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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: 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: 12/02/2023] [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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Guo Y, Shao J, Zhang R, Han M, Kong L, Liu Z, Li H, Wei D, Lu M, Zhang S, Zhang C, Wei H, Chen Z, Bian H. Large HBV Surface Protein-Induced Unfolded Protein Response Dynamically Regulates p27 Degradation in Hepatocellular Carcinoma Progression. Int J Mol Sci 2023; 24:13825. [PMID: 37762128 PMCID: PMC10530851 DOI: 10.3390/ijms241813825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Up to 50% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) infection, and the surface protein of HBV is essential for the progression of HBV-related HCC. The expression of large HBV surface antigen (LHB) is presented in HBV-associated HCC tissues and is significantly associated with the development of HCC. Gene set enrichment analysis revealed that LHB overexpression regulates the cell cycle process. Excess LHB in HCC cells induced chronic endoplasmic reticulum (ER) stress and was significantly correlated with tumor growth in vivo. Cell cycle analysis showed that cell cycle progression from G1 to S phase was greatly enhanced in vitro. We identified intensive crosstalk between ER stress and cell cycle progression in HCC. As an important regulator of the G1/S checkpoint, p27 was transcriptionally upregulated by transcription factors ATF4 and XBP1s, downstream of the unfolded protein response pathway. Moreover, LHB-induced ER stress promoted internal ribosome-entry-site-mediated selective translation of p27, and E3 ubiquitin ligase HRD1-mediated p27 ubiquitination and degradation. Ultimately, the decrease in p27 protein levels reduced G1/S arrest and promoted the progress of HCC by regulating the cell cycle.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Zhinan Chen
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi’an 710032, China; (Y.G.)
| | - Huijie Bian
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi’an 710032, China; (Y.G.)
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Fan G, Li F, Wang P, Jin X, Liu R. Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases. Int J Mol Sci 2022; 23:ijms232315109. [PMID: 36499429 PMCID: PMC9739742 DOI: 10.3390/ijms232315109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/11/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022] Open
Abstract
Autophagy is essential for the maintenance of hepatic homeostasis, and autophagic malfunction has been linked to the pathogenesis of substantial liver diseases. As a popular source of drug discovery, natural products have been used for centuries to effectively prevent the progression of various liver diseases. Emerging evidence has suggested that autophagy regulation is a critical mechanism underlying the therapeutic effects of these natural products. In this review, relevant studies are retrieved from scientific databases published between 2011 and 2022, and a novel scoring system was established to critically evaluate the completeness and scientific significance of the reviewed literature. We observed that numerous natural products were suggested to regulate autophagic flux. Depending on the therapeutic or pathogenic role autophagy plays in different liver diseases, autophagy-regulative natural products exhibit different therapeutic effects. According to our novel scoring system, in a considerable amount of the involved studies, convincing and reasonable evidence to elucidate the regulatory effects and underlying mechanisms of natural-product-mediated autophagy regulation was missing and needed further illustration. We highlight that autophagy-regulative natural products are valuable drug candidates with promising prospects for the treatment of liver diseases and deserve more attention in the future.
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Affiliation(s)
- Guifang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Fanghong Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Ping Wang
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xuejing Jin
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
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Proulx J, Ghaly M, Park IW, Borgmann K. HIV-1-Mediated Acceleration of Oncovirus-Related Non-AIDS-Defining Cancers. Biomedicines 2022; 10:biomedicines10040768. [PMID: 35453518 PMCID: PMC9024568 DOI: 10.3390/biomedicines10040768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/25/2022] Open
Abstract
With the advent of combination antiretroviral therapy (cART), overall survival has been improved, and the incidence of acquired immunodeficiency syndrome (AIDS)-defining cancers has also been remarkably reduced. However, non-AIDS-defining cancers among human immunodeficiency virus-1 (HIV-1)-associated malignancies have increased significantly so that cancer is the leading cause of death in people living with HIV in certain highly developed countries, such as France. However, it is currently unknown how HIV-1 infection raises oncogenic virus-mediated cancer risks in the HIV-1 and oncogenic virus co-infected patients, and thus elucidation of the molecular mechanisms for how HIV-1 expedites the oncogenic viruses-triggered tumorigenesis in the co-infected hosts is imperative for developing therapeutics to cure or impede the carcinogenesis. Hence, this review is focused on HIV-1 and oncogenic virus co-infection-mediated molecular processes in the acceleration of non-AIDS-defining cancers.
