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Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepatogastroenterol 2023; 13:152-158. [PMID: 38222956 PMCID: PMC10785131 DOI: 10.5005/jp-journals-10018-1412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/21/2023] [Indexed: 01/16/2024] Open
Abstract
Background and aims Bangladesh's unique epidemiological landscape presents an intriguing puzzle. This South Asian nation, with its complex sociodemographic and environmental factors, is home to a diverse array of hepatitis-B virus (HBV) genotypes, identified as Genotype C, with Genotypes D and A also making a significant contribution to the viral landscape. Reviewing such insights is necessary not only to underscore the country's regional diversity in HBV strains but also to bring into focus the clinical implications these genetic variations may have on disease progression and management. Methods A thorough database search covered various sources using relevant keywords like "Hepatitis B virus genotypes", "HBV genotypes in Bangladesh", and "HBV clinical implications". The review synthesized findings and analyzed HBV genotype prevalence and clinical implications in Bangladesh. Results Genotypes C and D collectively represent 82% of chronic hepatitis-B infection (CHB) cases in Bangladesh, underscoring their regional prevalence. The geographic context is pivotal in understanding HBV infection dynamics and disease progression in this area. Notably, genotype C and the presence of A1762T/G1764A mutations appear to have a distinct impact on disease development, potentially affecting the immune response in CHB patients. This highlights the need for tailored management approaches in this specific region. Further research is vital to confirm and elaborate on these findings, particularly in relation to how these mutations influence the host's immune response. Conclusion and clinical significance In summary, studies on HBV genotypes in Bangladesh stress the need for genotype-specific clinical considerations and more research to improve diagnostics and therapies. How to cite this article Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepato-Gastroenterol 2023;13(2):152-158.
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Affiliation(s)
- Ruksana Raihan
- Department of Microbiology, US Bangla Medical College and Hospital, University of Malaya, Dhaka, Bangladesh
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine; Research Center for Global and Local Infectious Diseases, Faculty of Medicine, Oita University, Oita; Miyakawa Memorial Research Foundation, Tokyo, Japan
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Castro GM, Sosa MJ, Sicilia PE, Riberi MI, Moreno C, Cattaneo R, Debes JD, Barbás MG, Cudolá AE, Pisano MB, Ré VE. Acute and chronic HBV infection in central Argentina: High frequency of sub-genotype F1b, low detection of clinically relevant mutations and first evidence of HDV. Front Med (Lausanne) 2023; 9:1057194. [PMID: 36698842 PMCID: PMC9868314 DOI: 10.3389/fmed.2022.1057194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/16/2022] [Indexed: 01/10/2023] Open
Abstract
Introduction Genomic analysis of hepatitis B virus (HBV) identifies phylogenetic variants, which may lead to distinct biological and clinical behaviors. The satellite hepatitis D virus (HDV) may also influence clinical outcomes in patients with hepatitis B. The aim of this study was to investigate HBV genetic variants, including clinically relevant mutations, and HDV infection in acute and chronic hepatitis B patients in central Argentina. Methods A total of 217 adult HBV infected patients [acute (AHB): n = 79; chronic (CHB): n = 138] were studied; 67 were HBV/human immunodeficiency virus (HIV) coinfected. Clinical and demographic data were obtained from medical records. Serological markers were determined. Molecular detection of HBV and HDV was carried out by RT-Nested PCR, followed by sequencing and phylogenetic analysis. Results Overall, genotype (gt) F [sub-genotype (sgt) F1b] was the most frequently found. In AHB patients, the gts/sgts found were: F1b (74.7%) > A2 (13.9%) > F4 (7.6%) > C (2.5%) > A1 (1.3%). Among CHB patients: F1b (39.1%) > A2 (23.9%) > F4 (18.2%) > D (9.4%) > C and F6 (3.6% each) > A1, A3 and B2 (0.7% each). The distribution of sgt A2 and gt D was significantly different between HBV mono and HBV/HIV coinfected patients [A2: 15.9% vs. 35.7% (p < 0.05), respectively and D: 14.6% vs. 1.8% (p < 0.05), respectively]. Mutation frequency in basal core promoter/pre-Core (BCP/pC) region was 35.5% (77/217) [AHB: 20.3% (16/79), CHB: 44.2% (61/138)]. In the open reading frame (ORF) S, mutations associated with vaccine escape and diagnostic failure were detected in 7.8% of the sequences (17/217) [AHB: 3.8% (3/79), CHB: 10.1% (14/138)]. ORF-P amino acid substitutions associated with antiviral resistance were detected in 3.2% of the samples (7/217) [AHB: 1.3% (1/79), CHB 4.3%, (6/138)]. The anti-HDV seropositivity was 5.2% (4/77); one sample could be sequenced, belonging to gt HDV-1 associated with sgt HBV-D3. Discussion We detected an increase in the circulation of genotype F in Central Argentina, particularly among AHB patients, suggesting transmission advantages over the other genotypes. A low rate of mutations was detected, especially those with antiviral resistance implications, which is an encouraging result. The evidence of HDV circulation in our region, reported for the first time, alerts the health system for its search and diagnosis.
