51Y/T/S/Q/P (30.4%), V68T/S/I (44.9%), T/N87S/T/P (46.2%) on PreS1 gene; T125S/N/P (30.8%), I150T (42.5%) on PreS2 gene; S53L (37.7%), A184V/G (39.3%), S210K/N/R/S (39.3%) on S gene. The rates of case(s) with any point-mutation on the Major Hydrophylic Region (MHR) and the "a" determinant region were 63.6% and 39.7%, respectively. Most of S point-mutations were presented with low rates such as T47A/E/V/K (9.3%), P120S/T (8.5%), G145R (2%). On multivariable analysis, males (OR = 4.51, 95%CI 1.78–11.4, p = 0.001), age≥40 (OR = 5.5, 95%CI 2.06–14.68, p = 0.001), W4P/R/Y on PreS1 (OR = 11.56, 95%CI 1.99–67.05, p = 0.006) and 4 S point-mutations as: T47A/E/V/K (OR = 3.67, 95%CI 1.19–11.29, p = 0.023), P120S/T (OR = 3.38, 95%CI 1.09–10.49, p = 0.035), S174N (OR = 29.73, 95%CI 2.12–417.07, p = 0.012), P203R (OR = 8.45, 95%CI 1.43–50.06, p = 0.019) were associated with HCC. Conclusions We detected 61% amino acid changes on PreS/S regions in Vietnamese CHB patients. One point-mutation at amino acid 4 on PreS1 gene and 4 point-mutations at amino acids 47, 120, 174, and 203 on S gene were associated with HCC. Further investigations are recommended to further clarify the relationship and interaction between mutations in HBV genome and HCC progression.
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Affiliation(s)
- Nguyen Thi Cam Huong
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Department of Gastroenterology, University Medical Center, Ho Chi Minh City, Vietnam
- * E-mail:
| | - Nguyen Quang Trung
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Department of Gastroenterology, University Medical Center, Ho Chi Minh City, Vietnam
| | - Bac An Luong
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Duong Bich Tram
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Hoang Anh Vu
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Hoang Huu Bui
- Department of Gastroenterology, University Medical Center, Ho Chi Minh City, Vietnam
| | - Hoa Pham Thi Le
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Department of Gastroenterology, University Medical Center, Ho Chi Minh City, Vietnam
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Abstract
Hepatitis B was discovered by researchers who were investigating jaundice associated with blood transfusions as well as parenterally administered medications. Through trial and error, the HBV was identified. There are specific tests that detect HBV infection, whether it is a previous exposure or active infection. The various HBV serologies are reviewed in this work as well. Hepatitis B surface antigen has emerged as a tool in defining treatment endpoint and its significance is reviewed. HBV genotypes are distributed uniquely throughout the world, in particular, genotype C is associated with higher rates of hepatocellular carcinoma. Various HBV genotypes and their impact on the clinical course are discussed. The relationship of HBV serologies and HBV DNA to disease progression is outlined. There are specific recommendations on monitoring those infected with HBV and this is reviewed here. HBV mutations have an impact on the disease course and those of significance are also discussed.
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Pisano MB, Giadans CG, Flichman DM, Ré VE, Preciado MV, Valva P. Viral hepatitis update: Progress and perspectives. World J Gastroenterol 2021; 27:4018-4044. [PMID: 34326611 PMCID: PMC8311538 DOI: 10.3748/wjg.v27.i26.4018] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis, secondary to infection with hepatitis A, B, C, D, and E viruses, are a major public health problem and an important cause of morbidity and mortality. Despite the huge medical advances achieved in recent years, there are still points of conflict concerning the pathogenesis, immune response, development of new and more effective vaccines, therapies, and treatment. This review focuses on the most important research topics that deal with issues that are currently being solved, those that remain to be solved, and future research directions. For hepatitis A virus we will address epidemiology, molecular surveillance, new susceptible populations as well as environmental and food detections. In the case of hepatitis B virus, we will discuss host factors related to disease, diagnosis, therapy, and vaccine improvement. On hepatitis C virus, we will focus on pathogenesis, immune response, direct action antivirals treatment in the context of solid organ transplantation, issues related to hepatocellular carcinoma development, direct action antivirals resistance due to selection of resistance-associated variants, and vaccination. Regarding hepatitis D virus, we describe diagnostic methodology, pathogenesis, and therapy. Finally, for hepatitis E virus, we will address epidemiology (including new emerging species), diagnosis, clinical aspects, treatment, the development of a vaccine, and environmental surveillance.
