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Tu T, McQuaid TJ, Jacobson IM. HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment. Liver Int 2025; 45:e16202. [PMID: 39720865 DOI: 10.1111/liv.16202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection. AIMS To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development. MATERIALS AND METHODS We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy. RESULTS We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention. CONCLUSION Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.
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Affiliation(s)
- Thomas Tu
- Storr Liver Centre, Westmead Clinical School, Centre for Infectious Diseases and Microbiology and Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
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2
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Xie C, Lu D. Evolution and diversity of the hepatitis B virus genome: Clinical implications. Virology 2024; 598:110197. [PMID: 39098184 DOI: 10.1016/j.virol.2024.110197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.
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Affiliation(s)
- Chengzuo Xie
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Daiqiang Lu
- Institute of Molecular and Medical Virology, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, Guangdong Province, 510632, China.
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Hepatitis B virus (HBV) is a hepatotropic virus and an important human pathogen. There are an estimated 296 million people in the world that are chronically infected by this virus, and many of them will develop severe liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). HBV is a small DNA virus that replicates via the reverse transcription pathway. In this review, we summarize the molecular pathways that govern the replication of HBV and its interactions with host cells. We also discuss viral and non-viral factors that are associated with HBV-induced carcinogenesis and pathogenesis, as well as the role of host immune responses in HBV persistence and liver pathogenesis.
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Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
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Lin J, Li J, Xie P, Han Y, Yu D, Chen J, Zhang X. Hepatitis B virus middle surface antigen loss promotes clinical variant persistence in mouse models. Virulence 2021; 12:2868-2882. [PMID: 34738866 PMCID: PMC8632123 DOI: 10.1080/21505594.2021.1999130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.
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Affiliation(s)
- Junyu Lin
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Li
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peilin Xie
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Han
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Demin Yu
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Chen
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lost Small Envelope Protein Expression from Naturally Occurring PreS1 Deletion Mutants of Hepatitis B Virus Is Often Accompanied by Increased HBx and Core Protein Expression as Well as Genome Replication. J Virol 2021; 95:e0066021. [PMID: 33910956 PMCID: PMC8223946 DOI: 10.1128/jvi.00660-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) transcribes coterminal mRNAs of 0.7 to 3.5 kb from the 3.2-kb covalently closed circular DNA, with the 2.1-kb RNA being most abundant. The 0.7-kb RNA produces HBx protein, a transcriptional transactivator, while the 3.5-kb pregenomic RNA (pgRNA) drives core and P protein translation as well as genome replication. The large (L) and small (S) envelope proteins are translated from the 2.4-kb and 2.1-kb RNAs, respectively, with the majority of the S protein being secreted as noninfectious subviral particles and detected as hepatitis B surface antigen (HBsAg). pgRNA transcription could inhibit transcription of subgenomic RNAs. The present study characterized naturally occurring in-frame deletions in the 3' preS1 region, which not only codes for L protein but also serves as the promoter for 2.1-kb RNA. The human hepatoma cell line Huh7 was transiently transfected with subgenomic expression constructs for envelope (and HBx) proteins, dimeric constructs, or constructs mimicking covalently closed circular DNA. The results confirmed lost 2.1-kb RNA transcription and HBsAg production from many deletion mutants, accompanied by increases in other (especially 2.4-kb) RNAs, intracellular HBx and core proteins, and replicative DNA but impaired virion and L protein secretion. The highest intracellular L protein levels were achieved by mutants that had residual S protein expression or retained the matrix domain in L protein. Site-directed mutagenesis of a high replicating deletion mutant suggested that increased HBx protein expression and blocked virion secretion both contributed to the high replication phenotype. Our findings could help explain why such deletions are selected at a late stage of chronic HBV infection and how they contribute to viral pathogenesis. IMPORTANCE Expression of hepatitis B e antigen (HBeAg) and overproduction of HBsAg by wild-type HBV are implicated in the induction of immune tolerance to achieve chronic infection. How HBV survives the subsequent immune clearance phase remains incompletely understood. Our previous characterization of core promoter mutations to reduce HBeAg production revealed the ability of the 3.5-kb pgRNA to diminish transcription of coterminal RNAs of 2.4 kb, 2.1 kb, and 0.7 kb. The later stage of chronic HBV infection often selects for in-frame deletions in the preS region. Here, we found that many 3' preS1 deletions prevented transcription of the 2.1-kb RNA for HBsAg production, which was often accompanied by increases in intracellular 3.5-, 0.7-, and especially 2.4-kb RNAs, HBx and core proteins, and replicative DNA but lost virion secretion. These findings established the biological consequences of preS1 deletions, thus shedding light on why they are selected and how they contribute to hepatocarcinogenesis.
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Zhang J, Wang Y, Fu S, Yuan Q, Wang Q, Xia N, Wen Y, Li J, Tong S. Role of Small Envelope Protein in Sustaining the Intracellular and Extracellular Levels of Hepatitis B Virus Large and Middle Envelope Proteins. Viruses 2021; 13:613. [PMID: 33918367 PMCID: PMC8065445 DOI: 10.3390/v13040613] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus (HBV) expresses co-terminal large (L), middle (M), and small (S) envelope proteins. S protein drives virion and subviral particle secretion, whereas L protein inhibits subviral particle secretion but coordinates virion morphogenesis. We previously found that preventing S protein expression from a subgenomic construct eliminated M protein. The present study further examined impact of S protein on L and M proteins. Mutations were introduced to subgenomic construct of genotype A or 1.1 mer replication construct of genotype A or D, and viral proteins were analyzed from transfected Huh7 cells. Mutating S gene ATG to prevent expression of full-length S protein eliminated M protein, reduced intracellular level of L protein despite its blocked secretion, and generated a truncated S protein through translation initiation from a downstream ATG. Truncated S protein was secretion deficient and could inhibit secretion of L, M, S proteins from wild-type constructs. Providing full-length S protein in trans rescued L protein secretion and increased its intracellular level from mutants of lost S gene ATG. Lost core protein expression reduced all the three envelope proteins. In conclusion, full-length S protein could sustain intracellular and extracellular L and M proteins, while truncated S protein could block subviral particle secretion.