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Affiliation(s)
- Gonzalo M. Castro
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina,*Correspondence: Gonzalo M. Castro,
| | - María J. Sosa
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - Paola E. Sicilia
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - María I. Riberi
- Laboratorio de Virología, Servicio de Microbiología, Clínica Universitaria Reina Fabiola, Universidad Católica de Córdoba, Córdoba, Argentina
| | - Claudia Moreno
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - Rodolfo Cattaneo
- Servicio de Gastroenterología, Hospital Rawson, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - José D. Debes
- Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - María G. Barbás
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - Analía E. Cudolá
- Departamento Laboratorio Central, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - María B. Pisano
- Laboratorio de Hepatitis Virales, Instituto de Virología “Dr. J. M. Vanella” (InViV)–CONICET, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Viviana E. Ré
- Laboratorio de Hepatitis Virales, Instituto de Virología “Dr. J. M. Vanella” (InViV)–CONICET, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
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Veronese P, Dodi I, Esposito S, Indolfi G. Prevention of vertical transmission of hepatitis B virus infection. World J Gastroenterol 2021; 27:4182-4193. [PMID: 34326618 PMCID: PMC8311536 DOI: 10.3748/wjg.v27.i26.4182] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/29/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is the leading cause of chronic viral hepatitis. Annually, almost two million children younger than 5 years acquire the infection, mostly through vertical or horizontal transmission in early life. Vertical transmission of HBV is a high efficacy phenomenon ranging, in the absence of any preventive interventions, from 70% to 90% for hepatitis e antigen positive mothers and from 10% to 40% for hepatitis e antigen-negative mothers. Maternal viraemia is a preeminent risk factor for vertical transmission of HBV. Maternal screening is the first step to prevent vertical transmission of HBV. Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection. Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low- and middle-income countries where the prevalence of the infection is at the highest.
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Affiliation(s)
- Piero Veronese
- Department of Medicine and Surgery, University of Parma, Parma 43121, Italy
| | - Icilio Dodi
- Department of Pediatrics, Pietro Barilla Children's Hospital, Parma 43121, Italy
| | - Susanna Esposito
- Department of Medicine and Surgery, University of Parma, Parma 43121, Italy
| | - Giuseppe Indolfi
- Department Neurofarba, University of Florence, Florence 50129, Italy
- Department Neurofarba, Meyer Children's University Hospital, Florence 50129, Italy
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Basen-Engquist K, Brown P, Coletta AM, Savage M, Maresso KC, Hawk E. Lifestyle and Cancer Prevention. ABELOFF'S CLINICAL ONCOLOGY 2020:337-374.e12. [DOI: 10.1016/b978-0-323-47674-4.00022-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol 2017; 31:249-255. [PMID: 28774406 DOI: 10.1016/j.bpg.2017.04.010] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Molecular epidemiologic studies reveal remarkable differences in the geographical distribution of hepatitis B virus (HBV) genotypes. The frequency of mutants among HBV genotypes also varies. The role of HBV genotypes/mutants in the pathogenesis of HBV infection and natural history of HBV infection has been extensively investigated. The distribution of HBV genotypes in acute hepatitis B patients reflects the predominant genotypes in a given geographic area. In chronic hepatitis B patients, genotype C and D have a higher frequency of basal core promoter A1762T/G1764A mutations than genotype A and B. HBV genotypes C, D and F carry a higher lifetime risk of cirrhosis and HCC development than genotype A and B. HBV pre-S/S gene mutations were associated with immune escape of hepatitis B immunoglobulin or vaccine-induced immunity. Mutations in the pre-S, core promoter and X regions correlate with an increased risk of cirrhosis and HCC. In summary, HBV genotypes and mutants are associated with the disease progression and long-term outcome of HBV infection. They may serve as viral genetic markers for risk stratification of chronic hepatitis B patients in clinical practice.