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Affiliation(s)
- María B Pisano
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - Cecilia G Giadans
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Diego M Flichman
- Institute of Biomedical Investigations in Retrovirus and AIDS (INBIRS), School of Medicine, University of Buenos Aires, CONICET, CABA C1121ABG, Buenos Aires, Argentina
| | - Viviana E Ré
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - María V Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
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30
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Phan NMH, Faddy HM, Flower RL, Dimech WJ, Spann KM, Roulis EV. Low Genetic Diversity of Hepatitis B Virus Surface Gene amongst Australian Blood Donors. Viruses 2021; 13:1275. [PMID: 34208852 PMCID: PMC8310342 DOI: 10.3390/v13071275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/11/2021] [Accepted: 06/25/2021] [Indexed: 12/13/2022] Open
Abstract
Variants in the small surface gene of hepatitis B virus (HBV), which codes for viral surface antigen (HBsAg), can affect the efficacy of HBsAg screening assays and can be associated with occult HBV infection (OBI). This study aimed to characterise the molecular diversity of the HBV small surface gene from HBV-reactive Australian blood donors. HBV isolates from 16 HBsAg-positive Australian blood donors' plasma were sequenced and genotyped by phylogenies of viral coding genes and/or whole genomes. An analysis of the genetic diversity of eight HBV small surface genes from our 16 samples was conducted and compared with HBV sequences from NCBI of 164 international (non-Australian) blood donors. Genotypes A-D were identified in our samples. The region of HBV small surface gene that contained the sequence encoding the 'a' determinant had a greater genetic diversity than the remaining part of the gene. No escape mutants or OBI-related variants were observed in our samples. Variant call analysis revealed two samples with a nucleotide deletion leading to truncation of polymerase and/or large/middle surface amino acid sequences. Overall, we found that HBV small surface gene sequences from Australian donors demonstrated a lower level of genetic diversity than those from non-Australian donor population included in the study.
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Affiliation(s)
- Ngoc Minh Hien Phan
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
| | - Helen M. Faddy
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
- School of Health and Behavioural Sciences, University of Sunshine Coast, Petrie, Queensland 4502, Australia
| | - Robert L. Flower
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
| | - Wayne J. Dimech
- Scientific & Business Relations, National Serology Reference Laboratory, Fitzroy, Victoria 3065, Australia;
| | - Kirsten M. Spann
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
| | - Eileen V. Roulis
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
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31
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Song A, Lin X, Chen X. Functional cure for chronic hepatitis B: accessibility, durability, and prognosis. Virol J 2021; 18:114. [PMID: 34082765 PMCID: PMC8176700 DOI: 10.1186/s12985-021-01589-x] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/28/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) clearance is regarded as the ideal endpoint for antiviral treatment in terms of drug withdrawal safety and improvements in prognosis. However, the overall rate of HBsAg clearance is low and differs based on treatment method and course. The recent application of combined and extended treatment strategies have improved the HBsAg clearance rate, and several patients achieved HBsAg clearance in clinical treatment. In addition, the durability of and clinical outcomes after HBsAg clearance have become the focus of both researchers and clinicians. This article reviews HBsAg clearance in terms of accessibility, durability, improvements in prognosis and relevant advances.
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Affiliation(s)
- Aixin Song
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiao Lin
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China.
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Li L, Ye Y, Ran Y, Liu S, Tang Q, Liu Y, Liao X, Zhang J, Xiao G, Lu J, Zhang G, He Q, Hu S. A non-invasive model for predicting liver fibrosis in HBeAg-positive patients with normal or slightly elevated alanine aminotransferase. Medicine (Baltimore) 2021; 100:e25581. [PMID: 33907107 PMCID: PMC8084058 DOI: 10.1097/md.0000000000025581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/24/2021] [Accepted: 03/30/2021] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Early and accurate diagnosis of liver fibrosis is necessary for HBeAg-positive chronic hepatitis B (CHB) patients with normal or slightly increased alanine aminotransferase (ALT), Liver biopsy and many non-invasive predicting markers have several application restrictions in grass-roots hospitals. We aimed to construct a non-invasive model based on routinely serum markers to predict liver fibrosis for this population.A total of 363 CHB patients with HBeAg-positive, ALT ≤2-fold the upper limit of normal and liver biopsy data were randomly divided into training (n = 266) and validation groups (n = 97). Two non-invasive models were established based on multivariable logistic regression analysis in the training group. Model 2 with a lower Akaike information criterion (AIC) was selected as a better predictive model. Receiver operating characteristic (ROC) was used to evaluate the model and was then independently validated in the validation group.The formula of Model 2 was logit (Model value) = 5.67+0.08 × Age -2.44 × log10 [the quantification of serum HBsAg (qHBsAg)] -0.60 × log10 [the quantification of serum HBeAg (qHBeAg)]+0.02 × ALT+0.03 × aspartate aminotransferase (AST). The area under the ROC curve (AUC) was 0.89 for the training group and 0.86 for the validation group. Using 2 cut-off points of -2.61 and 0.25, 59% of patients could be identified with liver fibrosis and antiviral treatment decisions were made without liver biopsies, and 149 patients were recommended to undergo liver biopsy for accurate diagnosis.In this study, the non-invasive model could predict liver fibrosis and may reduce the need for liver biopsy in HBeAg-positive CHB patients with normal or slightly increased ALT.