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Affiliation(s)
- Jing Zhang
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
| | - Yongxiang Wang
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
| | - Shuwen Fu
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (Q.Y.); (N.X.)
| | - Qianru Wang
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (Q.Y.); (N.X.)
| | - Yumei Wen
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
| | - Jisu Li
- Liver Research Center, Rhode Island Hospital, The Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
| | - Shuping Tong
- Key Laboratory of Medical Molecular Virology, Department of Pathobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (J.Z.); (Y.W.); (S.F.); (Q.W.); (Y.W.)
- Liver Research Center, Rhode Island Hospital, The Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
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Pfefferkorn M, Schott T, Böhm S, Deichsel D, Felkel C, Gerlich WH, Glebe D, Wat C, Pavlovic V, Heyne R, Berg T, van Bömmel F. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2021; 74:283-292. [PMID: 32931877 DOI: 10.1016/j.jhep.2020.08.039] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 07/27/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS During treatment of chronic HBV infections, loss or seroconversion of the HBV surface antigen (HBsAg) is considered a functional cure. HBsAg consists of the large (LHBs), middle (MHBs), and small surface protein (SHBs) and their relative proportions correlate strongly with disease stage. Our aim was to assess the association between HBsAg composition and functional cure during treatment. METHODS A total of 83 patients were retrospectively analyzed. HBsAg loss was achieved by 17/64 patients during nucleos(t)ide analogue (NA) treatment and 3/19 patients following treatment with pegylated interferon-alfa2a (PEG-IFN) for 48 weeks. Sixty-three patients without HBsAg loss were matched as controls. LHBs, MHBs and SHBs were quantified in sera collected before and during treatment. RESULTS Before treatment, median MHBs levels were significantly lower in patients with subsequent HBsAg loss than in those without (p = 0.005). During treatment, MHBs and LHBs proportions showed a fast decline in patients with HBsAg loss, but not in patients with HBV e antigen seroconversion only or patients without serologic response. MHBs became undetectable by month 6 of NA treatment in all patients with HBsAg loss, which occurred on average 12.8 ± 8.7 (0-52) months before loss of total HBsAg. Receiver-operating characteristic analyses revealed that the proportion of MHBs was the best early predictor of HBsAg loss before NA treatment (AUC = 0.726, p = 0.019). In patients achieving HBsAg loss with PEG-IFN, the proportions of MHBs and LHBs showed similar kinetics. CONCLUSION Quantification of HBsAg proteins shows promise as a novel tool to predict early treatment response. These assessments may help optimize individual antiviral treatment, increasing the rates of functional cure in chronically HBV-infected patients. LAY SUMMARY The hepatitis B surface antigen (HBsAg) is a key serum marker for viral replication. Loss of HBsAg is considered stable remission, which can be achieved with antiviral treatments. We have investigated whether the ratios of the different components of HBsAg, namely the large (LHBs) and medium (MHBs) HBsAg during different treatments are associated with the occurrence of HBsAg loss. We found that LHBs and MHBs decrease earlier than total HBsAg before HBsAg loss and we propose LHBs and MHBs as promising novel biomarker candidates for predicting cure of HBV infection.
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Affiliation(s)
- Maria Pfefferkorn
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Tina Schott
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Stephan Böhm
- Ludwig Maximilians-University, Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Munich, Germany
| | - Danilo Deichsel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Christin Felkel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Wolfram H Gerlich
- Justus Liebig University Giessen, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Giessen, Germany, German Centre for Infection Research (DZIF)
| | - Dieter Glebe
- Justus Liebig University Giessen, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Giessen, Germany, German Centre for Infection Research (DZIF)
| | | | | | - Renate Heyne
- Liver and Study Center Checkpoint, Berlin, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
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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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Choe WH, Kim H, Lee SY, Choi YM, Kwon SY, Moon HW, Hur M, Kim BJ. Three types of preS1 start codon deletion variants in the natural course of chronic hepatitis B infection. J Gastroenterol Hepatol 2018; 33:1370-1378. [PMID: 29232004 DOI: 10.1111/jgh.14069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/04/2017] [Accepted: 12/04/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Naturally occurring hepatitis B virus variants carrying a deletion in the preS1 start codon region may evolve during long-lasting virus-host interactions in chronic hepatitis B (CHB). The aim of this study was to determine the immune phase-specific prevalent patterns of preS1 start codon deletion variants and related factors during the natural course of CHB. METHODS A total of 399 CHB patients were enrolled. Genotypic analysis of three different preS1 start codon deletion variants (classified by deletion size: 15-base pair [bp], 18-bp, and 21-bp deletion variants) was performed. RESULTS PreS1 start codon deletion variants were detected in 155 of 399 patients (38.8%). The predominant variant was a 15-bp deletion in the immune-tolerance phase (18/50, 36%) and an 18-bp deletion in the immune-clearance phase (69/183, 37.7%). A 21-bp deletion was the predominant variant in the low replicative phase (3/25, 12.0%) and reactivated hepatitis Be antigen (HBeAg)-negative phase (22/141, 15.6%). The 15-bp and 18-bp deletion variants were more frequently found in HBeAg-positive patients (P < 0.010 and P < 0.001, respectively), whereas the 21-bp deletion variant was more frequently found in HBeAg-negative patients (P < 0.001). On multiple logistic regression analyses, the 21-bp deletion variant was independently associated with liver cirrhosis (P = 0.006), and the 15-bp deletion variant was significantly related to an incomplete response to antiviral agents (P = 0.012). CONCLUSIONS The predominant type of preS1 start codon deletion variants changes according to the immune phases of CHB infection, and each variant type is associated with different clinical parameters. PreS1 start codon deletion variants might interact with the host immune response differently according to their variant types.