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Nuclear Import of Hepatitis B Virus Capsids and Genome. Viruses 2017; 9:v9010021. [PMID: 28117723 PMCID: PMC5294990 DOI: 10.3390/v9010021] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/17/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is an enveloped pararetrovirus with a DNA genome, which is found in an up to 36 nm-measuring capsid. Replication of the genome occurs via an RNA intermediate, which is synthesized in the nucleus. The virus must have thus ways of transporting its DNA genome into this compartment. This review summarizes the data on hepatitis B virus genome transport and correlates the finding to those from other viruses.
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Nishizawa T, Hoshino T, Naganuma A, Kobayashi T, Nagashima S, Takahashi M, Takagi H, Okamoto H. Enhanced pregenomic RNA levels and lowered precore mRNA transcription efficiency in a genotype A hepatitis B virus genome with C1766T and T1768A mutations obtained from a fulminant hepatitis patient. J Gen Virol 2016; 97:2643-2656. [PMID: 27473751 DOI: 10.1099/jgv.0.000566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The viral factors associated with the development of fulminant hepatitis B are not fully understood. We recently found four unique mutations [G to A at nucleotide 1742 (G1742A), C1766T, T1768A and T1809C] in the basal core promoter (BCP) region of a genotype A hepatitis B virus (HBV) strain (FH) obtained from a 53-year-old man with fatal fulminant hepatitis. To elucidate the association of the mutations of the FH genome with the disease, we constructed a 1.3-fold FH genome and its five variants by replacing one or two mutated nucleotides with wild-type nucleotide(s) via site-directed mutagenesis, and transfected human hepatoma cells (HepG2/C3A) with the constructs. There were no discernible differences between FH and two variants (FH_A1742G and FH_C1809T) with regard to viral replication and protein expression. However, in comparison to three other variants (FH_T1766C, FH_A1768T and FH_T1766C/A1768T) with wild-type nucleotide(s) at 1766 and/or 1768, the FH genome exhibited a 2.5-5-fold enhancement of viral replication by heightened pregenomic RNA synthesis and a 1.5-2.5-fold reduction in the hepatitis B e antigen (HBeAg) synthesis by the downregulation of the precore mRNA level. An immunofluorescence analysis revealed the increased and predominant cytoplasmic localization of the core protein in the FH genome. The present study demonstrates that the C1766T/T1768A mutations in the BCP region of genotype A HBV enhance viral replication, downregulate HBeAg expression and are responsible for the predominant localization of the core protein in the cytoplasm, which are likely associated with the development of fulminant hepatitis.
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Affiliation(s)
- Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
| | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Gunma 370-0829, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Gunma 370-0829, Japan
| | - Tominari Kobayashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Gunma 370-0829, Japan.,Department of Gastroenterology and Hepatology, Kusunoki Hospital, Gunma 375-0024, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
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Abstract
At least 10 hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions and several HBV mutants, including precore/core promoter mutations and pre-S/S deletion mutations, have been recognized to be not only predictive of liver disease progression but also associated with response to antiviral therapy. HBV genotype-specific pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients across the world. For example, patients with HBV genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, HBV genotypes C and D have a higher frequency of core promoter and pre-S mutations than genotypes A and B. Genotypes C and D also carry a higher lifetime risk of cirrhosis and HCC development than genotypes A and B. Core promoter and pre-S mutations also correlate with an increased risk of hepatocellular carcinoma (HCC). Therapeutically, genotypes A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogs is comparable across different HBV genotypes. In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei 106, Taiwan Department of Psychology, National Chengchi University, Taipei 106, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan
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Besharat S, Poustchi H, Mohamadkhani A, Katoonizadeh A, Moradi A, Roshandel G, Freedman ND, Malekzadeh R. Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran. HEPATITIS MONTHLY 2015; 15:e23875. [PMID: 25788956 PMCID: PMC4350247 DOI: 10.5812/hepatmon.23875] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 10/28/2014] [Accepted: 01/24/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear. OBJECTIVES We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran. MATERIALS AND METHODS Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided. RESULTS Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 ± 1.66 IU/mL vs. 1.76 ± 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection. CONCLUSIONS In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease.