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Affiliation(s)
- Ling Li
- Department of Gastroenterology and Hepatology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing
- Department of Hepatology, Beijing University of Chinese Medicine Affiliated Shenzhen Hospital
| | - Yongan Ye
- Department of Gastroenterology and Hepatology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing
| | - Yun Ran
- Department of Hepatology, Beijing University of Chinese Medicine Affiliated Shenzhen Hospital
| | - Shuyan Liu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Qiyuan Tang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Yaya Liu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Xuejiao Liao
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Juanjuan Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Guohui Xiao
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Guoliang Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Qing He
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology
| | - Shiping Hu
- Department of Hepatology, Beijing University of Chinese Medicine Affiliated Shenzhen Hospital
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Wu Y, Zhu Z, Wu J, Bi W, Xu W, Xia X, Han D. Evolutionary Analysis of Pre-S/S Mutations in HBeAg-Negative Chronic Hepatitis B With HBsAg < 100 IU/ml. Front Public Health 2021; 9:633792. [PMID: 33981663 PMCID: PMC8107265 DOI: 10.3389/fpubh.2021.633792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/29/2021] [Indexed: 01/12/2023] Open
Abstract
Background: Hepatitis B surface antigen (HBsAg) and viral load are important clinical indicators for antiviral therapy. Few studies have evaluated viral sequence biomarkers predicting the risk of hepatocellular carcinoma (HCC) in the stage, which show a low serological response (HBsAg < 100 IU/ml) and high viral levels (HBV DNA > 2,000 IU/ml). This study aims to determine the trend of the biological prevalence within the pre-S/S regions of special model of inactive CHB infection. Methods: We used Sanger sequencing, quantitative HBV serology (HBeAg and HBsAg), and liver function index to identify whether HBV genome sequences are associated with long-term risk of further HCC progression in special inactive CHB infection. Results: HBV sequencing analysis of 28 CHB patients with special infectious pattern showed higher genetic diversity among four opening reading frames (ORFs) (p < 0.001). However, dN/dS ratios of HBsAg and pre-C/C regions in the experimental group showed no significantly different from those in the HCC group (p = 0.06), while significantly lower in polymerase and HBxAg regions of the experimental group (p < 0.001). In addition, seven positively selected sites were identified in pre-S1, five in pre-S2, and four in S, in which five sites (128H/135Q/135R/139L/141P) were among "α" determinant. Conclusions: These mutations in the pre-S/S region might be associated with the HCC phenotype of low HBsAg expression, with the P region possibly impacting high viral loads. Increased viral diversity across the HBV genome is also associated with low levels of HBsAg. The cumulative evolutionary changes in the HBV pre-S/S regions shows that facilitate immune evasion should be monitored individually. Due to the similarity of evolutionary characteristics in HCC, low serological responses and high viremia may be associated with the risk of further disease progression.
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Affiliation(s)
- Yingping Wu
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Zhiqiang Zhu
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jianyong Wu
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Wenzi Bi
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Wei Xu
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Xiaoping Xia
- Department of Clinical Laboratory, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Dongsheng Han
- Clinical Medical Examination Center, Northern Jiangsu People's Hospital, Yangzhou, China
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Song A, Wang X, Lu J, Jin Y, Ma L, Hu Z, Zheng Y, Shen C, Chen X. Durability of hepatitis B surface antigen seroclearance and subsequent risk for hepatocellular carcinoma: A meta-analysis. J Viral Hepat 2021; 28:601-612. [PMID: 33455067 PMCID: PMC7986681 DOI: 10.1111/jvh.13471] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
Hepatitis B surface antigen (HBsAg) seroclearance is regarded as the ideal endpoint for antiviral treatment. However, reports on the durability of and outcomes after HBsAg seroclearance are few, which has become a focus in clinical practice. This meta-analysis was performed to evaluate the durability and hepatocellular carcinoma (HCC) incidence after HBsAg seroclearance after treatment cessation. We searched PubMed, Embase, Medline and Web of Science for studies that reported the durability and HCC incidence after HBsAg seroclearance published between 1 January 2000 and 31 January 2020. Data were analysed by a random-effects model. Thirty-eight studies and 43,924 patients were finally included. The results showed that HBsAg seroclearance was durable, with a pooled recurrence rate of 6.19% (95% CI: 4.10%-8.68%). There was no significant difference in recurrence rates after different seroclearance methods or among recurrence types and different regions. Anti-HBs seroconversion resulted in a significantly reduced recurrence rate (RR = 0.25, p < .001). Patients who experienced HBsAg seroclearance had significantly lower HCC incidence than HBsAg-positive (RR = 0.41, p < .001). The pooled HCC incidence after HBsAg seroclearance was 1.88%; this rate was reduced to 0.76% among patients without baseline cirrhosis. In conclusion, the analysis during an average follow-up of 4.74 years suggested that in patients who experienced sustained HBsAg seroclearance and anti-HBs seroconversion, this was associated with low HCC incidence. Patients without baseline cirrhosis benefited even more. We emphasize the importance of gaining HBsAg seroclearance while highlighting the benefits of achieving this as early as possible.