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Affiliation(s)
- Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - So-Young Lee
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - Yu-Min Choi
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Hee Won Moon
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Mina Hur
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
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11
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Li F, Li X, Yan T, Liu Y, Cheng Y, Xu Z, Shao Q, Liao H, Huang P, Li J, Chen GF, Xu D. The preS deletion of hepatitis B virus (HBV) is associated with liver fibrosis progression in patients with chronic HBV infection. Hepatol Int 2018; 12:107-117. [PMID: 29651701 DOI: 10.1007/s12072-018-9858-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/15/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Limited data are available regarding the association of hepatitis B virus (HBV) mutations with liver fibrosis in HBV infection. The study aimed to clarify whether HBV preS deletion mutation is associated with liver fibrosis progression. METHODS A total of 469 patients were enrolled, including 324 with chronic hepatitis B (CHB), 28 with HBV-related compensated liver cirrhosis (LC), and 117 with HBV-related decompensated LC. All CHB and compensated LC patients received liver biopsy. Fibrosis grade was assessed using METAVIR score. HBV preS deletion was determined by direct sequencing and verified by clonal sequencing. RESULTS Overall preS deletion was detected in 12.6% (59/469) patients, specifically, in 7.51% (13/173), 10.60% (16/151), and 20.69% (30/145) of patients with no-to-mild liver fibrosis (F0-1), moderate-to-severe liver fibrosis (F2-3), and cirrhosis (F4), respectively (p < 0.01). Patients with preS-deleted HBV had lower serum HBV DNA and albumin levels compared to patients with wild-type HBV. The median length of preS deletion was 39-base pairs (bp) (3-204 bp) and the deletion most frequently emerged in preS2 initial region. Multivariate analysis identified the preS2 deletion rather than preS1 deletion to be an independent risk factor of significant fibrosis, i.e., METAVIR F ≥ 2 (p = 0.007). In addition, preS-deleted viral sequences were detected in the pool of intrahepatic HBV covalently closed circular DNA. CONCLUSIONS HBV preS deletion is positively associated with liver fibrosis progression in chronic HBV-infected patients. HBV preS2 deletion may serve as a warning indicator for liver fibrosis progression.
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Affiliation(s)
- Fan Li
- The Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Xiaodong Li
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Tao Yan
- International Liver Diseases Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Yan Liu
- Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, Beijing, 100039, China
| | - Yongqian Cheng
- International Liver Diseases Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Zhihui Xu
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Qing Shao
- The Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Hao Liao
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Pengyu Huang
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Jin Li
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China
| | - Guo-Feng Chen
- The Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China.
| | - Dongping Xu
- Institute of Infectious Diseases/Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, 100 Middle Street of 4th Ring Road, Beijing, 100039, China. .,Research Center for Clinical and Translational Medicine, Beijing 302 Hospital, Beijing, 100039, China.
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Peng L, Yang G, Wu C, Wang W, Wu J, Guo Z. Mutations in hepatitis B virus small S genes predict postoperative survival in hepatocellular carcinoma. Onco Targets Ther 2016; 9:7367-7372. [PMID: 27980426 PMCID: PMC5144890 DOI: 10.2147/ott.s121785] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Hepatitis B virus (HBV) DNA is prone to mutations due to proofreading deficiencies of HBV polymerase. We have previously identified hepatocellular carcinoma (HCC) survival-associated HBV mutations in the X, precore, and core regions. In the present study, we extended our research to assess HCC survival-associated HBV mutations in the small S gene of HBV genome in 115 HCC patients including 60 patients with HBV B genotype, 52 patients with HBV C genotype, and 3 patients with other genotypes. The overfrequencies of mutations at nucleotides 529 and 735 are 8.5% and 91.5%, respectively, but the distribution frequencies of these mutations are not different between HBV genotypes B and C. Mutational sites 529 (relative risk: 3.611, 95% confidence interval [CI]: 1.414-9.221, P=0.007) and 735 (relative risk: 1.905, 95% CI: 1.101-3.297, P=0.021) were identified as statistically significant independent predictors for HCC survival by multivariate survival analysis using a Cox proportional hazards model. Moreover, the mutated 529A and 735T were associated with both short survival time and high HBV DNA load score in HCC patients. The analysis of DNA mutations in the HBV S gene may help identify HCC subgroups with poor prognosis and may provide reference for therapeutic decisions.