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Affiliation(s)
- Sima Besharat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
- Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Hossein Poustchi, Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave., Shariati Hospital, P.O. Box: 14117-13135, Tehran, IR Iran. Tel: +98-2182415204, Fax: +98-21 82415400, E-mail:
| | - Ashraf Mohamadkhani
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Aezam Katoonizadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Abdolvahab Moradi
- Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Gholamreza Roshandel
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
- Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Neal David Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA
| | - Reza Malekzadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
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Park YM. Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome. World J Hepatol 2015; 7:113-120. [PMID: 25625002 PMCID: PMC4295188 DOI: 10.4254/wjh.v7.i1.113] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/12/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
The core promoter and proximal precore regions are the most complex portions of the hepatitis B virus (HBV) genome. These regions cooperatively regulate viral replication and differentially regulate the synthesis of the viral proteins E, core, and X. Multiple mutations in these regions are associated with the persistency of viral infection and the development of cirrhosis and hepatocellular carcinoma (HCC). In South Korea, nearly all HBVs are classified as HBV genotype C2; the majority of these viruses have the basal core promoter double mutation, a precore stop mutation, or both. These mutations may play a role in the alteration of viral and clinical features, and abundant and complex mutations are particularly prevalent in the core promoter and proximal precore regions. We previously demonstrated that the accumulation of ≥ 6 mutations at eight key nucleotides located in these regions (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A, and G1899A) is a useful marker to predict the development of HCC regardless of advanced liver disease. In addition, certain mutation combinations were predominant in cases with ≥ 4 mutations. In cases with ≤ 5 mutations, a low Hepatitis B e antigen titer (< 35 signal to noise ratio) was indicative of HCC risk. Viral mutation data of the single HBV genotype C2 suggest that the combined effect of the number and pattern of mutations in the core promoter and proximal precore regions is helpful in predicting HCC risk.
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Wang W, Liang H, Zeng Y, Lin J, Liu C, Jiang L, Yang B, Ou Q. Establishment of a novel two-probe real-time PCR for simultaneously quantification of hepatitis B virus DNA and distinguishing genotype B from non-B genotypes. Clin Chim Acta 2014; 437:168-74. [PMID: 25066032 DOI: 10.1016/j.cca.2014.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 06/04/2014] [Accepted: 07/16/2014] [Indexed: 01/01/2023]
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Deroubaix A, Osseman Q, Cassany A, Bégu D, Ragues J, Kassab S, Lainé S, Kann M. Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus. J Gen Virol 2014; 96:183-195. [PMID: 25274856 DOI: 10.1099/vir.0.064816-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Biopsies from patients show that hepadnaviral core proteins and capsids - collectively called core - are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that ϵ, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells.
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Affiliation(s)
- Aurélie Deroubaix
- Hepatitis Virus Diversity Research Programme, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.,CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Quentin Osseman
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Aurélia Cassany
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Dominique Bégu
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Jessica Ragues
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Somar Kassab
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
| | - Sébastien Lainé
- CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,Université Montpellier 1, CPBS, UMR 5236 CNRS, Montpellier, France
| | - Michael Kann
- Univ. de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France.,CHU de Bordeaux, Bordeaux, France.,CNRS, Microbiologie Fondamentale et Pathogénicité, UMR 5234, Bordeaux, France
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13
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Coexistence of hepatitis B virus quasispecies enhances viral replication and the ability to induce host antibody and cellular immune responses. J Virol 2014; 88:8656-66. [PMID: 24850745 DOI: 10.1128/jvi.01123-14] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
UNLABELLED Hepatitis B virus (HBV) quasispecies contain a large number of variants that serve as a reservoir for viral selection under antiviral treatment and the immune response, leading to the acute exacerbation and subsequent development of liver failure. However, there is no clear experimental evidence for a significant role of HBV quasispecies in viral pathogenesis. In the present study, HBV sequences were amplified from a patient with severe liver disease and used for construction of HBV replication-competent plasmids. Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining were performed to analyze the expression, secretion, and subcellular localization of viral proteins in vitro. Viral replication intermediates were detected by Southern blotting. HBV gene expression and replication and the induction of specific immune responses in an HBV hydrodynamic injection (HI) mouse model were investigated. The results demonstrated that two naturally occurring HBV variants, SH and SH-DPS, were identified. The variant SH-DPS expressed only a nonexportable hepatitis B virus surface antigen (HBsAg) with abnormal intracellular accumulation. The coexistence of the HBV variants at a ratio of 1 to 4 (SH to SH-DPS) increased HBV replication. Significantly stronger intrahepatic cytotoxic T lymphocyte (CTL) responses and antibody responses specific to HBsAg were induced in mice by the HBV variants when coapplied by HI. These findings uncovered an unexpected aspect of HBV quasispecies: the coexistence of different variants can significantly modulate specific host immune responses, representing a novel mechanism for the immunopathogenesis of HBV infection. IMPORTANCE Hepatitis B virus (HBV) is an important human pathogen. HBV quasispecies with genetically heterogenous variants are thought to play a role in the progression of HBV-associated liver diseases. So far, direct evidence is available in only a few cases to confirm the proposed role of HBV variants in the pathogenesis. We report here that the coexistence of two naturally occurring HBV variants at a ratio of 1 to 4 increased HBV replication and induced significantly stronger intrahepatic cytotoxic T lymphocyte responses and antibody responses specific to HBV surface antigen (HBsAg) in mice. Our discovery uncovered an unexpected aspect of HBV quasispecies: the coexistence of different variants can significantly modulate specific host immune responses and may enhance immune-mediated liver damage under some circumstances, representing a novel mechanism for the immunopathogenesis of HBV infection.
