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)

To investigate the clinical significance of mutation in hepatitis B virus (HBV) surface gene, DNA sequence analysis of the "a" determinant was performed on sera from 27 carrier children with immunoprophylaxis, their mothers, and 21 carriers without vaccination. A precore mutant (G to A) at nucleotide 1896 was detected in sera from 11 carriers without vaccination. Mutations in the "a" determinant were detected in 6 (22%) of the vaccinated children. Four HBV strains showed a Gly-to-Arg mutation at the 145th codon of the surface gene. Amino acid substitutions at amino acid 133 and 144 were noted in the other 2 children. Only 1 mother had the same predominant strain of mutant virus as her child. These observations indicate that immune pressure exerted by immunoprophylaxis at birth may select for a mutant virus.
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PMID:Detection of hepatitis B surface gene mutation in carrier children with or without immunoprophylaxis at birth. 923 8

Serum hepatitis B virus (HBV) DNA from 4 infants with fulminant hepatitis B, 3 infants with acute self-limited hepatitis B, and 15 infants with chronic HBV infection were amplified by polymerase chain reaction followed by direct sequencing of the region of HBV genome encoding the major antigenic epitopes of hepatitis B surface antigen (HBsAg). All infants were born to carrier mothers and administered immunoprophylaxis from birth. Serum HBV DNA from 13 carrier children born to carrier mothers who did not receive immunoprophylaxis and had comparable length of infection were studied as controls. An S mutant (residue 126, Thr to Ala) initially found in an infant with fulminant hepatitis was replaced by another S mutant (residue 145, Gly to Arg) 4 days later. In a girl with chronic hepatitis B, Ala-126 variant and Arg-145 variant were found at 17 and 25 months of age, respectively. The Arg-145 variant persisted for 8 years in an asymptomatic male carrier and for 1 year in an infant with chronic hepatitis B. The Ala-126 variant persisted for 11 years in one child who had an early loss of hepatitis B e antigen. In the majority of the infants' mothers, corresponding mutations in HBsAg were not detected in serum by direct sequencing. The S mutants detected in three carrier infants were not found in their mothers' serum after cloning and sequencing of 10 DNA clones from each maternal sample. None of the 13 control patients had detectable S mutants. These results suggest that S variants emerge or are selected under the immune pressure generated by the host or by administration of hepatitis B immune globulin and hepatitis B vaccination. An S mutant (residue 129, Gln to Arg) found in one mother-infant pair suggested a direct maternal-infant transmission, resulting in immunoprophylaxis failure. None of the family members of children infected with Arg-145 variant had the same variant infection, implying this variant's low transmissability.
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PMID:Surface gene mutants of hepatitis B virus in infants who develop acute or chronic infections despite immunoprophylaxis. 930 14

The 'a' determinant of hepatitis B virus (HBV) surface antigen (HBsAg) is the most important target for diagnosis and immunoprophylaxis. Several HBV variants with point mutations within the 'a' determinant have been identified among fully vaccinated children in Taiwan. We investigated the effect of each of these mutations on the antigenic nature of the S protein by cloning and expression of the mutant S antigens in Pichia pastoris. Four variants, Ser-126, His-129, Arg-129 and Arg-145, all exhibited various degrees of altered binding of HBsAg to several monoclonal antibodies. Arg-145, a well-characterized immune escape mutant, and Arg-129 had the lowest binding capacities to all monoclonal antibodies as compared with other variants. Similar to Arg-145, the Arg-129 variant could be isolated from both vaccinated children and unvaccinated adults, thus representing a naturally occurring mutant with an altered 'a' determinant. Whether these 'a' determinant variants with altered antigenicity might gradually become major circulating strains, as a consequence of the immune pressure against the wild-type HBV created by vaccination, remains to be monitored.
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PMID:Altered antigenicity of 'a' determinant variants of hepatitis B virus. 934 86