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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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Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 2016; 64:S84-S101. [PMID: 27084040 DOI: 10.1016/j.jhep.2016.02.021] [Citation(s) in RCA: 692] [Impact Index Per Article: 76.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 02/17/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation.
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Affiliation(s)
- Massimo Levrero
- Cancer Research Center of Lyon (CRCL) - INSERM U1052, Lyon, France; IIT Centre for Life Nanoscience (CLNS), Rome, Italy; Dept of Internal Medicine (DMISM), Sapienza University, Rome, Italy.
| | - Jessica Zucman-Rossi
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France; Université Paris Diderot, Paris, France.
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Guerrieri F, Belloni L, Pediconi N, Levrero M. Pathobiology of Hepatitis B Virus-Induced Carcinogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-22330-8_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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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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Kim H, Lee SA, Kim DW, Lee SH, Kim BJ. Naturally occurring mutations in large surface genes related to occult infection of hepatitis B virus genotype C. PLoS One 2013; 8:e54486. [PMID: 23349904 PMCID: PMC3548799 DOI: 10.1371/journal.pone.0054486] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 12/12/2012] [Indexed: 12/21/2022] Open
Abstract
Molecular mechanisms related to occult hepatitis B virus (HBV) infection, particularly those based on genotype C infection, have rarely been determined thus far in the ongoing efforts to determine infection mechanisms. Therefore, we aim to elucidate the mutation patterns in the surface open reading frame (S ORF) underlying occult infections of HBV genotype C in the present study. Nested PCRs were applied to 624 HBV surface antigen (HBsAg) negative Korean subjects. Cloning and sequencing of the S ORF gene was applied to 41 occult cases and 40 control chronic carriers. Forty-one (6.6%) of the 624 Korean adults with HBsAg-negative serostatus were found to be positive for DNA according to nested PCR tests. Mutation frequencies in the three regions labeled here as preS1, preS2, and S were significantly higher in the occult subjects compared to the carriers in all cases. A total of two types of deletions, preS1 deletions in the start codon and preS2 deletions as well as nine types of point mutations were significantly implicated in the occult infection cases. Mutations within the "a" determinant region in HBsAg were found more frequently in the occult subjects than in the carriers. Mutations leading to premature termination of S ORF were found in 16 occult subjects (39.0%) but only in one subject from among the carriers (2.5%). In conclusion, our data suggest that preS deletions, the premature termination of S ORF, and "a" determinant mutations are associated with occult infections of HBV genotype C among a HBsAg-negative population. The novel mutation patterns related to occult infection introduced in the present study can help to broaden our understanding of HBV occult infections.
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Affiliation(s)
- Hong Kim
- Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - Seoung-Ae Lee
- Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - Dong-Won Kim
- Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
| | - Sueng-Hyun Lee
- Department of Microbiology, Family Medicine, and Internal Medicine, Konkuk University school of Medicine, Chungju, Korea
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul, Korea
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Levrero M, Belloni L. HBV Signaling. SIGNALING PATHWAYS IN LIVER DISEASES 2010:465-481. [DOI: 10.1007/978-3-642-00150-5_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
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Affiliation(s)
- Thomas F Baumert
- Department of Medicine I, Schlosspark Klinik, Teaching Hospital of the Charite, Humboldt University, Heubnerweg 2, D-14059 Berlin, Germany
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Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes. Hepatology 2005; 41:247-56. [PMID: 15660384 DOI: 10.1002/hep.20553] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis B virus (HBV) core promoter mutations have been implicated in the pathogenesis of fulminant hepatitis B. Due to the limited availability of primary human hepatocytes, the functional characterization of HBV mutants has been performed predominantly in transformed cells, which may not represent ideal model systems for studying virus-cell interactions. We and others have shown that primary hepatocytes of the tree shrew Tupaia belangeri support HBV infection and replication. In this study, we used primary Tupaia hepatocytes to analyze the phenotype of two HBV core promoter mutations that have been associated with a clinical outbreak of fatal fulminant hepatitis. Similar to previous findings in human hepatoma cells, the HBV core promoter mutations resulted in enhanced viral replication and core expression. Surprisingly, however, the presence of the mutations had a marked effect on hepatocyte viability not previously observed in hepatoma cells. Reduced cell viability was found to be due to the induction of apoptosis, as evidenced by caspase-3 activation and nuclear fragmentation. In conclusion, HBV mutants exhibit a novel phenotype in primary hepatocytes distinctly different from previous findings in hepatoma cell lines. This phenotype may have important implications for the understanding of the fulminant clinical course associated with HBV mutations.