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Affiliation(s)
- Aixin Song
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Xiaoxiao Wang
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Junfeng Lu
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Yi Jin
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Lina Ma
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Zhongjie Hu
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Yanhong Zheng
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Chengli Shen
- Division of Surgical OncologyJames Cancer HospitalThe Ohio State University Wexner Medical CenterColumbusOHUSA
| | - Xinyue Chen
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
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35
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HBV-Integration Studies in the Clinic: Role in the Natural History of Infection. Viruses 2021; 13:v13030368. [PMID: 33652619 PMCID: PMC7996909 DOI: 10.3390/v13030368] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.
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Matsuda S, Maekawa S, Komiyama Y, Nakakuki N, Muraoka M, Suzuki Y, Sato M, Tatsumi A, Miura M, Amemiya F, Shindo H, Takano S, Fukasawa M, Yamaguchi T, Nakayama Y, Inoue T, Sato T, Yamashita A, Moriishi K, Enomoto N. Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy. Hepatol Res 2021; 51:39-50. [PMID: 32961003 DOI: 10.1111/hepr.13574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/29/2022]
Abstract
AIM Recently, serum hepatitis B virus (HBV)-RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV-RNA sequence compared with those of HBV-DNA during the emergence of antiviral resistance are yet to be elucidated. METHODS First, we quantified serum HBV-RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV-RNA/HBV-DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. RESULTS Serum HBV-RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen-positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core-related antigen was significantly correlated with serum HBV-RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV-RNA immediately before the breakthrough. However, NA-resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA-resistant HBV-RNA sequence rate was correlated with the peak HBV-DNA titer multiplied by the HBV-DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV-DNA following the addition of new NA. CONCLUSION Serum HBV-RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core-related antigen. The dynamics of HBV-RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver.
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Affiliation(s)
- Shuya Matsuda
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuyuki Komiyama
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Natsuko Nakakuki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuichiro Suzuki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mitsuaki Sato
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Akihisa Tatsumi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mika Miura
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Fumitake Amemiya
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hiroko Shindo
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mitsuharu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Tadashi Sato
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Atsuya Yamashita
- Department of Microbiology, University of Yamanashi, Yamanashi, Japan
| | - Kohji Moriishi
- Department of Microbiology, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Sun H, Chang L, Yan Y, Wang L. Hepatitis B virus pre-S region: Clinical implications and applications. Rev Med Virol 2020; 31. [PMID: 33314434 DOI: 10.1002/rmv.2201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/22/2020] [Accepted: 11/29/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) infection is a major threat to global public health, which can result in many acute and chronic liver diseases. HBV, a member of the family Hepadnaviridae, is a small enveloped DNA virus containing a circular genome of 3.2 kb. Located upstream of the S-open-reading frame of the HBV genome is the pre-S region, which is vital to the viral life cycle. The pre-S region has high variability and many mutations in the pre-S region are associated with several liver diseases, such as fulminant hepatitis (FH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). In addition, the pre-S region has been applied in the development of several pre-S-based materials and systems to prevent or treat HBV infection. In conclusion, the pre-S region plays an essential role in the occurrence, diagnosis, and treatment of HBV-related liver diseases, which may provide a novel perspective for the study of HBV infection and relevant diseases.
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Affiliation(s)
- Huizhen Sun
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, PR China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
| | - Le Chang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, PR China
| | - Ying Yan
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, PR China
| | - Lunan Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, PR China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
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38
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Yuen L, Revill PA, Rosenberg G, Wagner J, Littlejohn M, Bayliss J, Jackson K, Tan SK, Gaggar A, Kitrinos K, Subramanian M, Gane E, Chan HLY, Li X, Bowden S, Locarnini S, Thompson A. HBV variants are common in the 'immune-tolerant' phase of chronic hepatitis B. J Viral Hepat 2020; 27:1061-1070. [PMID: 32384174 DOI: 10.1111/jvh.13318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/09/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogues (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk of hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC; however, the frequency of these variants during the seemingly benign immunotolerant (IT) phase is unknown. Next-generation sequencing and detailed virological characterization on a cohort of treatment-naïve IT subjects were performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV-DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10 IU/mL, median HBeAg 3.6 log10 PEIU/mL) were analysed. Despite subjects being in the IT phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X (HBx) gene), precore and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV-DNA titres. Precore variants were independently associated with higher baseline ALT. Increased viral diversity was associated with increased age and lower HBV-DNA, HBsAg and HBeAg levels. Low-level (<5%) drug resistance-associated amino acid substitutions in the HBV reverse transcriptase were detected in 9 (9%) subjects at pre-treatment but were not associated with reduced antiviral activity. Future studies should evaluate whether the detection of HBV variant during IT CHB is predictive of progression to immune clearance and poor prognosis, and whether early initiation of antiviral therapy during IT CHB to prevent the selection of HBV variants is clinically beneficial.
