Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus X protein (HBX) was studied for its capacity to form a specific complex with the retinoblastoma tumour suppressor protein (pRB), and for its effect on the expression of pRB. HBX was synthesized by in vitro transcription and translation in the presence of [35S]methionine. The synthesized HBX was assayed for its binding to a glutathione-S-transferase (GST)-pRB fusion protein bound to Sepharose beads. The in vivo binding was investigated by a co-immunoprecipitation and Western blot analysis of the cell extract from a CMV-HBX-transfected hepatoblastoma cell line, Hep G2 cells. These experiments demonstrated that HBX was unable to form a detectable complex with pRB. However, the level of pRB increased considerably in Hep G2 cells transfected with CMV-HBX clone. The alteration of pRB expression by HBX could be a mechanism, contributing to the development of hepatocellular carcinoma (HCC) in human.
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PMID:Effect of hepatitis B virus X protein on the expression of retinoblastoma gene product. 938 99

Hepatitis B virus (HBV) variant strains may develop during therapy for chronic infection with the nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC). HBV mutants result from isoleucine (I) or valine (V) substitutions in the methionine (M) of the YMDD motif in the viral reverse-transcriptase catalytic domain. In addition, other mutations in the reverse-transcriptase "B domain" involving either a phenylalanine (F)-to-leucine (L) at amino acid 501 (F501L) or an L-to-M substitution at amino acid 515 (L515M) have been observed during 3TC and Famciclovir therapy as well. To determine the biologic consequences of these mutations on viral replication, variant viral genomes were constructed and transiently transfected into hepatocellular carcinoma (HCC) and HEK 293 human embryo kidney-derived cell lines. In transiently transfected HCC cells, the viruses bearing the YI/VDD or F501L mutations had greatly impaired replication as compared to wild-type virus, whereas the virus carrying the L515M substitution showed the least defect. Double mutants with the L515M substitution showed intermediate defect between the YI/VDD or F501L and the L515M single-mutant strains. In contrast, when transfected into HEK 293 cells, the viruses bearing the YI/VDD or L515M mutation replicated as wild-type. However, under conditions of deoxynucleotide depletion produced by hydroxyurea treatment of HEK 293 cells, all mutants but not the wild-type virus exhibited a reduced replication phenotype similar to that observed in HCC cells. In both HCC and HEK 293 cells, the mutant viruses carrying the F501L substitution showed a decreased pregenomic RNA encapsidation level, suggesting that the defect in HBV DNA synthesis occurs at the RNA packaging level. These findings show that 3TC and Famciclovir selected mutations alter the properties of the HBV reverse transcriptase, resulting in impaired viral replication within the cell.
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PMID:Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. 946 67

Four potential serine/threonine phosphorylation sites [(S/T)-P motif], designated P1-P4, on the pre-S protein of duck hepatitis B virus (DHBV) have been mutated. Mutants include single (P2, P3, P4) and double amino acid substitutions (P1 + P2, P3 + P4) and one with all four sites mutated (4P). Serine at position 118 (P3) was identified as the major site of phosphorylation by Western blotting and radioimmunoprecipitation after in vitro cell labeling with [35S]methionine or [33P]orthophosphate. Mutant virions generated by transfection of LMH cells were infectious both in vitro in duck hepatocyte primary cultures and in vivo in Pekin ducks. Intracellular relaxed circular (RC) and covalently closed circular (ccc) DNA syntheses were not affected by the P3 mutation or even the quadruple mutant. Extracellular virus production was slightly increased when the P3 site was mutated. CsCl gradient centrifugation showed no clear difference between mutant and wild-type virus with respect to the ratios of enveloped virus and nucleocapsid particles in hepatocyte culture supernatants. Trypsin or V8 protease digestion with or without NP-40 indicated that phosphorylation of the pre-S domain is not involved in determining the transmembrane topology of DHBV large protein. This phenotypic analysis indicates that DHBV pre-S phosphorylation has no apparent effect on DHBV replication and formation of mature viral particles in duck hepatocyte primary culture and does not affect infectivity in ducklings.
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PMID:Phosphorylation of DHBV pre-S: identification of the major site of phosphorylation and effects of mutations on the virus life cycle. 950 Oct 48

Lamivudine has been shown to be a potent and nontoxic inhibitor of hepatitis B virus (HBV) replication in chronically infected patients. During prolonged treatment, drug resistance may develop, related to a mutation of Met to Val or Ile in the YM552DD motif of the HBV DNA polymerase gene. Analysis of the HBV DNA polymerase gene from 8 chronic hepatitis B patients with suspected resistance to lamivudine showed that in addition to a mutation in the YM552DD motif, a second mutation located in the B domain of this gene, a Leu528-to-Met528 change, was consistently and exclusively found in 4 patients showing the YV552DD motif. This suggests a functional or structural relationship between these domains. Since the presence of both the YI552DD and YV552DD motif sometimes preceded the exclusive presence of the YV552DD motif, we conclude that the YI552DD motif could occur as a temporal intermediate. After cessation of therapy, the wild type sequences reemerged.
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PMID:Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine treatment. 959 29