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Affiliation(s)
- Li Peng
- Department of Hepatobiliary Surgery
| | | | - Chensi Wu
- Department of Gastroenterology and Hepatology
| | | | - Jianhua Wu
- Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology
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14
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Coppola N, Onorato L, Minichini C, Di Caprio G, Starace M, Sagnelli C, Sagnelli E. Clinical significance of hepatitis B surface antigen mutants. World J Hepatol 2015; 7:2729-2739. [PMID: 26644816 PMCID: PMC4663392 DOI: 10.4254/wjh.v7.i27.2729] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/27/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major public health problem in many countries, with nearly 300 million people worldwide carrying HBV chronic infection and over 1 million deaths per year due to cirrhosis and liver cancer. Several hepatitis B surface antigen (HBsAg) mutations have been described, most frequently due to a single amino acid substitution and seldom to a nucleotide deletion. The majority of mutations are located in the S region, but they have also been found in the pre-S1 and pre-S2 regions. Single amino acid substitutions in the major hydrophilic region of HBsAg, called the “a” determinant, have been associated with immune escape and the consequent failure of HBV vaccination and HBsAg detection, whereas deletions in the pre-S1 or pre-S2 regions have been associated with the development of hepatocellular carcinoma. This review article will focus on the HBsAg mutants and their biological and clinical implications.
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15
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First hepatitis B virus full-length genomic study among blood donors from Argentina: unexpected mutations in the circulating subgenotypes' proteins. Virus Genes 2014; 50:286-91. [PMID: 25537951 DOI: 10.1007/s11262-014-1159-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 12/12/2014] [Indexed: 10/24/2022]
Abstract
Hepatitis B virus (HBV) is a worldwide public health concern. The circulation of strains carrying mutations in the viral proteins implies both clinical and therapeutics challenges. HBV complete genomes (HBV-CGs) were reported from injecting drug users and HBV chronically infected patients from Argentina-including Amerindians-although no studies were conducted in blood donors. Here, we described HBV-CG sequences from the latter population. Some of the HBV sequences classified as B2 and C2 subgenotypes clustering together with Asian isolates, while others, such as D3, F1b, and F4, were homologous to European and Latin America sequences. New substitutions for all analyzed open reading frames and changes in the HBsAg hydrophobicity profiles were detected. Several HBV-CG subgenotypes are described for the first time in this population. Mutations observed in X, PreS, and P proteins have been associated with advanced liver disease, hepatocellular carcinoma, and/or natural resistance to nucleos(t)ide antiviral treatment. It deserves to be highlighted that these substitutions were detected in a population without epidemiological risk factors for viral infection, and most importantly, without any previous antiviral treatment (natural resistance). Regarding the remaining mutations, further research is warranted in order to determine their clinical and therapeutics relevance.
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16
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Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications. J Hepatol 2014; 61:408-17. [PMID: 24801416 DOI: 10.1016/j.jhep.2014.04.041] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 04/24/2014] [Indexed: 12/16/2022]
Abstract
The emergence and takeover of hepatitis B virus (HBV) variants carrying mutation(s) in the preS/S genomic region is a fairly frequent event that may occur spontaneously or may be the consequence of immunoprophylaxis or antiviral treatments. Selection of preS/S mutants may have relevant pathobiological and clinical implications. Both experimental data and studies in humans show that several specific mutations in the preS/S gene may induce an imbalance in the synthesis of the surface proteins and their consequent retention within the endoplasmic reticulum (ER) of the hepatocytes. The accumulation of mutated surface proteins may cause ER stress with the consequent induction of oxidative DNA damage and genomic instability. Viral mutants with antigenically modified surface antigen may be potentially infectious to immune-prophylaxed patients and may account for cases of occult HBV infection. In addition, preS/S variants were reported to be associated with cases of fulminant hepatitis as well as of fibrosing cholestatic hepatitis, and they are associated with cirrhosis and hepatocellular carcinoma development.
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17
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Qu LS, Liu JX, Liu TT, Shen XZ, Chen TY, Ni ZP, Lu CH. Association of hepatitis B virus pre-S deletions with the development of hepatocellular carcinoma in Qidong, China. PLoS One 2014; 9:e98257. [PMID: 24849936 PMCID: PMC4029943 DOI: 10.1371/journal.pone.0098257] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 04/30/2014] [Indexed: 01/05/2023] Open
Abstract
Background/Aim To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. Methods We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC. Results After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease. Conclusion Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.
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Affiliation(s)
- Li-Shuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China
| | - Jin-Xia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tao-Yang Chen
- Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China
| | - Zheng-Pin Ni
- Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu Province, China
- * E-mail:
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18
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Hepatitis B vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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19
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Pollicino T, Amaddeo G, Restuccia A, Raffa G, Alibrandi A, Cutroneo G, Favaloro A, Maimone S, Squadrito G, Raimondo G. Impact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface antigen and HBV DNA serum levels. Hepatology 2012; 56:434-43. [PMID: 22271491 DOI: 10.1002/hep.25592] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 12/30/2011] [Indexed: 12/16/2022]
Abstract
UNLABELLED To evaluate whether hepatitis B virus (HBV) preS/S gene variability has any impact on serum hepatitis B surface antigen (HBsAg) levels and to analyze the replication capacity of naturally occurring preS/S variants, sera from 40 untreated patients with HBV-related chronic liver disease (hepatitis B e antigen [HBeAg]-positive, n = 11; HBeAg-negative, n = 29) were virologically characterized. Additionally, phenotypic analysis of three different preS/S variant isolates (carrying a 183-nucleotide deletion within the preS1 region, the deletion of preS2 start codon, and a stop signal at codon 182 within the S gene, respectively) was performed. HBV infecting 14 (35%) patients had single or multiple preS/S genomic mutations (i.e., preS1 and/or preS2 deletions, preS2 start codon mutations, C-terminally truncated and/or "a" determinant mutated S protein). Presence of preS/S variants negatively correlated with HBsAg titers (r = -0.431; P = 0.005) and its prevalence did not significantly differ between HBeAg-positive and HBeAg-negative patients. No correlation was found between HBsAg and HBV DNA levels in patients infected with preS/S mutants, whereas a significant correlation was found between HBsAg and viremia levels (r = 0.607; P = 0.001) in patients infected with wild-type HBV strains. HepG2 cells replicating the above-mentioned three preS/S variants showed significant reduction of HBsAg secretion, retention of envelope proteins in the endoplasmic reticulum, less efficient virion secretion and nuclear accumulation of significantly higher amounts of covalently closed circular DNA compared with wild-type HBV replicating cells. CONCLUSION In patients infected with preS/S variants, HBV DNA replication and HBsAg synthesis/secretion appear to be dissociated. Therefore, the use of HBsAg titer as diagnostic/prognostic tool has to take into account the frequent emergence of preS/S variants in chronic HBV infection.
