UMLS:C0019163 - FACTA Search

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Query: UMLS:C0019163 (hepatitis B)
38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recovery from a hepatitis B virus (HBV) infection or vaccination with hepatitis B surface antigen (HBsAg) leads to a physiologic immune response specific for the alpha determinant, common to all subtypes of HBsAg. In contrast, an absence of immune response to the alpha determinant is characteristic of persistent HBV infection as well as of the nonresponders to vaccination. Therefore, our goal is to characterize the alpha determinant for synthesis of a bifunctional vaccine which may be useful for active immunization as well as for the safe termination of immune tolerance to HBsAg in carriers. Because the immunochemical activity of the alpha determinant of HBsAg is dependent upon cysteine and lysine residues that are localized in the hydrophilic stretch between amino acid sequence 121-160, we synthesized the following peptide analogues of HBsAg (HBsPA): 122-137, 128-134, 139-147, 139-158, 140-158, 145-158 and 150-158. Serologic inhibition of human antibodies against the alpha determinant indicated the antigenicity of the HBsPAs containing the Cys-Thr-Lys-Pro-Thr-Asp-Gly-Asn-Cys sequence. After coupling with keyhole limpet hemocyanin (KLH), carrier-peptide conjugates induced in rabbits anti-HBs which was neutralized equally by eight different serotypes of HBsAg. Therefore, HBsPA/139-147 represents an essential part of the alpha determinant. By substituting alpha-aminobutyric acid (Aba) for Cys at residue 147 a homogeneous dimeric form of this nonapeptide was prepared. After coupling with purified tetanus toxoid or KLH as a carrier by means of carbodiimide, the product induced sustained high level anti-HBs/alpha response in carrier-primed rabbits. Experiments in chimpanzees should validate our concept of a bifunctional synthetic vaccine against HBV infection.
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PMID:Appraisal and prospects of a dimeric synthetic peptide coupled with tetanus toxoid for a bifunctional vaccine against hepatitis B virus infection. 619 28

The major polypeptides composing hepatitis B surface antigen (HBsAg) particles are P-I and P-II. P-II shares the same amino acid sequence as P-I and contains an additional carbohydrate moiety of mol. wt approximately 5000. When a purified preparation of P-II was digested with Nagarse and then with Pronase P, it gave rise to a glycopeptide containing 15 amino acid residues and the carbohydrate moiety of P-II. The N-terminal amino acid sequence of the glycopeptide was determined to be Lys-Pro-Thr-Asp-Gly-Asn-. The polysaccharide moiety contained 5 moles of N-acetylglucosamine and was connected with Asn at the sixth position from the N-terminus. When mice were immunized against this HBsAg glycopeptide, they raised humoral antibodies which bound to each of three preparations of P-I derived from HGsAg particles of subtypes adw, adr and ayw, thereby indicating that the sequence of 15 amino acids in the glycopeptide would constitute a common antigenic structure of HBsAg.
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PMID:A glycopeptide containing 15 amino acid residues derived from hepatitis B surface antigen particles: demonstration of immunogenicity to raise anti-HBs in mice. 714 54

Perinatal infection with variants of hepatitis B virus occurs despite combined immunoprophylaxis with hepatitis B immunoglobulin and currently licensed plasma-derived and recombinant yeast hepatitis B vaccines. Several variants have been detected during a large study of infants born to carrier mothers in Singapore. The most frequent variant was a virus in which a single amino acid substitution Gly to Arg occurred at amino acid position 145 of the outer protein coat of the virus. Similar mutations have been described in Italy, Japan, the USA and a number of other countries. The emergence of antibody escape mutants is a cause for concern for the detection of virus and possibly for future immunization programmes.
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PMID:Molecular epidemiology of hepatitis B virus vaccine variants in Singapore. 748 83

HLA-DR13 has been associated with resistance to two major infectious diseases of humans. To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position. The eluted peptides were subjected to pool sequencing or individual peptide sequencing by tandem MS or Edman microsequencing. Sequences were obtained for 23 peptides from nine source proteins. Three pool sequences for each allele and the sequences of individual peptides were used to define binding motifs for each allele. Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301. Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1*1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly-->Val change at position 86. These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.
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PMID:Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain. 760 34