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Affiliation(s)
- Lilly Yuen
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.,Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
| | | | - Josef Wagner
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Julianne Bayliss
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | | | | | | | - Ed Gane
- New Zealand Transplant Unit, Auckland, New Zealand
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Xin Li
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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39
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Lin Y, Zhao Z, Huang A, Lu M. Interplay between Cellular Autophagy and Hepatitis B Virus Replication: A Systematic Review. Cells 2020; 9:2101. [PMID: 32942717 PMCID: PMC7563265 DOI: 10.3390/cells9092101] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
Autophagy, a conserved process in which cells break down and destroy old, damaged, or abnormal proteins and other substances in the cytoplasm through lysosomal degradation, occurs via autophagosome formation and aids in the maintenance of intracellular homeostasis. Autophagy is closely associated with hepatitis B virus (HBV) replication and assembly. Currently, HBV infection is still one of the most serious public health issues worldwide. The unavailability of satisfactory therapeutic strategies for chronic HBV infection indicates an urgent need to elucidate the mechanisms underlying the pathogenesis of HBV infection. Increasing evidence has shown that HBV not only possesses the ability to induce incomplete autophagy but also evades autophagic degradation, indicating that HBV utilizes or hijacks the autophagy machinery for its own replication. Therefore, autophagy might be a crucial target pathway for controlling HBV infection. The definite molecular mechanisms underlying the association between cellular autophagy and HBV replication require further clarification. In this review, we have summarized and discussed the latest findings on the interplay between autophagy and HBV replication.
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Affiliation(s)
- Yong Lin
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Zhenyu Zhao
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Ailong Huang
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
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40
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A Highly Prevalent Polymorphism in the Core Region Impairs Quantification of Hepatitis B Virus (HBV) by the cobas TaqMan HBV Assay. J Clin Microbiol 2020; 58:JCM.00647-20. [PMID: 32669381 DOI: 10.1128/jcm.00647-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/15/2020] [Indexed: 12/22/2022] Open
Abstract
The high genetic variability of hepatitis B virus (HBV) can impair DNA quantification. Here, we investigate a major underquantification of HBV by the cobas TaqMan HBV assay (CTM; Roche). In France, between 2005 and 2017, HBV DNA was detected in 3,102 blood donations by use of the CTM (95% limit of detection [LOD95], 4.8 IU/ml). HBV strains were sequenced in the S region (LOD95, ∼30 IU/ml). Concordant (n = 120) and discordant (n = 45) samples were identified according to the agreement between the plasma viral load (pVL) determined by the CTM and sequencing; all samples were also quantified using the RealTime HBV assay (RTH; Abbott). The viral signature, cloning, and mutagenesis were used to characterize the polymorphism responsible for CTM misquantification. A CTM-RTH discordance (>1 log IU/ml) was found in 14/45 samples that had low pVLs and were successfully genotyped (pVLlow genoS+). PreC/C clones of concordant (C1, C2) and discordant (D1, D2) strains were used to challenge the CTM. Strains D1 and D2 were highly underquantified (42- and 368-fold). In clones, mutating the region corresponding to the CTM reverse primer from a discordant sequence to a concordant sequence restored the levels of quantification to 24% (D1→C1) and 59% (D2→C1) of theoretical levels, while mutating the sequence of a concordant strain to that of a discordant strain led to 78-fold (C1→D1) and 146-fold (C1→D2) decreases in quantification. Moreover, mutating positions 1961 and 1962 was enough to induce a 5-fold underquantification. We conclude that the CTM underestimates pVLs for HBV strains with mutations in the reverse primer target. Specifically, the polymorphism at nucleotides 1961 and 1962 is naturally present in 4.79 and 4.22% of genotype A and D strains, which are highly frequent in Europe, leading to a 5-fold decrease in quantification. Quantification using the new-generation Roche C4800 assay is not affected by this polymorphism.