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Affiliation(s)
- Teresa Pollicino
- Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy.
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20
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Biswas A, Panigrahi R, Banerjee A, Pal M, De BK, Chakrabarti S, Chakravarty R. Differential pattern of pre-S mutations/deletions and its association with hepatitis B virus genotypes in Eastern India. INFECTION GENETICS AND EVOLUTION 2012; 12:384-91. [PMID: 22266243 DOI: 10.1016/j.meegid.2012.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 12/23/2011] [Accepted: 01/08/2012] [Indexed: 12/15/2022]
Abstract
The presence of three different HBV genotypes (A, C and D) in Eastern India provided us a unique opportunity to study HBV pre-S mutants in these genotypes and subtypes among the same ethnic population. Furthermore, we also aimed to investigate the association of the HBV pre-S mutation with clinical outcome. Pre-S1-S2 and S gene was amplified and sequenced from 86 HBsAg positive study subjects with varying clinical manifestation. The genetic variability in the pre-S region (mutations) was studied with respect to different HBV genotypes, subtypes and different clinical categories. Six different types of HBV pre-S mutations were detected in 25 cases (29.07%), among which pre-S2 start codon mutation (28.0%) and pre-S2 deletion (24.0%) were most common. Pre-S mutation was highest in HBV/C (7/18; 38.89%) followed by HBV/A (9/27; 33.33%) and HBV/D (9/40; 22.50%). Pre-S1 deletion is common in HBV/D, whereas pre-S2 start codon mutation and pre-S2 deletions are frequent among HBV/A and HBV/C, respectively. Interestingly, in HBV/A and HBV/C the tendency of mutation/deletion increases from pre-S1 to pre-S2 region while in HBV/D the opposite tendency was observed. A significantly higher association of pre-S mutation (p=0.013) and pre-S2 deletion/ablation (p=0.016) was found among the HBeAg negative cases. Pre-S1 deletion and pre-S2 deletion were common among the ASC and CLD cases respectively, while pre-S2 start codon mutation was significantly associated with cirrhosis (p<0.05). The study underscores the association of types of pre-S mutations with particular HBV genotype and clinical outcome in the study population.
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21
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Na B, Huang Z, Wang Q, Qi Z, Tian Y, Lu CC, Yu J, Hanes MA, Kakar S, Huang EJ, Ou JHJ, Liu L, Yen TSB. Transgenic expression of entire hepatitis B virus in mice induces hepatocarcinogenesis independent of chronic liver injury. PLoS One 2011; 6:e26240. [PMID: 22022578 PMCID: PMC3192172 DOI: 10.1371/journal.pone.0026240] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Accepted: 09/22/2011] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV ("preS2 mutant") that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged--2-year-old--mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines--expressing either mutant or wildtype HBV--therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.
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Affiliation(s)
- Bing Na
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America
| | - Zhiming Huang
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
| | - Qian Wang
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
| | - Zhongxia Qi
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, United States of America
| | - Yongjun Tian
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America
| | - Cheng-Chan Lu
- Department of Pathology, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Jingwei Yu
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, United States of America
| | - Martha A. Hanes
- Department of Laboratory Animal Resources, University of Texas Health Science Center, San Antonio, Texas, United States of America
| | - Sanjay Kakar
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
- Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America
| | - Eric J. Huang
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
- Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America
| | - J.-H. James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America
| | - Limin Liu
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America
| | - T. S. Benedict Yen
- Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America
- Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America
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Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011; 32:1122-32. [PMID: 21665892 DOI: 10.1093/carcin/bgr108] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Teresa Pollicino
- Department of Internal Medicine, Unit of Clinical and Molecular Hepatology, University Hospital of Messina, Via Consolare Valeria, Messina, Italy.
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23
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Novel F141L pre-S2 mutation in hepatitis B virus increases the risk of hepatocellular carcinoma in patients with chronic genotype C infections. J Virol 2010; 85:123-32. [PMID: 20962085 DOI: 10.1128/jvi.01524-10] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L-LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52; P = 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony-forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC.
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24
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Novel F141L pre-S2 mutation in hepatitis B virus increases the risk of hepatocellular carcinoma in patients with chronic genotype C infections. J Virol 2010. [PMID: 20962085 DOI: 10.1128/jvi.01524-10.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L-LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52; P = 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony-forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC.
