The crystal structure of the human hepatitis B virus capsid.
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Hepatitis B is a small enveloped DNA virus that poses a major hazard to human health. The crystal structure of the T = 4 capsid has been solved at 3.3 A resolution, revealing a largely helical protein fold that is unusual for icosahedral viruses. The monomer fold is stabilized by a hydrophobic core that is highly conserved among human viral variants. Association of two amphipathic alpha-helical hairpins results in formation of a dimer with a four-helix bundle as the major central feature. The capsid is assembled from dimers via interactions involving a highly conserved region near the C terminus of the truncated protein used for crystallization. The major immunodominant region lies at the tips of the alpha-helical hairpins that form spikes on the capsid surface. (+info)
c-Myb protein binds to the EP element of the HBV enhancer and regulates transcription in synergy with NF-M.
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The hepatitis B virus (HBV) enhancer contains multiple active elements, one of which is the EP element, a 15 bp site important for its regulation by acting on other functional elements like the E site. The EP element, in the HBV enhancer context, contains two putative binding sites for c-myb family gene products. Electrophoretic mobility shift assays showed that the minimal c-Myb DNA-binding domain binds to the EP sequence. DNase I footprinting experiments revealed that only one consensus binding site was effectively protected. We found that c-Myb down-regulates transcription driving by the HBV enhancer in CAT assays performed in a haematopoietic (K562) and in a hepatic (HepG2) cell line. Interestingly, co-expression of both c-Myb and NF-M, a C/EBPbeta homologue which recognises the E element of the HBV enhancer, showed a synergistic transactivation of the HBV enhancer while, separately, each of them had an inhibitory effect on transcription in HepG2 and K562 cell lines, two cell types potentially infected by the hepatitis B virus. (+info)
Effect of schistosomiasis and hepatitis on liver disease.
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Infection with hepatitis C virus (HCV) has become the most important public health problem in Egypt. In Egypt, viral hepatitis along with infection with Schistosoma mansoni is the major cause of chronic liver disease and liver cirrhosis. Although HCV infection is highly prevalent in Egypt, very little information is available on the distribution of the different genotypes of HCV. Our aims in this study were first to determine the prevalence of viral and parasite infections in patients with chronic liver disease and then to assess the distribution of HCV genotypes in these patients. In the present study, 151 individuals (50 with chronic liver disease, 51 with chronic diseases of organs other than the liver, and 50 apparently healthy persons) were investigated. The last 2 groups served as control groups. These individuals were subjected to routine liver function tests and detection of serum antibodies to bilharziasis, hepatitis B surface antigen (HBsAg), and HCV. Furthermore, the presence of hepatitis G virus (HGV) and HCV in the serum samples were tested for by a reverse transcription polymerase chain reaction (RT-PCR). Prevalence of different genotypes of HCV in patients positive for HCV were determined by RT-PCR using type-specific primers. Results of the study revealed that 84, 74, 12, and 20% of patients with chronic liver disease were positive for Schistosoma mansoni, HCV, HBsAg, and HGV, respectively, as compared to 51, 43.1, 2, and 4% of patients with other chronic diseases and 22, 6, 0, and 0% of apparently healthy individuals. One hundred percent of patients with chronic liver disease, 72.5% of those with other diseases, and 26% of normal controls were shown to have at least one of the studied infectious agents. Two or more of the agents were highly coincident in patients with chronic liver disease. In Egypt, HCV genotype 4a is highly prevalent, where it contributed 85% of the tested samples in comparison to 10, 2.5, and 2.5% for subtypes 1b, 2a, and 3a, respectively. In conclusion, these results suggest that in Egypt, HCV along with schistosomal parasite infection is the major risk factor for chronic liver disease. In most Egyptian patients, HCV genotype 4 is highly prevalent. (+info)
High prevalence of anti-hepatitis B virus serological markers in patients with hepatitis C virus related chronic liver disease in Japan.
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BACKGROUND/AIMS: Evidence is accumulating that hepatitis B virus (HBV) is present in patients who are hepatitis B surface antigen negative but have antibody to hepatitis B core antigen (anti-HBc). Furthermore, recent studies have shown that patients with hepatocellular carcinoma who have antibody to hepatitis C virus (HCV) often possess HBV related serological markers. Data on the seroprevalence of HBV infection in patients with HCV related chronic liver disease were collected to evaluate the significance of the presence of antibodies to HBV. METHODS: The prevalence of HBV related serological markers was analysed in a total of 2014 Japanese patients with HCV infection. The control group comprised 352 subjects without liver disorder. RESULTS: A large number of patients (49.9%) with HCV related chronic liver disease including hepatocellular carcinoma were positive for anti-HBc. In addition, the prevalence of anti-HBc closely correlated with the clinical stage of the liver disease. There was no relation between a past history of blood transfusion and the prevalence of anti-HBc. Notably, anti-HBc was the only serological marker for HBV infection in a significant number of patients with HCV related chronic liver disease (24.1%). CONCLUSIONS: Our data provide further evidence for the high prevalence of anti-HBc in patients with HCV related chronic liver disease, particularly those with hepatocellular carcinoma, suggesting that HBV infection, probably including latent infection, may play an important role in carcinogenesis in these patients. (+info)
Selection of hepatitis B surface "escape" mutants during passive immune prophylaxis following liver transplantation: potential impact of genetic changes on polymerase protein function.