L(-)SddC (3TC) has been shown to be the most promising nucleoside analogue used for the treatment of hepatitis B virus (HBV) infection. Unfortunately, it has been reported that about 12% of HBV-infected patients experience a recurrence of HBV after a period of treatment with 3TC. Point mutations were detected in the HBV polymerase of those viruses from 3TC-resistant patients. A common mutation occurred at methionine in the YMDD motif. In this report, we present mutants that were generated from the HBV genome (adr subtype) by site-directed mutagenesis based on clinical reports from other investigators. With the transient transfection system, it was found that by changing methionine to valine or isoleucine at the YMDD motif, the viral DNA replication would be more than 100-fold less efficient than that of the wild-type virus. Some additional mutations outside the YMDD motif could enhance the replication of the virus containing a YMDD mutation. Various levels of resistance to 3TC were observed in HBV mutants containing point mutations both inside and outside the YMDD motif. These results suggest that the mutations outside the YMDD motif compensate the YMDD mutation to some extent for the viral replication and may also contribute to clinical viral resistance to 3TC.
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PMID:Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance. 963 92

Mutations in the "a" determinant of the surface gene have been associated with failure of hepatitis B immunoglobulin (HBIg) prophylaxis. We compared sequences from the surface and polymerase regions of hepatitis B virus (HBV) from 4 patients who failed high-dose HBIg therapy with two control groups: HBIg-treated patients who remained hepatitis B surface antigen (HBsAg)-negative (n = 4) and HBV-infected transplant recipients who never received HBIg (n = 4). Mutations within the surface and overlapping polymerase region were more common in patients failing HBIg than controls (P = .03), and mutations in the region of the "a" determinant were present only in patients failing HBIg. To examine the relationship between HBIg failure and duration of therapy, five additional treatment failures from a second transplantation center were sequenced (total with HBIg failure = 9). Mutations in the "a" determinant developed in 1 of 3 patients receiving HBIg for less than 6 months compared with 5 of 6 patients failing HBIg after 6 months of therapy (P = .23). The most frequently identified amino acid substitution was glycine to arginine at position 145 (present in 4 of 6 patients who failed HBIg after at least 6 months of treatment). A unique mutation within the YMDD motif (methionine to leucine) was present in 1 patient who failed HBIg treatment and who received a short course of ganciclovir. We conclude that the emergence of mutations in the "a" determinant accounts for some, but not all, treatment failures in patients receiving HBIg prophylaxis. Mutations in other regions of the S gene were more common in patients failing HBIg than controls, suggesting that domains other than the "a" determinant may be important.
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PMID:Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. 969 24

A variant of hepatitis B virus (HBV) containing a Met-to-Val substitution (M539V) in the YMDD motif of the polymerase nucleoside-binding domain exhibited resistance to the cytosine analogue lamivudine (3TC). To determine if the mutation responsible for the M539V polymerase variant affected the sensitivity of the virus to other nucleoside analogues, we constructed a tetracycline-responsive cell line, HepAD79. This cell line is stably transfected with a cDNA copy of the pregenomic RNA of an HBV genome containing an A-to-G mutation in the first position of the polymerase gene codon 539. This mutation results in a Met-to-Val substitution at amino acid 539 of the polymerase. When grown under the proper conditions, HepAD79 cells produced HBV RNA, contained HBV DNA associated with immature core particles and released core-associated HBV DNA into the medium. The M539V polymerase variant produced in this cell line was approximately 26-fold less sensitive to the antiviral effects of 3TC than wild-type virus. In addition, this variant demonstrated decreased sensitivity to the cytosine analogues FTC and ddC, as well as the thymidine analogue AZT.
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PMID:The hepatitis B virus M539V polymerase variation responsible for 3TC resistance also confers cross-resistance to other nucleoside analogues. 987 78

A double mutation which converts nucleotide 1765 from A to T and nucleotide 1767 from G to A is frequently found in the hepatitis B virus (HBV) genome isolated from HBV patients with chronic hepatitis symptoms. This double mutation is located in the core promoter that controls the transcription of the precore RNA and the core RNA. In addition, this double mutation also resides in the X protein coding sequence, converting codon 130 from Lys to Met and codon 131 from Val to Ile. Previous studies indicate that this double mutation removes a nuclear receptor binding site in the core promoter, suppresses specifically precore RNA transcription, and enhances viral replication. In this study, we further investigated how this double mutation suppresses precore RNA transcription. We found that this double mutation not only removed the nuclear receptor binding site but also created an HNF1 transcription factor binding site. Further transfection studies using Huh7 hepatoma cells indicate that the removal of the nuclear receptor binding site has no effect on the transcription of HBV RNAs, the two-codon change in the X protein sequence suppresses the transcription of both precore and core RNAs, and the creation of the HNF1 binding site restores the core RNA level. Hence, the specific suppression of precore RNA transcription by this frequent double-nucleotide mutation is the combined result of multiple factors.
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PMID:Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. 988 27

The MET protooncogene encodes a transmembrane tyrosine kinase identified as the receptor of a polypeptide known as hepatocyte growth factor/scatter factor. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the tyrosine kinase domain of the MET gene (exon 15-19) in 75 primary liver cancers. Three missense mutations were detected exclusively in 10 childhood hepatocellular carcinomas (HCCs), while no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. The extremely short incubation period from hepatitis B virus infection to the genesis of childhood HCC as compared with the adult HCC suggests that there may be an additional mechanism that accelerates the carcinogenesis of childhood HCC. Our results indicate that mutations of the tyrosine kinase domain of the MET gene may be involved in the acceleration of the carcinogenesis in childhood HCC.
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PMID:Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. 992 37

This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P <.001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (>/=2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B.
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PMID:Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. 1005 94


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