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25
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Ohkawa K, Takehara T, Ishida H, Kodama T, Shimizu S, Hikita H, Yamamoto M, Kohga K, Sasakawa A, Uemura A, Sakamori R, Yamaguchi S, Li W, Hosui A, Miyagi T, Tatsumi T, Katayama K, Hayashi N. Fatal exacerbation of type B chronic hepatitis triggered by changes in relaxed circular viral DNA synthesis and virion secretion. Biochem Biophys Res Commun 2010; 394:87-93. [PMID: 20175994 DOI: 10.1016/j.bbrc.2010.02.114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 02/18/2010] [Indexed: 10/24/2022]
Abstract
Virological features of fulminant liver disease-causing hepatitis B virus (HBV) have not been fully elucidated. We studied longitudinally the viruses obtained before and after fulminant liver disease in a patient with chronic HBV infection showing fatal exacerbation. HBV strains were obtained before and after exacerbation (designated as FEP1 and FEP2). Their virological features were investigated by in vitro transfection. FEP1 and FEP2 possessed higher activity of overall HBV DNA synthesis than the wild-type. FEP1 lacked competence for relaxed circular (RC) HBV DNA synthesis and RC HBV DNA-containing virion secretion, but FEP2 maintained it. Chimeric analysis revealed that the preS/S gene, where FEP1 had a considerable number of mutations and deletions but FEP2 did not, was responsible for impaired RC HBV DNA synthesis and virion secretion. Furthermore, incompetence of FEP1 strain was transcomplemented by the preS/S protein of wild-type strain. In conclusion, the viral strain after exacerbation showed resurgent RC HBV DNA synthesis and virion secretion, which was caused by conversion of the preS/S gene from a hypermutated to hypomutated state. This may have been responsible for disease deterioration in the patient. This is a novel type of HBV genomic variation associated with the development of fulminant liver disease.
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Affiliation(s)
- Kazuyoshi Ohkawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
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The pre-s2 domain of the hepatitis B virus is dispensable for infectivity but serves a spacer function for L-protein-connected virus assembly. J Virol 2010; 84:3879-88. [PMID: 20130049 DOI: 10.1128/jvi.02528-09] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The envelope of the human hepatitis B virus (HBV) contains three membrane proteins (L, M, and S). They accomplish different functions in HBV infectivity and nucleocapsid envelopment. Infectivity determinants have been assigned to the N-terminal part of the pre-S1 domain of the L protein and the antigenic loop of the S domain in the L and/or S protein. Nucleocapsid envelopment requires a C-terminal sequence within pre-S1, including the five N-terminal amino acids of pre-S2 as part of the L protein. However, the role of the M protein and the pre-S2 domain of the L protein are not entirely understood. We addressed this question and analyzed assembly competence and infectivity of viruses that lack the M protein and, at the same time, carry alterations in the pre-S2 domain of L. These include deletions, in part frameshift mutations and a randomization of virtually the entire pre-S2 sequence. We found that the M protein is dispensable for HBV in vitro infectivity. Viruses that lack the M protein and contain a mostly randomized pre-S2 sequence assemble properly and are infectious in HepaRG cells and primary human hepatocytes. While deletions of 20 amino acids in the pre-S2 domain of L protein allowed the production of infectious virions, more extended deletions interfered with assembly. This indicates that the pre-S2 domain of the L protein serves an important role for virus assembly, presumably as a spacer that supports conformational changes of L protein but does not participate as part of the M protein or as a subdomain of the L protein in virus entry.
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27
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Kim JH, Jung YK, Joo MK, Kim JH, Yim HJ, Park JJ, Kim JS, Bak YT, Yeon JE, Byun KS. Hepatitis B viral surface mutations in patients with adefovir resistant chronic hepatitis B with A181T/V polymerase mutations. J Korean Med Sci 2010; 25:257-64. [PMID: 20119580 PMCID: PMC2811294 DOI: 10.3346/jkms.2010.25.2.257] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2008] [Accepted: 03/25/2009] [Indexed: 12/24/2022] Open
Abstract
The hepatitis B virus (HBV) polymerase gene has overlapping reading frames with surface genes, which allows to alter the amino acid codon of the surface genes. In adefovir (ADV) treated chronic hepatitis B patients carrying rtA181T/rtA181V mutations, overlap with surface gene mutations such as sW172stop/sL173F has been reported. However, the clinical consequences of such surface mutations have not been determined. The aim of this study was to determine the surface gene sequence in ADV-resistant patients carrying the A181T/V mutation and to describe the clinical significance. Of the 22 patients included in this study, 13 were ADV-resistant with rtA181T/V mutations (polymerase mutation group, Group P) and nine were antiviral treatment-naïve (control group, Group C). The Pre-S1 gene mutation, V60A, was detected in 11 patients (Group P=8, Group C=3). A start codon mutation in the Pre-S2 gene was found in five patients (Group P=3, Group C=2). An S gene mutation, sA184V, was found in nine patients, all of whom were in group P. Although sW172stop and sL173F mutations were detected, reduced HBsAg titer was not observed. Further study of these mutations and their clinical implications are needed.
