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Hepatitis B virus genotypes and precore and core mutants in Brazilian patients.

ABSTRACT: A method for genotyping hepatitis B virus by partial HBsAg gene sequencing with primers common to all known genotypes was developed. Mutations related to anti-HBs resistance are also detected with this method. Samples from 103 Brazilian patients were analyzed. Precore and core region of these viruses were also sequenced in 101 patients. Genotypes A, B, C, D, and F were found with frequencies of 49.5, 2.9, 13.6, 24.3, and 9.7%, respectively. Genotypes B and C were found only in Asian patients, whereas genotypes A, D, and F were more common in patients without an Asian background. Precore mutants were found in 32 (31.7%) of 101 patients, with a higher frequency in those infected with genotype D (22 of 25 [88.0%]). Analysis of nucleotide 1858 showed presence of thymine in all patients with genotypes B, C, and D and in a few patients with genotypes A (10.0%) and F (30.0%), who showed more frequently the presence of cytosine. This nucleotide was closely related to the presence of precore mutants. Mutations in the basal core promoter were found in 64 of 101 (63.4%) samples. These mutations were more frequent in patients infected with genotype F (90.0%) and less frequent in patients infected with genotype B (33.3%). Deletions in this region were found in two genotype C-infected patients.

SUBMITTER: Sitnik R

PROVIDER: S-EPMC427827 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

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Hepatitis B virus genotypes and precore and core mutants in Brazilian patients.

Sitnik Roberta R Pinho João Renato Rebello JR Bertolini Dennis Armando DA Bernardini Antonio Plinio AP Da Silva Luiz Caetano LC Carrilho Flair José FJ

Journal of clinical microbiology 20040601 6

A method for genotyping hepatitis B virus by partial HBsAg gene sequencing with primers common to all known genotypes was developed. Mutations related to anti-HBs resistance are also detected with this method. Samples from 103 Brazilian patients were analyzed. Precore and core region of these viruses were also sequenced in 101 patients. Genotypes A, B, C, D, and F were found with frequencies of 49.5, 2.9, 13.6, 24.3, and 9.7%, respectively. Genotypes B and C were found only in Asian patients, wh ...[more]

PMID: 15184419

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Project description:BackgroundKnowledge of the HBV genotype with which a patient is infected is crucial information for a physician to have when planning clinical treatment for that patient. Previous studies have suggested that there are possible differences in the pathogenicity and therapeutic response of different HBV genotypes. However, the prevalence of the various HBV genotypes and Precore and Core mutations is unknown in the UAE. Therefore, we sought to determine the prevalence of the different HBV genotypes in the UAE population.Methodology/principal findingsA total of 88 HBsAg-positive patients were included in the study. A method for genotyping and subtyping HBV by partial HBsAg gene sequencing using primers that are complementary to all known genotypes was used. Precore and core region of these viruses were also sequenced in 88 patients.HBV genotype D was the most prevalent (79.5%) genotype identified in our study population, followed by genotypes A (18.2%) and C (2.3%). The following subtypes were isolated: ayw2 (80.7%), adw2 (14.8%), and adw (2.3%). The HBV-DNA viral load was higher in HBeAg-positive patients than it was in patients who were HBeAg-negative. Precore mutants were found in 51 (58.0%) of 88 patients. Mutations in the basal core promotor were found in 22 (25.3%) of 88 patients.Conclusion/significanceHBV infection is a major health problem in the UAE, and while genotypes B and C are the most prevalent HBV genotypes in the Asian population, our study reveals that genotype D is the predominant genotype that is present in the UAE. More patients were HBeAg-negative than were HBeAg-positive in our study sample, which could be due to the duration of infection of the included patients. Additionally, the viral loads of the HBeAg-positive patients were higher those of the HBeAg-negative patients. Analysis of nucleotide 1858 showed presence of thymine in all patients with genotypes C, and D and in a few patients with genotypes A. This nucleotide was closely related to the presence of precore mutants. Mutations in the basal core promoter were found in 22 of 88 (25.3%) samples. These mutations were more frequent in patients infected with genotype A (37.5%) and not found in patients infected with genotype C.