A monoclonal antibody (I-18) was raised against an enneapeptide representing amino acids 125 to 133 of the product of the S gene of hepatitis B virus DNA [S(125-133) segment] with a sequence of Thr-Ile-126-Pro-Ala-Gln-Gly-Thr-Ser-Met. Another monoclonal antibody (T-7) was raised against an S(125-133) segment in which Ile-126 was replaced by Thr-126. In a panel of 16 samples of hepatitis B surface antigen (HBsAg) with known S gene sequences, I-18 reacted with 5 with Ile-126. T-7 reacted with 10 HBsAg samples with Thr-126; it did not, however, react with the remaining one of subtype ayw with Thr-126 flanked by Met-125 and Thr-127. The two allelic subtypic determinants, specified by Ile-126 and Thr-126 and distinct from d/y or w/r, were named i and t after isoleucine and threonine, which regulate them. They were expressed in a mutually exclusive fashion in 216 (83%) of 260 HBsAg samples from asymptomatic carriers. They were not detected in 36 (14%) samples; the failure to detect an i or t determinant was particularly common in HBsAg samples of subtype ayw (26 [79%] of 33). A part of the S gene sequence was determined for eight HBsAg samples without a detectable i or t determinant. They had an Ile-126 or Thr-126 residue that was flanked by Thr-127, not the Pro-127 commonly possessed by HBsAg samples displaying an i or t determinant. Expression of the i/t allele, therefore, would require Pro-127. In eight (3%) of the samples, both i and t determinants were detected; the presence of i and t on the selfsame HBsAg particles was verified by sandwiching the particles between I-18 and T-7. A point mutation from thymine to cytosine at nucleotide 377 in the S gene, contributing different second letters to codon 126 (ATT for Ile and ACT for Thr), would have been responsible for the assembly of HBsAg particles with both i and t determinants by means of phenotypic mixing.
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PMID:Allelic subtypic determinants of hepatitis B surface antigen (i and t) that are distinct from d/y or w/r. 767 9

Hepatitis delta virus (HDV) encodes two proteins, the small hepatitis delta antigen (SHDAg) and large hepatitis delta antigen (LHDAg). Both proteins are identical except for the presence of additional 19 amino acids at the C terminus of LHDAg. While SHDAg is required for HDV RNA replication, LHDAg inhibits replication and is required together with hepatitis B surface antigen for the assembly of HDV. The C-terminal last 4 amino acids of LHDAg (Cys-Arg-Pro-Gln) is an isoprenylation motif. It has previously been shown that the mutation of the Cys inhibited the assembly of HDV. In order to discern whether this effect is due to change of amino acid residue or abolition of isoprenylation, we constructed several LHDAg mutants of the terminal three amino acid residues and tested their abilities to be packaged with HBsAg by cotransfection experiments. We also made GST-fusion proteins of these mutants and tested their abilities to be isoprenylated in rabbit reticulocyte lysate system. We found that some, but not all, of the substitutions of the amino acid residues other than the Cys also inhibited isoprenylation and that the status of isoprenylation of these mutant proteins correlated well with their abilities to be packaged with HBsAg into virions. This result indicates that isoprenylation, rather than the primary amino acid sequence, is required for LHDAg packaging. Furthermore, we found that the attachment of an isoprenylation motif to SHDAg did not enable it to be packaged with HBsAg and that the deletions of any 5 amino acids in the last 15 amino acids (amino acids 196 to 210) unique to the LHDAg abolished the packaging ability. In contrast, the deletion of 33 amino acids (amino acids 163 to 195) upstream of the last C-terminal 19 amino acids of LHDAg did not interfere with its packaging ability. Therefore, we conclude that the 15 amino acids upstream of the isoprenylation site of LHDAg are also essential for HDV assembly, and a large portion of the alleged C-terminal Pro/Gly-rich region (amino acids 146 to 195) is not required for the assembly process.
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PMID:Isoprenylation of large hepatitis delta antigen is necessary but not sufficient for hepatitis delta virus assembly. 811 40

Hepatitis B virus (HBV) DNA was extracted from sera of six carriers with hepatitis B e antigen as well as antibody to hepatitis B surface antigen and sequenced within the pre-S regions and the S gene. HBV DNA clones from five of these carriers had point mutations in the S gene, resulting in conversion from Ile-126 or Thr-126 of the wild-type virus to Ser-126 or Asn-126 in three carriers and conversion from Gly-145 to Arg-145 in three of them; clones with Asn-126 or Arg-145 were found in one carrier. All 12 clones from the other carrier had an insertion of 24 bp encoding an additional eight amino acids between Thr-123 and Cys-124. In addition, all or at least some of the HBV DNA clones from these carriers had in-phase deletions in the 5' terminus of the pre-S2 region. These results indicate that HBV escape mutants with mutations in the S gene affecting the expression of group-specific determinants would survive in some carriers after they seroconvert to antibody against surface antigen. Carriers with HBV escape mutants may transmit HBV either by donation of blood units without detectable surface antigen or through community-acquired infection, which would hardly be prevented by current hepatitis B immuneglobulin or vaccines.
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PMID:Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. 813 44