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Affiliation(s)
- Jeong Han Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Moon Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jong-Jae Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jae Seon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young-Tae Bak
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jong Eun Yeon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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Jiang SZ, Gao ZY, Li T, Li YJ, Chen XM, Wang L, Lu FM, Zhuang H. T3098C and T53C mutations of HBV genotype C is associated with HBV infection progress. BIOMEDICAL AND ENVIRONMENTAL SCIENCES : BES 2009; 22:511-517. [PMID: 20337225 DOI: 10.1016/s0895-3988(10)60009-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
OBJECTIVE To analyze the association between mutation(s) in preS region of HBV and hepatitis B disease progress in Chinese patients with genotype C chronic HBV infection. METHODS Ninety-three patients with chronic genotype C HBV infection, including 24 asymptomatic carriers (ASC), 26 patients with chronic hepatitis B (CHB), 22 patients with liver cirrhosis (LC) and 21 HCC patients were investigated. Levels of HBV DNA, HBeAg, alanine aminotransferase (ALT), asparate transaminase (AST) were measured. HBV preS region was analyzed by PCR direct sequencing. RESULTS The prevalence of preS T3098C and T53C mutations of genotype C HBV was significantly higher in LC and HCC patients than ASC and CHB patients. The rate of T3098C mutation in ASC, CHB, LC, and HCC patients were 0.00% (0/24), 3.85% (1/26), 9.09% (2/22), and 30.77% (8/22), respectively (P=0.0015), while the rate of T53C mutation was 12.50% (3/24), 3.85% (1/26), 40.91% (9/22), and 42.31% (11/26), respectively (P=0.0012). CONCLUSION The frequency of genotype C HBV preS T3098C and T53C mutations is associated with hepatitis B infection progression
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Affiliation(s)
- Su-Zhen Jiang
- Department of Microbiology, Peking University Health Scienice Center, Beijing 100191, China
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Manzini P, Abate ML, Valpreda C, Milanesi P, Curti F, Rizzetto M, Smedile A. Evidence of acute primary occult hepatitis B virus infection in an Italian repeat blood donor. Transfusion 2009; 49:757-64. [DOI: 10.1111/j.1537-2995.2008.02041.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Fang ZL, Sabin CA, Dong BQ, Wei SC, Chen QY, Fang KX, Yang JY, Huang J, Wang XY, Harrison TJ. Hepatitis B virus pre-S deletion mutations are a risk factor for hepatocellular carcinoma: a matched nested case-control study. J Gen Virol 2009; 89:2882-2890. [PMID: 18931087 PMCID: PMC2886956 DOI: 10.1099/vir.0.2008/002824-0] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
A matched nested case-control study of 33 paired cases and controls was conducted, based on a study cohort in Long An county, Guangxi, China, to determine whether infection with hepatitis B virus (HBV) with pre-S deletions is independently associated with the development of hepatocellular carcinoma (HCC), without the confounding effects of basal core promoter (BCP) double mutations. The prevalence of pre-S deletions was significantly higher in HCC (45.5 %, 15 of 33) than the controls (18.2 %, 6 of 33) (P<0.01), under the control of the influence of BCP double mutations. Most of the pre-S deletions occurred in, or involved, the 5' half of the pre-S2 region and the difference between HCC (93.3 %, 14 of 15) and controls (66.7 %, four of six) was significant for this region (P=0.015). There was no significant difference in pre-S deletions between the BCP mutant group and BCP wild-type group (P>0.05), nor was the prevalence of pre-S deletions significantly different between genotypes B and C (P>0.1). These results suggest that pre-S deletions constitute an independent risk factor for HCC and their emergence and effect are independent of BCP mutations. The 5' terminus of pre-S2 is the favoured site for the deletion mutations, especially in HCC cases. Further prospective studies are required to confirm the role of these mutations in the development of HCC.
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Affiliation(s)
- Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China.,Department of Medicine, UCL Medical School, London W1T 4JF, UK
| | - Caroline A Sabin
- Research Department of Infection and Population Health, Division of Population Health, UCL Medical School, University College London, London NW3 2PF, UK
| | - Bai-Qing Dong
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China
| | - Shao-Chao Wei
- Sanitary and Antiepidemic Station of Long An, ChengXi Road, Cheng Xiang Town, Long An, Guangxi 532700, PR China
| | - Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China
| | - Kong-Xiong Fang
- Sanitary and Antiepidemic Station of Long An, ChengXi Road, Cheng Xiang Town, Long An, Guangxi 532700, PR China
| | - Jin-Ye Yang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China
| | - Jian Huang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China
| | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Jin Zhou Road, Nanning, Guangxi 530028, PR China
| | - Tim J Harrison
- Department of Medicine, UCL Medical School, London W1T 4JF, UK
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High prevalence of hepatitis B virus pre-S mutation and its association with hepatocellular carcinoma in Qidong, China. Arch Virol 2008; 153:1807-12. [PMID: 18726170 DOI: 10.1007/s00705-008-0176-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Accepted: 07/14/2008] [Indexed: 02/07/2023]
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Gao ZY, Li T, Wang J, Du JM, Li YJ, Li J, Lu FM, Zhuang H. Mutations in preS genes of genotype C hepatitis B virus in patients with chronic hepatitis B and hepatocellular carcinoma. J Gastroenterol 2007; 42:761-8. [PMID: 17876546 DOI: 10.1007/s00535-007-2085-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Accepted: 06/06/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) preS mutations are frequently isolated from patients with severe forms of liver disease. Meanwhile, genotype C has been shown to cause more serious liver disease than genotype B. This study assesses the frequency of preS mutation in Chinese patients with genotype C chronic HBV infection and its relation to liver damage. METHODS Seventy-nine persistently infected patients (25 asymptomatic carriers, 28 with chronic hepatitis, and 26 with hepatocellular carcinoma) with genotype C HBV were analyzed. Levels of HBV DNA, hepatitis B e antigen (HBeAg), alanine aminotransferase, and aspartate transaminase and mutations in the preS region were determined. RESULTS The correlations of preS deletion with disease progression were distinct: preS deletion mutations were more commonly found in the hepatocellular carcinoma (HCC) group than in the chronic hepatitis B (CHB) or asymptomatic carrier (ASC) groups, with the frequencies of 38.46% (10/26) in the HCC, 7.14% (2/28) in the CHB, and 4.00% (1/25) in the ASC (P = 0.001) groups. The HBeAg-positive rate and HBV DNA levels were comparable between patients with the preS mutation and those without. CONCLUSIONS PreS deletion mutations of genotype C HBV might play a role in HBV-related hepatocarcinogenesis.