Envelopment of the hepatitis B virus (HBV) nucleocapsid depends on the large envelope protein L, which is expressed as a transmembrane polypeptide at the endoplasmic reticulum membrane. Previous studies demonstrated that the cytosolic exposure of the N-terminal pre-S domain (174 amino acids) of L was required for virion formation. N-terminal truncations of L up to Arg 103 were tolerated. To map sites in the remaining C-terminal part of pre-S important for virion morphogenesis, a series of 11 L mutants with linker substitutions between Asn 98 and Pro 171 was generated. The mutants formed stable proteins and were secreted in transfected cell cultures, probably as components of subviral hepatitis B surface antigen particles. All four constructs with mutations between Asn 98 and Thr 125 were unable to complement in trans the block in virion formation of an L-negative HBV genome in cotransfected HuH7 cells. These mutants had a transdominant negative effect on virus yield in cotransfections with the wild-type HBV genome. In contrast, all seven mutants with substitutions downstream of Ser 124 were able to envelop the nucleocapsid and to secrete HBV. The sequence between Arg 103 and Ser 124 is highly conserved among different HBV isolates and also between HBV and the woodchuck hepatitis virus. Point mutations in this region introducing alanine residues at conserved positions blocked virion formation, in contrast to mutations at nonconserved residues. These results demonstrate that the pre-S sequence between Arg 103 and Ser 124 has an important function in HBV morphogenesis.
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PMID:A short linear sequence in the pre-S domain of the large hepatitis B virus envelope protein required for virion formation. 937 94

Duck gp180 was previously identified by its ability to bind to the preS envelope protein of duck hepatitis B virus particles (Kuroki, K. , Cheung, R., Marion, P. L., and Ganem, D. (1994) J. Virol. 68, 2091-2096). Cloning and sequencing of gp180 cDNA revealed that it is a polyprotein with three carboxypeptidase-like domains (Kuroki, K., Eng, F., Ishikawa, T., Turck, C., Harada, F., and Ganem, D. (1995) J. Biol. Chem. 270, 15022-15028). To evaluate enzymatic properties of this protein, a soluble 170-kDa form of the protein (gp170) lacking the C-terminal transmembrane domain and cytoplasmic tail was expressed in a baculovirus system. The purified 170-kDa protein cleaved 5-dimethylaminonaphthalene-1-sulfonyl (dansyl)-Phe-Ala-Arg with a pH optimum of 5.5-6.5. With this substrate at pH 5.5, the 170-kDa protein displayed a Km of 12 microM and a Kcat of 57 s-1. Dansyl-Pro-Ala-Arg and dansyl-Phe-Phe-Arg were cleaved with Km values of 17 and 21 microM, and Kcat values of 57 and 17 s-1, respectively. Constructs containing only the first or second carboxypeptidase domains also showed enzymatic activity. The effects of inhibitors and ions on enzyme activity of gp170 were generally similar to the effects of these compounds on purified bovine carboxypeptidase D. To evaluate the regions within gp180 necessary for binding preS, a series of deletion mutants were expressed in the 293T human kidney cell line. Deletions of the first and second domains, leaving the third domain intact, eliminated carboxypeptidase activity but retained preS binding. Deletion of the third domain eliminated preS binding but not carboxypeptidase activity. These results indicate that the third domain is responsible for preS binding, and this binding does not require carboxypeptidase activity.
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PMID:gp180, a protein that binds duck hepatitis B virus particles, has metallocarboxypeptidase D-like enzymatic activity. 952 48

Twenty-four infants who became positive to the surface antigen of hepatitis B virus (HBsAg) despite a complete course of active postexposure immunization with plasma derived hepatitis B vaccine were studied. The polymerase chain reaction amplified products of the common neutralizing epitope 'a' determinant of HBsAg (Nucleotide 419-598) from serum samples were sequenced and analyzed for nucleotide mutations. Four cases (16.7%) had mutations that led to amino acid substitutions between codons 124 and 147. Only one case (N1) showed a substitution at codon 145 (from glycine to arginine, 145R), the other three were at codons 126-129. The mother of N1 was co-infected with the wild type and the mutant virus. Five years later, serum of N1 showed only the wild type virus. There was no significant relationship between the mutation rate and the anti-HBs response to hepatitis B vaccination. Results suggest that without immune selective pressure, 145R variant was not frequently observed, and was not stable. Mutation in the 'a' determinant was not an important cause of failure to prevent maternal-infant transmission of HBV by active postexposure hepatitis B immunization in Chinese children.
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PMID:Mutations in the 'a' determinant of hepatitis B surface antigen among Chinese infants receiving active postexposure hepatitis B immunization. 960 26