Project description:Hepatitis B virus (HBV) is one of the most common DNA viruses that can cause aggressive hepatitis, cirrhosis and hepatocellular carcinoma. Although many people are persistently infected with HBV, the kinetics in serum levels of viral loads and the host immune responses vary from person to person. HBV precore/core open reading frame (ORF) encoding proteins, hepatitis B e antigen (HBeAg) and core antigen (HBcAg), are two indicators of active viral replication. The aim of this study was to discover a variety of amino acid covariances in responses to viral kinetics, seroconversion and genotypes during the course of HBV infection. A one year follow-up study was conducted with a total number of 1,694 clones from 23 HBeAg-positive chronic hepatitis B patients. Serum alanine aminotransferase, HBV DNA and HBeAg levels were measured monthly as criteria for clustering patients into several different subgroups. Monthly derived multiple precore/core ORFs were directly sequenced and translated into amino acid sequences. For each subgroup, time-dependent covariances were identified from their time-varying sequences over the entire follow-up period. The fluctuating, wavering, HBeAg-nonseroconversion and genotype C subgroups showed greater degrees of covariances than the stationary, declining, HBeAg-seroconversion and genotype B. Referring to literature, mutation hotspots within our identified covariances were associated with the infection process. Remarkably, hotspots were predominant in genotype C. Moreover, covariances were also identified at early stage (spanning from baseline to a peak of serum HBV DNA) in order to determine the intersections with aforementioned time-dependent covariances. Preserved covariances, namely representative covariances, of each subgroup are visually presented using a tree-based structure. Our results suggested that identified covariances were strongly associated with viral kinetics, seroconversion and genotypes. Moreover, representative covariances may benefit clinicians to prescribe a suitable treatment for patients even if they have no obvious symptoms at the early stage of HBV infection.

Project description:Current therapies rarely cure chronic hepatitis B virus (HBV) infection due to the persistence of the viral episome, the covalently closed circular DNA (cccDNA), in hepatocytes. The hepatitis B virus core-related antigen (HBcrAg), a mixture of the viral precore/core gene products, has emerged as one potential marker to monitor the levels and activities of intrahepatic cccDNA. In this study, a comprehensive characterization of precore/core gene products revealed that HBcrAg components included the classical hepatitis B virus core antigen (HBc) and e antigen (HBeAg) and, additionally, the precore-related antigen, PreC, retaining the N-terminal signal peptide. Both HBeAg and PreC antigens displayed heterogeneous proteolytic processing at their C termini resulting in multiple species, which varied with viral genotypes. HBeAg was the predominant form of HBcrAg in HBeAg-positive patients. Positive correlations were found between HBcrAg and PreC, between HBcrAg and HBeAg, and between PreC and HBeAg but not between HBcrAg and HBc. Serum HBeAg and PreC shared similar buoyant density and size distributions, and both displayed density and size heterogeneity. HBc, but not HBeAg or PreC antigen, was found as the main component of capsids in DNA-containing or empty virions. Neither HBeAg nor PreC protein was able to form capsids in cells or in vitro under physiological conditions. In conclusion, our study provides important new quantitative information on levels of each component of precore/core gene products as well as their biochemical and biophysical characteristics, implying that each component may have distinct functions and applications in reflecting intrahepatic viral activities.IMPORTANCE Chronic hepatitis B virus (HBV) infection afflicts approximately 257 million people, who are at high risk of progressing to chronic liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. Current therapies rarely achieve cure of HBV infection due to the persistence of the HBV episome, the covalently closed circular DNA (cccDNA), in the nuclei of infected hepatocytes. Peripheral markers of cccDNA levels and transcriptional activities are urgently required to guide antiviral therapy and drug development. Serum hepatitis B core-related antigen (HBcrAg) is one such emerging peripheral marker. We have characterized the components of HBcrAg in HBV-infected patients as well as in cell cultures. Our results provide important new quantitative information on levels of each HBcrAg component, as well as their biochemical and biophysical characteristics. Our findings suggest that each HBcrAg component may have distinct functions and applications in reflecting intrahepatic viral activities.

Dataset Information

Hepatitis B virus genotypes and precore and core mutants in Brazilian patients.

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Hepatitis B virus genotypes and precore and core mutants in Brazilian patients.

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