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41
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Cornberg M, Glebe D. Editorial: which factors influence HBsAg levels in HBV-infected patients? Aliment Pharmacol Ther 2020; 52:547-548. [PMID: 32656837 DOI: 10.1111/apt.15864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Centre for Individualized Infection Medicine (CIIM), Hannover, Germany.,German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Dieter Glebe
- Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Giessen, Germany.,German Center for Infection Research (DZIF), Giessen-Marburg-Langen, Germany
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42
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Brunetto MR, Cavallone D. Editorial: which factors influence HBsAg levels in HBV-infected patients? Authors' reply. Aliment Pharmacol Ther 2020; 52:549-550. [PMID: 32656824 DOI: 10.1111/apt.15910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy.,Biostructure and Bio-imaging Institute of National Research Council of Italy, Naples, Italy
| | - Daniela Cavallone
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
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43
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Taniguchi H, Iwasaki Y, Aimi M, Shimazaki G, Moriya A. Clinical features of chronic hepatitis B patients with low hepatitis B surface antigen levels and determinants of hepatitis B surface antigen seroclearance. JGH Open 2020; 4:698-706. [PMID: 32782959 PMCID: PMC7411555 DOI: 10.1002/jgh3.12321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM A low hepatitis B surface antigen (HBsAg) level is reported to be predictive of future HBsAg seroclearance. A hospital-based cohort study was conducted to clarify the clinical features of patients with low HBsAg levels and to demonstrate the usefulness of low HBsAg levels for predicting HBsAg seroclearance. METHODS A total of 1459 patients with chronic hepatitis B were included in the study. Of these, 587 had repeated measurements for HBsAg levels and two or more records of HBsAg-positive results. HBsAg levels were measured with a commercially available HBsAg assay. Based on a cut-off index (COI) of 2000, a high HBsAg level was defined as HBsAg ≥2000 COI, and a low HBsAg level was defined as HBsAg <2000 COI. RESULTS The proportion of patients with low HBsAg levels at baseline tended to increase with age. Patients with low HBsAg levels at baseline had significantly older age, lower transaminase levels, and lower hepatitis B virus (HBV) DNA levels than those with high HBsAg levels. The annual HBsAg seroclearance rate was 1.30%/year. The cumulative incidences of HBsAg seroclearance differed significantly by HBsAg level at baseline (<2000 vs ≥2000 COI), age (≥50 vs <50 years), and HBV DNA level (<4.0 vs ≥4.0 log copies/mL). Cox proportional hazards regression analyses showed that low HBsAg level (<2000 COI) and low HBV DNA level (<4.0 log copies/mL) were significantly associated with HBsAg seroclearance. CONCLUSION Aging was one of the factors affecting HBsAg level. HBsAg seroclearance was significantly associated with low HBsAg level and low HBV DNA level at baseline.
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Affiliation(s)
| | | | - Masahito Aimi
- Internal MedicineTottori Municipal HospitalTottoriJapan
| | | | - Akio Moriya
- GastroenterologyMitoyo General HospitalJapan
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44
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Biological features of hepatitis B virus strains associated with fulminant hepatitis. Future Virol 2020. [DOI: 10.2217/fvl-2020-0011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Accumulating evidence suggests that hepatitis B virus (HBV) biological features may influence the course and clinical manifestations of infection and possibly the development of fulminant hepatitis (FH). Since HBV is not a cytocidal virus, virus-induced liver damage results from an interplay between the virus replication and the host's defense. Therefore, viral factors contributing to enhanced replication, induction of a stronger immune attack or apoptosis of hepatocytes could be crucial in development of FH. Numerous mutations in basal core promoter, pre-C, C and S regions of the HBV genome contribute to development of FH by different mechanisms, including enhanced viral replication, the loss of a decoy for immune response, unbalanced expression of viral proteins and retention of unprocessed cytotoxic proteins in hepatocytes.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology & Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Ana Banko
- Institute of Microbiology & Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Danijela Miljanovic
- Institute of Microbiology & Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Maja Cupic
- Institute of Microbiology & Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
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45
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Cavallone D, Ricco G, Oliveri F, Colombatto P, Moriconi F, Coco B, Romagnoli V, Salvati A, Surace L, Bonino F, Brunetto MR. Do the circulating Pre-S/S quasispecies influence hepatitis B virus surface antigen levels in the HBeAg negative phase of HBV infection? Aliment Pharmacol Ther 2020; 51:1406-1416. [PMID: 32390175 DOI: 10.1111/apt.15753] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/19/2019] [Accepted: 04/06/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Virus, host factors and their interplay influence Hepatitis B surface Antigen serum levels during Hepatitis B Virus (HBV) infection course and treatment. AIM To study the Pre-S/S circulating quasispecies in a cohort of untreated, HBeAg negative, genotype-D, HBsAg carriers. METHODS We studied 260 carriers: 71 with HBeAg negative infection (ENI; HBV-DNA ≤2000 IU/mL); 42 Grey Zone (GZ; HBV-DNA ≤20 000 IU/mL); 82 chronic hepatitis (CH) and 65 cirrhosis (CI) (HBV-DNA > 20 000 IU/mL). Population sequencing was applied to identify Pre-S/S gene mutations responsible for any amino acid substitution or potential biological/antigenic implications (M-muts) on HBsAg. RESULTS HBsAg serum levels were lower in ENI + GZ than in CH + CI (2.61 [-1.10/4.06] vs 3.62 [2.41/4.92] log10 IU/mL, P < 0.001) and in CI than CH (3.48 [2.41/4.38] vs 3.66 [2.57/4.92] log10 IU/mL, P < 0.001). M-muts were found in 73 (28.1%) cases: 5 (7.0%) ENI, 3 (7.1%) GZ, 26 (31.7%) CH, 39 (60.0%) CI (P < 0.001) and mostly in Pre-S2 (17.6%) than Pre-S1 (5.8%) and Small-S (10.8%; P < 0.001). Overall HBsAg serum levels were higher in carriers with M-muts (3.56 [0.95/4.38] vs 3.17 [-1.10/4.92] log10 IU/mL, P < 0.001), but comparable in carriers with or without M-mut when considering separately ENI + GZ (2.84 [0.95/3.89] vs 2.61 [-1.10/4.06] log10 IU/mL, P = 0.330] and CH + CI (3.57 [2.67/4.38] vs 3.63 [2.41/4.92] log10 IU/mL, P = 0.37). Infection phase (β: 0.422, P < 0.001), age (β: -0.260, P < 0.001), ALT (β: -0.103, P = 0.045), liver stiffness (β: -0.118, P = 0.039) and HBV-DNA (β: 0.384, P < 0.001), but not M-mut were independently associated with HBsAg serum levels. CONCLUSIONS In HBeAg negative, genotype-D, carriers Pre-S/S heterogeneity increases with severity of liver disease, but does not influence HBsAg serum levels, that in low viraemic carriers are associated with an effective control of HBV.