The envelope proteins of hepadnaviruses are highly cross-linked by disulfide bonds in complete virions and 20 nm subviral envelope particles. We have previously shown which of the cysteines in the envelope proteins of the human hepatitis B virus (HBV) are essential for assembly and secretion of 20 nm particles and for the structure of the major antigenic determinants (HBsAg). Now we have analyzed the intermolecular disulfide bonds between S proteins. We have constructed mutants lacking cysteines and have analyzed their capacity for oligomerization in COS-7 cells. We demonstrate that C121 and C147 located in the second hydrophilic region carrying the major antigenic determinants of the HBV S protein participate in intermolecular disulfide bonding. A disulfide bond involving C124 blocks the accessibility of arginine/lysine at position 122, as shown by trypsin digestion of cysteine mutants. Alkylation studies using N-ethyl-maleimide indicate that C76, C90, and/or C221 carry the only free sulfhydryl group(s) present in 20 nm particles secreted from cell lines.
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PMID:Analysis of intermolecular disulfide bonds and free sulfhydryl groups in hepatitis B surface antigen particles. 967 91

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

The gene coding for the small (S) envelope protein of hepatitis B virus was mutated to identify sequences important for the envelopment of the nucleocapsid during morphogenesis of hepatitis delta virus (HDV) virions. This study was focused on a domain of the S protein that is exposed in the cytoplasm during synthesis and thereby represented a good candidate for interaction with the viral nucleocapsid during virion assembly. The mutations consisted of deletion/insertions spanning the entire cytosolic domain of S between amino acid residues 24 and 80. Although the expression of mutants clustered between residues 59 and 80 could not be obtained, we demonstrated that a large part of the cytosolic loop, from residues 29-47 and 49-59, does not contain motifs essential for production of hepatitis B virus subviral particles or HDV virions. However, deletion of residues 24-28 led to the synthesis of S protein mutant, which was competent for secretion of subviral particles but deficient for production of HDV. We concluded that the sequence between Arg-24 and Ile-28 located at the carboxyl boundary of the transmembrane signal I for S contains residue or residues important for HDV particle assembly.
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PMID:Effect of mutations in the small envelope protein of hepatitis B virus on assembly and secretion of hepatitis delta virus. 981 13

Recently, lamivudine used to treat patients with hepatitis B virus (HBV) infection was revealed to have potent antiviral activity. However, HBV resistance to lamivudine has been reported and shown to have amino acid substitutions in the methionine residue of the conserved tyrosine (Y), methionine (M), aspartate (D), aspartate (D) motif of RNA-dependent DNA polymerase. To explore the consequences of substitutions in this motif (YMDD), we made 7 variants by substituting the methionine of the YMDD motif with isoleucine (I), valine (V), alanine (A), leucine (L), lysine (K), arginine (R), and threonine (T). Replication ability of these variants was evaluated by transfection into human hepatoma cells. Sensitivity to lamivudine was tested for replication-competent variants. Four variants with hydrophobic substitutions (I, V, A, and L) remained replication-competent, whereas 3 others with hydrophilic substitutions (K, R, and T) exhibited impaired replication. Of the 4 replication-competent variants, 2 (I and V) were resistant, and 2 (A and L) were sensitive to lamivudine. Because the polymerase and the surface gene overlap, the introduction of these mutations affected the secretion of hepatitis B surface antigen (HBsAg), namely 4 variants (I, V, L, and R) secreted HBsAg, whereas 3 variants (A, K, and T) did not. Our study elucidated that only one amino acid substitution in the YMDD motif was sufficient to cause lamivudine resistance in vitro. As a result of replication competence and lamivudine sensitivity, only viruses having YIDD or YVDD sequences may appear during treatment with lamivudine. This in vitro system could be used to study HBV mutations, replication competence, and their susceptibility to antivirals.
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PMID:YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: A study by in vitro full-length viral DNA transfection. 1005 1


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