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Lin CL, Kao JH. Hepatitis B Virus Genotypes: Clinical Relevance and Therapeutic Implications. CURRENT HEPATITIS REPORTS 2013; 12:124-132. [DOI: 10.1007/s11901-013-0166-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Kitab B, Essaid El Feydi A, Afifi R, Trepo C, Benazzouz M, Essamri W, Zoulim F, Chemin I, Alj HS, Ezzikouri S, Benjelloun S. Variability in the precore and core promoter regions of HBV strains in Morocco: characterization and impact on liver disease progression. PLoS One 2012; 7:e42891. [PMID: 22905181 PMCID: PMC3419231 DOI: 10.1371/journal.pone.0042891] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 07/13/2012] [Indexed: 12/12/2022] Open
Abstract
Background Hepatitis B virus (HBV) is one of the most common human pathogens that cause aggressive hepatitis and advanced liver disease (AdLD), including liver cirrhosis and Hepatocellular Carcinoma. The persistence of active HBV replication and liver damage after the loss of hepatitis B e antigen (HBeAg) has been frequently associated with mutations in the pre-core (pre-C) and core promoter (CP) regions of HBV genome that abolish or reduce HBeAg expression. The purpose of this study was to assess the prevalence of pre-C and CP mutations and their impact on the subsequent course of liver disease in Morocco. Methods/Principal Findings A cohort of 186 patients with HBeAg-negative chronic HBV infection was studied (81 inactive carriers, 69 with active chronic hepatitis, 36 with AdLD). Pre-C and CP mutations were analyzed by PCR-direct sequencing method. The pre-C stop codon G1896A mutation was the most frequent (83.9%) and was associated with a lower risk of AdLD development (OR, 0.4; 95% CI, 0.15–1.04; p = 0.04). HBV-DNA levels in patients with G1896A were not significantly different from the other patients carrying wild-type strains (p = 0.84). CP mutations C1653T, T1753V, A1762T/G1764A, and C1766T/T1768A were associated with higher HBV-DNA level and increased liver disease severity. Multiple logistic regression analysis showed that older age (≥40 years), male sex, high viral load (>4.3 log10 IU/mL) and CP mutations C1653T, T1753V, A1762T/G1764A, and C1766T/T1768A were independent risk factors for AdLD development. Combination of these mutations was significantly associated with AdLD (OR, 7.52; 95% CI, 4.8–8; p<0.0001). Conclusions This study shows for the first time the association of HBV viral load and CP mutations with the severity of liver disease in Moroccan HBV chronic carriers. The examination of CP mutations alone or in combination could be helpful for prediction of the clinical outcome.