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Affiliation(s)
- Daniela Cavallone
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Gabriele Ricco
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Francesco Moriconi
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Veronica Romagnoli
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Antonio Salvati
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Lidia Surace
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Ferruccio Bonino
- Biostructure and Bio-imaging Institute of National Research Council of Italy, Naples, Italy
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
- Biostructure and Bio-imaging Institute of National Research Council of Italy, Naples, Italy
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46
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Ye X, Li T, Zhang R, Liu H, Zeng J, Hong W, Lu L, Zhu W, Li S, Xu M, Wu S, Chen L. Comprehensive analysis of hepatitis B virus infections in blood donors in southern China that are surface antigen positive but nucleic acid testing negative. Transfusion 2020; 60:1476-1482. [PMID: 32358842 DOI: 10.1111/trf.15824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is one of the major concerns for the safety of blood transfusion in high-prevalent countries such as in China. Prior studies outside of China have shown hepatitis B surface antigen (HBsAg) false-reactive rate of 0.02% to 0.04%. Similarly, false-negative HBsAg and HBV DNA results may occur in infected donors. Our study analyzed HBsAg enzyme-linked immunosorbent assay (ELISA)-reactive but NAT-negative donations in Shenzhen Blood Center, China. STUDY DESIGN AND METHODS HBsAg ELISA-positive/NAT-negative plasma samples identified from screening 101,025 donations during 2017-2018 were analyzed by molecular and serologic tests including neutralization, chemiluminescence immunoassays, and various HBV DNA amplification assays. Molecular characterizations of HBsAg-positive/NAT-negative samples were determined by quantitative polymerase chain reaction (qPCR) and nested PCR amplification of the basic core and precore promotor regions (295 base pairs) and HBsAg (S) region (496 base pairs). RESULTS Screening of 101,025 eligible blood donations identified 157 (0.16%, 95% confidence interval, 0.13%-0.18%) HBsAg ELISA-positive/NAT-negative plasma samples; of those, 71 (45.2%) were HBsAg confirmed positive by further HBsAg testing and DNA positive by molecular tests with increased sensitivity. Of the 71, all but one was antibody to hepatitis B core antigen reactive without antibody to hepatitis B surface antigen, yielding one recent (window-period) HBV infection. Of the remaining donations, 80 (51%) were not considered as HBV-infected donors, and 6 (3.8%) were interpreted as indeterminate since HBsAg results were discordant with unconfirmed HBV DNA results. In the 71 confirmed positives, HBsAg levels ranged from 0.05 to 400 IU/mL and HBV DNA from 6 to 2654 IU/mL; however, the correlation between the two was weak (R2 = 0.24). CONCLUSION Fewer than half of HBsAg ELISA-positive/NAT-negative samples were confirmed as HBsAg positive. Our study demonstrates that in highly HBV-endemic countries, assays with high sensitivity and specificity may be required.