We conducted a large-scale survey to determine the frequency and clinical significance of mutations in the pre-core region of hepatitis B virus (HBV). Sera from 263 patients with chronic HBV infection were analyzed by direct sequencing of PCR-amplified HBV DNA. Four major missense/nonsense mutations (M) were found: (M1) C-->T at nucleotide position 1856, Pro-->Ser at codon 15; (M2) G-->A at position 1896, Trp-->stop at codon 28; (M3) G-->A at position 1898, Gly-->Ser at codon 29; and (M4) G-->A at position 1899, Gly-->Asp at codon 29. The commonest conserved mutation was M0: T-->C at position 1858, Pro-->Pro at codon 15. We found that M1 and M2 were mutually exclusive, M3 was only found in association with M1, and M4 was predominantly found in association with M2. All patients with M1 but none of those with M2 had M0. The invariable coexistence of certain mutations in codon 15 and codons 28 and 29 and the mutual exclusion of other mutations in these two noncontiguous regions is related to the stem-loop structure of the pre-genome encapsidation sequence located in the precore/core region. M2 and M4 enhance the stability of the stem by providing two additional paired sites. M1 destroys an existing base pair. However, M1 only occurred in the presence of M0, which provides an extra paired site, and 50% of patients with M1 had M3, a compensatory mutation that restores base pairing at this site. Our data support the proposed secondary structure of the pre-genome encapsidation sequence. The primary function of the mutations in the pre-core region is to enhance stability of this secondary structure to ensure perpetuation of viral replication.
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PMID:Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. 817 Oct 38

A G:C-->T:A mutational hotspot at codon 249 of the p53 tumor suppressor gene has previously been identified in hepatocellular carcinoma (HCC) of patients from Qidong, China and southern Africa in which aflatoxin B1 (AFB1) and hepatitis B virus (HBV) are known synergistic risk factors. We have examined p53 mutation patterns of HCC from geographic areas in which the risk factors vary. Nine HCC lines and four hepatoblastoma lines (HB) were examined for p53 gene mutations and the relationship with HBV infection. Five of the nine HCC lines had homozygous mutation or deletion randomly distributed in exons 6-8, whereas none of the four HB cell lines had p53 mutations. One of the four HB lines (HepG2) had an N-ras mutation at codon 61 position 2. The p53 point mutations in the three HCC cell lines from Japan resulted in the amino acid changes of cysteine for tyrosine in cell line HuH 7 at codon 220 (A:T-->G:C), alanine for glycine in cell line HLF at codon 244 (G:C-->C:G), and serine for arginine in cell line HLE at codon 249 (G:C-->C:G). In addition, the deletion of 18 base pairs from codon 264 position 3 to codon 270 position 1 has resulted in the deletion of Leu-Gly-Arg-Asn-Ser-Phe from the amino acids sequences 256-270 in the Japanese cell line HuH 4. The cell line PLC/PRF/5 that showed p53 mutation at codon 249 (G:C-->T:A) with substitution of serine for arginine was derived from a South African patient. Our results indicate that whereas the p53 gene is not mutated in the HB cell lines, the HCC cell lines frequently contain an abnormal p53 gene. In addition, p53 point mutations were not detected in the four Japanese HCC cell lines that were positive for genomic integration of HBV X-gene and surface antigen gene. The three Japanese HCC cell lines with p53 mutations did not contain HBV sequences, indicating that hepatocarcinogenesis associated with p53 mutation does not require the genomic integration of HBV sequences.
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PMID:p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. 838 56

Hepatitis delta virus expresses two forms of a single protein, the small (delta Ag-S) and large (delta Ag-L) antigens, which are identical except for an additional 19 residues present at the C terminus of delta Ag-L. While delta Ag-S is required to promote genome replication, delta Ag-L potently inhibits this process and also facilitates packaging of the viral genome by envelope proteins of the helper virus (hepatitis B virus). Regions within the antigens responsible for nuclear localization, RNA binding, and dimerization have been identified, yet it is not clear how these particular activities contribute to the ultimate replication and packaging phenotypes. Here we report the following findings. (i) Although the removal of the nuclear localization signal from either antigen resulted in significant cytoplasmic accumulation, both proteins still had access to the nucleus. As a consequence, no functional defect was observed with either mutant. (ii) The RNA-binding domain, although necessary for delta Ag-S function, could be deleted from delta Ag-L without compromising its ability to either inhibit replication or promote packaging. (iii) In contrast, the coiled-coil dimerization domain was required for both the activation of replication by delta Ag-S and the inhibition of replication by delta Ag-L. This region, with an additional 20 amino acids C-terminal to it, was necessary and sufficient to potently inhibit replication by interacting with the small antigen. (iv) The packaging property of delta Ag-L required a C-terminal Pro/Gly-rich region which is hypothesized to interact with the hepatitis B virus envelope proteins during the assembly process.
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PMID:Relating structure to function in the hepatitis delta virus antigen. 847 67

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