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Affiliation(s)
- Bouchra Kitab
- Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, Casablanca, Morocco
- Laboratoire de Recherche sur les Lipoprotéines et l′Athérosclérose, Unité Associée au CNRST -URAC 34- Université Hassan II, Faculté des Sciences Ben M′sik, Casablanca, Morocco
| | | | - Rajaa Afifi
- Service Médecine C, CHU Ibn Sina, Rabat, Morocco
| | | | | | | | | | | | - Hanane Salih Alj
- Laboratoire de Recherche sur les Lipoprotéines et l′Athérosclérose, Unité Associée au CNRST -URAC 34- Université Hassan II, Faculté des Sciences Ben M′sik, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Laboratoire des Hépatites Virales, Institut Pasteur du Maroc, Casablanca, Morocco
- * E-mail:
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Liu CJ, Cheng HR, Chen CL, Chen TC, Tseng TC, Wang ZL, Chen PJ, Liu CH, Chen DS, Kao JH. Effects of hepatitis B virus precore and basal core promoter mutations on the expression of viral antigens: genotype B vs C. J Viral Hepat 2011; 18:e482-90. [PMID: 21914067 DOI: 10.1111/j.1365-2893.2011.01480.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hepatitis B virus (HBV) genotypes/mutants are known to affect natural outcomes. The virologic differences among HBV genotype, precore and basal core promoter (BCP) mutations were investigated. HBV strains were isolated from 18 hepatitis B e antigen (HBeAg)-positive patients (nine genotype B and nine genotype C). All had precore and BCP wild-type sequences. After cloning of full-length HBV genome, the effects of viral genotype, precore and BCP mutations singly or additively on the expression of viral DNA and antigens were investigated by mutagenesis and transfection assays in Huh7 cells. Significant findings included the following: (i) expression of intracellular core protein increased when precore or BCP mutation was introduced in genotype C strains; (ii) expression of intracellular surface protein was lower in genotype C precore wild-type strain compared with genotype B; (iii) precore mutation was associated with a lower extracellular expression level of HBV DNA; (iv) secretion of hepatitis B surface antigen in genotype C was lower than that in genotype B; and (v) secretion of HBeAg in genotype B was lower than that in genotype C. No additive effect was observed by combining precore and BCP mutations. Hence, HBV genotype and precore/BCP mutations correlate with intrahepatic expression of viral antigens in vitro.
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Affiliation(s)
- C-J Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Abstract
Although safe and effective vaccines for hepatitis B virus (HBV) have been available for nearly three decades, this virus kills at least 600,000 people annually worldwide and remains the leading global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Because the HBV reverse transcriptase lacks a proofreading function, many HBV genotypes, subgenotypes, mutants, and recombinants exist. At least 10 HBV genotypes (HBV-A through J) with distinct geographic distributions have been identified; by definition, their complete genomic sequences diverge by more than 8%. HBV genotype is increasingly becoming recognized as an important factor in the progression and clinical outcome of HBV-induced disease. Infections by HBV-C or -D are significantly more likely to lead to cirrhosis and hepatocellular carcinoma than are infections by HBV-A or -B. Additionally, the hepatitis B e antigen seroconversion response to standard or pegylated interferon is more favorable in patients with HBV-A or -B than in those with HBV-C or -D. However, therapeutic responses to nucleos(t)ide analogues are generally comparable among HBV genotypes. In conclusion, genotyping of HBV is useful in identifying chronic hepatitis B patients who are at increased risk of disease progression, thereby enabling physicians to optimize antiviral therapy for these patients.
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Affiliation(s)
- Jia-Horng Kao
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, Hepatitis Research Center, and Department of Medical Research, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
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18
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Characterization of occult hepatitis B virus infection from blood donors in China. J Clin Microbiol 2011; 49:1730-7. [PMID: 21411575 DOI: 10.1128/jcm.00145-11] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Prevalence and characteristics of occult hepatitis B virus (HBV) infection (OBI) of genotypes B and C prevalent in China have not been extensively explored. Characterization of OBI strains obtained from Chinese blood donors was based on clinical and serological analyses, follow-up testing, and sequence analyses. Twenty-eight samples from 165,371 HBV surface antigen (HBsAg)-negative plasmas were confirmed HBsAg negative and DNA positive(HBsAg(-)/DNA(+)), of which 22 were classified as OBIs and 6 as window period infections. The OBI incidence was 1:7,517 in blood donors, whose ages ranged between 20 and 45 years (median, 28 years). OBI donors had normal alanine aminotransferase (ALT) levels and low viral loads ranging between unquantifiable amounts and 178 IU/ml (median, 14 IU/ml). Sequences from 21 basic core promoter/precore (BCP/PC) regions, five whole genomes, and two additional pre-S/S regions from OBI strains were compared to genotypes B and C HBsAg(+) reference strains. Eighty-six percent (6/7) of OBI strains were genotype C. Deletions, insertions, stop codons, and substitutions were detected in 15/21 (71%) core regulatory elements of OBI strains. Critical mutations were found in the core proteins of 5/5 OBI strains in parallel with random substitutions in pre-S/S proteins from 6/7 (86%) OBI strains. Critical mutations in core regulatory elements and core proteins might affect OBI genotype B and C strain replication. That there were few S protein substitutions suggests a minor role of the host immune defenses in OBI occurrence.