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Affiliation(s)
- Xianlin Ye
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Tong Li
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Ruohao Zhang
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Heng Liu
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Jinfeng Zeng
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Wenxu Hong
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Liang Lu
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Weigang Zhu
- Shenzhen Blood Center, Shenzhen, Guangdong, China
| | - Shilin Li
- Provincial Key Laboratory for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Chengdu, Sichuan, China
| | - Min Xu
- Provincial Key Laboratory for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Chengdu, Sichuan, China
| | - Shaobo Wu
- Provincial Key Laboratory for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Chengdu, Sichuan, China
| | - Limin Chen
- Provincial Key Laboratory for Transfusion-transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Chengdu, Sichuan, China.,Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
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47
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Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Semin Immunopathol 2020; 42:173-185. [PMID: 32185454 PMCID: PMC7174266 DOI: 10.1007/s00281-020-00780-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
The human hepatitis B virus (HBV) is a small-enveloped DNA virus causing acute and chronic hepatitis. Despite the existence of an effective prophylactic vaccine and the strong capacity of approved antiviral drugs to suppress viral replication, chronic HBV infection (CHB) continues to be a major health burden worldwide. Both the inability of the immune system to resolve CHB and the unique replication strategy employed by HBV, which forms a stable viral covalently closed circular DNA (cccDNA) minichromosome in the hepatocyte nucleus, enable infection persistence. Knowledge of the complex network of interactions that HBV engages with its host is still limited but accumulating evidence indicates that epigenetic modifications occurring both on the cccDNA and on the host genome in the course of infection are essential to modulate viral activity and likely contribute to pathogenesis and cancer development. Thus, a deeper understanding of epigenetic regulatory processes may open new venues to control and eventually cure CHB. This review summarizes major findings in HBV epigenetic research, focusing on the epigenetic mechanisms regulating cccDNA activity and the modifications determined in infected host cells and tumor liver tissues.
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Affiliation(s)
- Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Hamburg, Germany.
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48
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Ou Q, Guo J, Zeng Y, Chen H. Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection. J Viral Hepat 2020; 27:224-232. [PMID: 31954089 DOI: 10.1111/jvh.13260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 10/19/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA), which is stably present in the nucleus of hepatocytes, is an important indicator for evaluating antiviral efficacy. Since cccDNA quantification requires an invasive procedure, serum biological markers that can effectively reflect the transcriptional activity of intrahepatic virus and the efficacy of treatment are required. Here, from the aspects of virus and host, we outline the focus of clinical research of HBV in recent years, including HBV RNA, empty virus, hepatitis B core-related antigen and changes in the immune response. We briefly discuss their significance in predicting disease activity and monitoring treatment response in chronic hepatitis B. On this basis, some issues worthy of attention in laboratory diagnosis are proposed.
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Affiliation(s)
- Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Jianhui Guo
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Huijuan Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
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49
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Brouwer WP, Zhao Q, Hansen BE, Lau D, Khalili M, Terrault NA, Di Bisceglie AM, Perrillo RP, Fried MW, Wong D, Feld JJ, Belle SH, Janssen HLA. HBV Genotype-Specific Levels of Hepatitis B Surface Antigen Improve HBV Phenotype Definition. Clin Gastroenterol Hepatol 2020; 18:259-261. [PMID: 30630104 PMCID: PMC6612468 DOI: 10.1016/j.cgh.2018.12.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/27/2018] [Accepted: 12/27/2018] [Indexed: 02/07/2023]
Abstract
Controversies exist regarding the classification of the different clinical phases of chronic hepatitis B (CHB) because hepatitis B virus (HBV) DNA and alanine aminotransferase levels fluctuate over time.1,2 To improve the distinction of clinical phases and the associated spectrum of clinical outcome,3,4 hepatitis B surface antigen (HBsAg) levels may be of help.5-7 We hypothesize that HBV genotype specific HBsAg levels are needed for the identification of different clinical HBV disease phases.7.
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Affiliation(s)
- Willem P Brouwer
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada; Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Qian Zhao
- Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Daryl Lau
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Mandana Khalili
- Department of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, California
| | - Norah A Terrault
- Department of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, California
| | | | - Robert P Perrillo
- Hepatology Division, Baylor University Medical Center, Dallas, Texas
| | - Michael W Fried
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - David Wong
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada
| | - Steven H Belle
- Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada; Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands.
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50
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Gill US, Battisti A, Kennedy PTF. Emerging tools in the changing landscape of chronic hepatitis B management. Expert Rev Anti Infect Ther 2019; 17:943-955. [PMID: 31738607 DOI: 10.1080/14787210.2019.1694906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: The availability of a preventative vaccine, interferon, and nucleos(t)ide analogs have provided progress in the control of chronic hepatitis B (CHB). Despite this, it remains a major contributor to global morbidity and mortality. Developments in our understanding of the pathogenesis of CHB and the emergence of new therapies are paving the way, as we move toward HBV cure.Areas covered: We performed bibliographical searches of online databases to review the literature regarding conventional disease phases of CHB. We provide the latest evidence challenging the perception of the natural history of CHB, noting that previously considered quiescent disease phases may not represent benign disease states devoid of progression. We explore the use of potential novel immunological and viral tools which should enhance disease stratification and management decisions in the coming years. Finally, we discuss the timing of treatment and how this could be initiated earlier to improve treatment outcomes, preventing sequelae of chronic infection.Expert opinion: The treatment paradigm in CHB is set to change with multiple novel agents in early phase clinical trials with the aim of a functional cure. An improved understanding of disease pathogenesis and the timing of treatment will be critical to the success of new therapies.
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Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Arianna Battisti
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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