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Affiliation(s)
- Zhi Yong Gao
- Department of Microbiology, Peking University Health Science Center, 38 Xueyuan Road, 100083, Beijing, China
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Choi MS, Kim DY, Lee DH, Lee JH, Koh KC, Paik SW, Rhee JC, Yoo BC. Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection. J Viral Hepat 2007; 14:161-8. [PMID: 17305881 DOI: 10.1111/j.1365-2893.2006.00784.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We investigated the overall and site-specific prevalence of pre-S mutations and its clinical significance in patients with genotype C hepatitis B virus (HBV) infection. Three hundred subjects were included: 50 asymptomatic carriers (AC), 87 chronic hepatitis (CH), 91 liver cirrhosis (LC) and 72 hepatocellular carcinoma (HCC). Pre-S mutations were determined by nucleotide sequence analysis. Possible correlations between pre-S mutations and clinical/virological parameters were examined. Pre-S mutations were detected in 82 cases (27.3%); it was more frequently found in HCC (43.1%) and LC (35.2%) group than in the CH (20.7%) and AC (2.0%) group. Pre-S2 deletion was the most commonly found mutation (10.7%), followed by pre-S2 start codon mutation (9.7%), pre-S1-S2 deletion (3.0%) and both pre-S2 deletion and start codon mutation (2.7%). Pre-S2 deletion and pre-S2 start codon mutation were more frequently detected in advanced diseases (LC and HCC). Pre-S mutations were associated with older age and higher rates of positive HBV DNA (>/=0.5 pg/mL). Advanced disease and positive HBV DNA were shown to be independent predictors of pre-S mutations by logistic regression analysis. These findings suggest that pre-S mutations, especially pre-S2 deletions and pre-S2 start codon mutations, are common in patients with genotype C HBV infection and are associated with advanced liver disease and active viral replication.
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Affiliation(s)
- M S Choi
- Department of Medicine and Digestive Disease Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Pollicino T, Raffa G, Costantino L, Lisa A, Campello C, Squadrito G, Levrero M, Raimondo G. Molecular and functional analysis of occult hepatitis B virus isolates from patients with hepatocellular carcinoma. Hepatology 2007; 45:277-85. [PMID: 17256766 DOI: 10.1002/hep.21529] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Occult HBV infection is characterized by the persistence of HBV DNA in the liver of individuals negative for HBV surface antigen (HBsAg). Occult HBV may exist in the hepatocytes as a free genome, although the factors responsible for the very low viral replication and gene expression usually observed in this peculiar kind of infection are mostly unknown. Aims of this study were to investigate whether the viral genomic variability might account for the HBsAg negativity and the inhibition of the viral replication in occult HBV carriers, and to verify in vitro the replication capability of occult HBV strains. We studied liver viral isolates from 17 HBV patients, 13 with occult infection and 4 HBsAg-positive. Full-length HBV genomes from each case were amplified and directly sequenced. Additionally, full-length HBV DNA from eight occult-HBV and two HBsAg-positive cases were cloned and sequenced. Finally, three entire, linear HBV genomes from occult cases were transiently transfected in HuH7 cells. Direct sequencing showed the absence of mutations capable of interfering with viral replication and gene expression in the major viral population of each case. Cloning experiments showed highly divergent HBV strains both in HBsAg-positive and HBsAg-negative individual cases (range of divergence 1.4%-7.1%). All of the 3 transfected full-length HBV isolates showed normal patterns of replication in vitro. CONCLUSION Multiple viral variants accumulate in the liver of occult HBV-infected patients. Occult HBV strains are replication-competent in vitro, suggesting that host, rather than viral factors are responsible for cryptic HBV infection.
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Affiliation(s)
- Teresa Pollicino
- Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy.
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Wang HC, Chang WT, Chang WW, Wu HC, Huang W, Lei HY, Lai MD, Fausto N, Su IJ. Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology 2005; 41:761-70. [PMID: 15726643 DOI: 10.1002/hep.20615] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Naturally occurring mutants with a deletion in the pre-S2 region of the large surface protein (Delta S2-LHBs) are prevalent in serum and livers of patients with chronic hepatitis B virus (HBV) infection associated with cirrhosis. The Delta S2-LHBs protein is retained in the endoplasmic reticulum (ER) and may induce ER stress. One interesting observation is the consistently clustered distribution of hepatocytes expressing Delta S2-LHBs. In this study, complementary DNA microarray analysis identified cyclin A and several groups of genes as being significantly upregulated by Delta S2-LHBs in the HuH-7 cell line. This observation was confirmed in liver tissues. The induction of cyclin A expression may occur via the specific transactivator function of Delta S2-LHBs independent of ER stress. In the presence of Delta S2-LHBs, hepatocytes sustained cyclin A expression and cell cycle progression under ER stress and displayed increased BrdU incorporation with multinuclear formation. Furthermore, Delta S2-LHBs could enhance anchorage-independent cell growth in a nontransformed human hepatocyte line and induced nodular proliferation of hepatocytes in transgenic mice. In conclusion, these in vitro and in vivo data support a role for Delta S2-LHBs in the hepatocyte hyperplasia and a likely role in the process of HBV-related tumorigenesis.
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Affiliation(s)
- Hui-Ching Wang
- Division of Clinical Research, National Health Research Institutes, Tainan, Taiwan
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:2737-2739. [DOI: 10.11569/wcjd.v12.i11.2737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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