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CASE REPORT: A patient is described who developed hepatitis B virus (HBV) reinfection five months following liver transplantation. Failure of hepatitis B immunoglobulin prophylaxis was associated with the emergence of mutations. HBV gene sequencing identified nucleotide substitutions associated with amino acid changes, one within the major hydrophilic region (MHR) of the HBV surface antigen at amino acid position 144 and one outside the MHR. Because of the overlapping reading frames of surface and polymerase genes, the latter surface antigen change was associated with an amino acid change in the polymerase protein. The patient developed significant allograft hepatitis and was treated with lamivudine (3TC) 100 mg daily. Rapid decline of serum HBV DNA was observed with loss of HBV e antigen and HBV surface antigen from serum. There was normalisation of liver biochemistry, and liver immunohistochemistry showed a reduction in HBV core and disappearance of HBs antigen staining. CONCLUSION: Surface antigen encoding gene mutations associated with HBIg escape may be associated with alteration of the polymerase protein. The polymerase changes may affect sensitivity to antiviral treatment. Selection pressure on one HBV reading frame (for example, HBIg pressure on HBsAg, or nucleoside analogue pressure on polymerase protein) may alter the gene product of the overlapping frame. Such interactions are relevant to strategies employing passive immune prophylaxis and antiviral treatment. (+info)
Human hepatitis B virus mutants: significance of molecular changes.
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Human hepatitis B virus, the leading pathogen for hepatitis B, is a compact DNA virus with viral genes that largely overlap. An increasing number of mutations have emerged following human interventions such as vaccination and anti-viral therapy. While vaccine escape mutants are characterized by mutations on the antigenic hepatitis B surface antigen, those carrying mutations in other viral proteins are either resistant to anti-viral therapy or implicated in acute liver diseases. Molecular identification of these various mutants should shed new lights on the underlying mechanism of hepatitis B virus viral escape and resistance and provide helpful information on their effective eradication. (+info)
Comparison of the second-generation digene hybrid capture assay with the branched-DNA assay for measurement of hepatitis B virus DNA in serum.
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The optimal hepatitis B virus (HBV) DNA quantitative assay for clinical use remains to be determined. We examined the sensitivity, linearity, and variability of a novel second-generation antibody capture solution hybridization assay, the Digene Hybrid Capture II assay (HCII), and compared it with another widely used solution hybridization assay, the branched-DNA (bDNA) assay (Quantiplex; Chiron Corp.). Our results showed similar and satisfactory assay linearity values, as well as interassay and intra-assay variability values, for both HCII and bDNA assays across different ranges of HBV DNA. Ninety-one percent of 102 serum samples from hepatitis B surface antigen-positive patients showed concordant results with the two assays. The HCII assay was more sensitive than the bDNA assay by 1 dilution, with the lowest reading being 0.9 pg/ml (3.8 pg/ml by bDNA assay). The HBV DNA seropositivity rates for the 102 samples were 58, 67, and 97% by bDNA, HCII, and nested PCR, respectively. While the relationship between results obtained with the bDNA assay and those with the HCII assay was nonlinear, with the bDNA assay yielding values 2.83 +/- 0.92-fold higher than those of the HCII assay, especially at high HBV DNA levels, a linear relationship was observed between the two sets of data after logarithmic conversion. The formula for interassay conversion of results was derived as follows: HBV DNA by HCII (picograms per milliliter) = 3.19 x [HBV DNA by bDNA (megaequivalents per milliliter)](0.866). The HCII assay was technically less complex and required a shorter assay time (4 h) than the bDNA assay (24 h). We conclude that the HCII assay compares favorably with the bDNA assay and offers the additional advantages of increased sensitivity and shorter assay time. The increased sensitivity should be particularly useful in monitoring the efficacy of antiviral therapies and detecting the emergence of drug-resistant HBV mutants. (+info)
Improved detection of hepatitis B virus surface antigen by a new rapid automated assay.
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The performance of hepatitis B virus (HBV) surface antigen (HBsAg) screening assays is continuously improved in order to reduce the residual risk of transfusion-associated hepatitis B. In a multicenter study, a new automated rapid screening assay, Elecsys HBsAg (Roche Diagnostics), was compared to well-established tests (Auszyme Monoclonal [overnight incubation] version B and IMx HBsAg [Abbott]). Included in the evaluation were 23 seroconversion panels; sera from the acute and chronic phases of infection; dilution series of various HBsAg standards, HBV subtypes, and S gene mutants; and isolated anti-HBV core antigen-positive samples. To challenge the specificity of the new assay, sera from HBsAg-negative blood donors, pregnant women, and dialysis and hospitalized patients and potentially cross-reactive samples were investigated. Elecsys HBsAg showed a higher sensitivity for HBsAg subtypes ad, ay, adw2, adw4, ayw1, ayw2, ayw4, and adr detection in dilution series of different standards or sera than Auszyme Monoclonal version B and/or IMx HBsAg. Acute hepatitis B was detected in 11 to 16 of 23 seroconversion panels between 2 and 16 days earlier with Elecsys HBsAg than with the alternative assays. Elecsys HBsAg and Auszyme Monoclonal version B detected HBsAg surface mutants with equal sensitivity. The sensitivity and specificity of Elecsys HBsAg were 100%. Auszyme Monoclonal version B had a 99.9% specificity, and its sensitivity was 96.6%. IMx HBsAg showed a poorer sensitivity and specificity than the other assays. In conclusion, Elecsys HBsAg permits earlier detection of acute hepatitis B and different HBV subtypes than the alternative assays. By using highly sensitive HBsAg screening assays, low-level HBsAg carriers among isolated anti-HBV core antigen-positive individuals can be detected. (+info)