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19
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Recent advances in the research of hepatitis B virus-related hepatocellular carcinoma: epidemiologic and molecular biological aspects. Adv Cancer Res 2011; 108:21-72. [PMID: 21034965 DOI: 10.1016/b978-0-12-380888-2.00002-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, and more than half of HCC patients are attributable to persistent hepatitis B virus (HBV) infections. The best and cheapest way to prevent HBV-related HCC is the implementation of universal hepatitis B vaccination program, by which the incidence rates of childhood HCC have been reduced in several countries, including Taiwan. However, there are still hundreds of millions of HBV carriers in the world that remain a global health challenge. In the past decade, several hepatitis B viral factors such as serum HBV DNA level, genotype, and naturally occurring mutants have already been identified to influence liver disease progression and HCC development in HBV carriers. Several easy-to-use scoring systems based on clinical and viral characteristics are developed to predict HCC risk in HBV carriers and may facilitate the communication between practicing physicians and patients in clinical practice. In addition, the role of nonviral factors in HBV-related HCC has also been increasingly recognized. On the basis of these emerging data, it is recommended that HBV carriers should be screened and monitored to identify those who have a higher risk of liver disease progression and require antiviral treatments. Regarding the molecular carcinogenesis of HCC development, despite some progress in the research of cell biology of HCC in the past decade, aberrant pathways involved in maintaining HCC phenotypes have not been completely elucidated yet. In the future, through comprehensive and integrated approaches to analyze the genomes of human HCC, novel target genes or pathways critically involved in hepatocarcinogenesis may hopefully be identified.
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20
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Ni YH. Natural history of hepatitis B virus infection: pediatric perspective. J Gastroenterol 2011; 46:1-8. [PMID: 20812021 DOI: 10.1007/s00535-010-0304-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 07/30/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection is an important disease globally. Chronic HBV infection may result in serious complications. Its transmission may be either perinatal or horizontal. Perinatal transmission is particularly important after the implementation of a universal vaccination program. Through either route, chronic carrier status is usually established in early childhood. The course of the disease course is determined by the host-virus interaction. The host's immune system initially tolerates the virus, and then gradually attempts to clear it. The virus, on the other hand, tries to avoid host immune system attack by a strategy involving targeted epitope mutations. By generating mutants, the virus can survive attacks from the host's immune system, enabling the infection to persist. Different individuals have different responses to HBV infection; genetic polymorphisms in cytokines, hormones, and other immune modulators may affect the final outcome of chronic HBV infection. Due to the implementation of a universal infant HBV vaccination program, HBV infection is now under control. Unfortunately, there still are some cases of vaccination failure. Very high maternal viremia, in utero infection, or escape mutants are possible reasons for vaccination failure. Immunocompromised hosts also risk vaccination failure. Blood or organ donors with occult HBV infection are possible sources for immunocompromised hosts. These victims of vaccination failure may exhibit a different disease course due to chronic HBV infection from those who acquired the infection before the universal vaccination era. The achievement of our ultimate goal of HBV elimination depends on a globally effective universal vaccination program, as well as the application of some novel successful medications to control those who are already infected.
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Affiliation(s)
- Yen-Hsuan Ni
- Department of Pediatrics, College of Medicine and Children's Hospital, National Taiwan University, 8 Chung-Shan South Road, Taipei, Taiwan.
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Abstract
Outcomes of chronic hepatitis B virus (HBV) infection are heterogeneous. Estimates of annual incidence of cirrhosis and hepatocellular carcinoma (HCC) are 2-10% and 1-3%, respectively. Several viral factors, including HBV genotype, viral load and specific viral mutations, have been associated with disease progression. Among these, HBV genotype is not only predictive of clinical outcomes but has also been associated with response to interferon treatment. Currently, at least 10 HBV genotypes and several subtypes have been identified; they have distinct geographic distribution. Acute infection with genotypes A and D results in higher rates of chronicity than genotypes B and C. Compared to genotype A and B cases, patients with genotypes C and D have lower rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion; when this occurs, it tends to be delayed. HBV genotype C has a higher frequency of basal core promoter (BCP) A1762T/G1764A mutation, pre-S deletion and is associated with higher viral load than genotype B. Similarly, genotype D has a higher prevalence of BCP A1762T/G1764A mutation than genotype A. These observations suggest important pathogenic differences between HBV genotypes. These may contribute to more severe liver disease, including cirrhosis and HCC with genotypes C and D HBV infection. In addition, genotype A and B patients have better responses to interferon-based therapy than genotypes C and D, but there are few consistent differences for direct HBV antivirals. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Taiwan