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Lefkowitch JH. Hepatobiliary pathology. Curr Opin Gastroenterol 2004; 20:188-97. [PMID: 15703643 DOI: 10.1097/00001574-200405000-00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW Liver biopsy continues to be an essential component in the evaluation of many widely prevalent liver diseases, including chronic hepatitis C, fatty liver, and liver tumors. This annual review of publications in hepatobiliary pathology highlights recent pathologic studies that can be applied to the daily practice of interpreting liver biopsy, explant, and postmortem specimens. RECENT FINDINGS The problem of the fatty liver was the subject of many studies. In chronic hepatitis C, genotype 3 infection results in moderate to marked fat that is ameliorated with successful antiviral therapy. In nonalcoholic steatohepatitis, in which the metabolic syndrome is often operative, gene microarray analysis showed altered expression of genes involved in insulin sensitivity and maintenance of mitochondrial function. Pathologic changes affecting centrilobular regions were described in the context of heart disease, Budd-Chiari syndrome, and the sinusoidal obstruction syndrome (venoocclusive disease). A mutation in ferroportin 1 produced a form of hemochromatosis with excessive iron in hepatocytes and also in Kupffer cells and macrophages. Immunostains for Hep Par 1 and polyclonal carcinoembryonic antigen remain important cornerstones in the immunohistochemical diagnosis of hepatocellular carcinoma and its distinction from metastatic adenocarcinoma and cholangiocarcinoma. SUMMARY This report reviews recent articles addressing hepatobiliary pathology. In the areas of viral and drug hepatitis, fatty liver, hemochromatosis, Wilson disease, several biliary tract disorders, and pathology of liver tumors, the emerging data have important diagnostic applications.
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Affiliation(s)
- Jay H Lefkowitch
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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Raimondo G, Costantino L, Caccamo G, Pollicino T, Squadrito G, Cacciola I, Brancatelli S. Non-sequencing molecular approaches to identify preS2-defective hepatitis B virus variants proved to be associated with severe liver diseases. J Hepatol 2004; 40:515-519. [PMID: 15123368 DOI: 10.1016/j.jhep.2003.11.025] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2003] [Revised: 11/17/2003] [Accepted: 11/20/2003] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS PreS2-defective hepatitis B virus (HBV) variants may emerge during chronic HBV infection. These variants carry mutation(s) at the ATG-start-codon and/or in-frame deletion into the preS2 genomic region and are commonly detected by sequencing analyses. We evaluated the prevalence of these variants in a large series of chronic HBV infected patients through non-sequencing molecular approaches. METHODS We examined HBV isolates from 110 HBV carriers: 15 were inactive carriers (IC); 50 had chronic hepatitis (CH); 25 were cirrhotics; 19 had hepatocellular carcinoma (HCC). The entire preS2 genomic region was amplified by PCR technique. The amplicons were processed: (A) through electrophoresis on acrylamide gel to reveal deleted genomes; (B) through electrophoresis on agarose gel after digestion by NlaIII enzyme that cuts the wild ATG-start-codon but not the mutated one. RESULTS We detected preS2 variants in 56/110 cases (51%). In particular, we found preS2-defective mutants in 2/15 IC, 25/50 CH, 13/26 cirrhotics, and 16/19 HCC. The presence of these variants was thus significantly associated with active infection and liver disease (P<0.002). Moreover, among cases with liver disease preS2-mutants were more prevalent in HCC patients (P<0.02). CONCLUSIONS Our non-sequencing molecular methods are sensitive and specific, and simplify the identification of all preS2 HBV variant forms. Infection by these variants is significantly associated with active infection and HCC.
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Affiliation(s)
- Giovanni Raimondo
- Unità di Epatologia Clinica e Biomolecolare, Dipartimento di Medicina Interna, Policlinico Universitario di Messina, 98124 Messina, Italy.
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