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Core antigen expression is associated with hepatic necroinflammation in e antigen-negative chronic hepatitis B patients with low DNA loads. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2010; 17:1048-53. [PMID: 20427626 DOI: 10.1128/cvi.00460-09] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Intrahepatic hepatitis B virus (HBV) core antigen (HBcAg) is a hallmark of viral replication in hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B (CHB). The aim of this study was to evaluate the role of HBcAg in HBeAg-negative CHB. One hundred six HBeAg-negative CHB patients who underwent ultrasonographically guided liver biopsy were reviewed for their HBV DNA load and clinical and histological data. Factors associated with the expression of intrahepatic HBcAg were analyzed. Among the patients, 35 (33%) were positive for HBcAg by immunohistostaining. In patients whose HBV DNA loads were higher than 10(7) copies (cp)/ml, nearly one-half (52%) had detectable HBcAg. Compared with HBcAg-negative patients, HBcAg-positive patients had higher serum alanine transaminase (ALT) and HBV DNA levels and more-severe hepatic necroinflammation. High serum ALT level (>160 U/liter) and HBV viral load were the determinants of HBcAg expression in multivariate analysis. Large amounts of HBcAg expression were frequently detected in patients with high DNA loads, and the patterns of HBcAg distribution were not related to histological activity or HBV DNA levels. In patients with lower HBV DNA loads, the expression of HBcAg was the key factor associated with active hepatic necroinflammation (hazard ratio = 11.25; 95% confidence interval [CI], 1.42 to 89.26; P = 0.022). In conclusion, the expression of HBcAg is not frequent in HBeAg-negative CHB. The expression of intrahepatic HBcAg indicates active hepatic necroinflammation, even in patients with low HBV DNA load. Both HBV viral load and HBcAg expression have implications in the pathogenesis of HBeAg-negative CHB.
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Abstract
Hepatitis B virus (HBV) causes important human health problems. It has infected one-third of the world's population and approximately 360 million people are chronic carriers. Worldwide, 0.5-1.2 million deaths are attributed to HBV infection annually. Therefore, global control of HBV infection is important. HBV infection can be intervened by interrupting routes of transmission, treating the chronically infected, and preventing the susceptibles with immunoprophylaxis. All these measures are effective. Nevertheless, although pegylated interferons or nucleos(t)ide analogs are effective for the treatment of chronic hepatitis B, chronic carriage of HBV is not easy to eliminate, as revealed by the frequent persistence of hepatitis B surface antigen, despite satisfactory responses to these treatments. On the other hand, hepatitis B vaccination has been shown to preclude HBV infection effectively. This is particularly true for pre-exposure prophylaxis. Worthy of note is the universal vaccination of newborn infants. This is the most effective means of preventing HBV infection, especially for those born to HBV carrier mothers. To eliminate and eradicate hepatitis B, first, HBV in the chronically infected should be eradicated or strongly and efficiently suppressed, so that the infection does not spread rampantly. Second, all the transmission routes should be interrupted. Lastly, but most effectively, is to immunize all susceptibles. The difficulties and possible solutions of each approach are discussed. In conclusion, the existing means to prevent and treat HBV infection render our goal toward eliminating and eradicating hepatitis B possible, although it will take much time and effort to achieve this objective.
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Affiliation(s)
- Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Inoue J, Ueno Y, Nagasaki F, Wakui Y, Kondo Y, Fukushima K, Niitsuma H, Shimosegawa T. Enhanced intracellular retention of a hepatitis B virus strain associated with fulminant hepatitis. Virology 2009; 395:202-9. [PMID: 19850315 DOI: 10.1016/j.virol.2009.09.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2009] [Revised: 06/22/2009] [Accepted: 09/23/2009] [Indexed: 12/17/2022]
Abstract
A plasmid carrying 1.3-fold HBV genome was constructed from a HBV strain that caused five consecutive cases of fulminant hepatitis (pBFH2), and HepG2 cells were transfected with pBFH2 or its variants. The pBFH2 construct with A1762T/G1764A, G1862T, and G1896A showed the largest amount of core particle-associated intracellular HBV DNA, but no significant increase of extracellular HBV DNA in comparison with the wild construct, suggesting that these mutations might work together for retention of the replicative intermediates in the cells. The retention might relate to the localization of hepatitis B core antigen (HBcAg) in the nucleus of HepG2, which was observed by confocal fluorescence microscopy. HBcAg immunohistochemical examination of liver tissue samples obtained from the consecutive fulminant hepatitis patients showed stronger staining in the nucleus than acute hepatitis patients. In conclusion, the fulminant HBV strain caused retention of the core particles and the core particle-associated HBV DNA in the cells.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai 980-8574, Japan.
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