ISSN:0300-5526    

DOI:10.1159/000150407

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:0300-5526    

DOI:10.1159/000150408

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Hepatitis B surface proteins play a central role in the assembly of the virus and in the infection of the host cells. Whereas some functional aspects of the proteins have been studied in detail, little is known about their structure. Since X-ray analysis of these proteins appear unlikely in the near future, we chose to use a variety of computer-aided methods to improve the model for the major surface protein (SHBs). We here describe the model, discuss it in light of current results in the literature and discuss new functional implications of SHBs.

ISSN:0300-5526    

DOI:10.1159/000150409

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The 20-nm noninfectious empty envelope particles carrying the hepatitis B surface antigen are secreted in large excess from hepatocytes during a hepatitis B infection. Similar particles produced in cell lines or yeast are an efficient vaccine against hepatitis B virus. We have analyzed the assembly of 20-nm particles using a mutagenesis approach. Specific mutations were introduced into the S gene and the preS region encoding the viral envelope proteins using recombinant DNA techniques. The mutant genes were expressed in cell lines to identify the amino acid residues that are critical for the assembly and the secretion of the 20-nm particles.

ISSN:0300-5526    

DOI:10.1159/000150410

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unque substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

ISSN:0300-5526    

DOI:10.1159/000150411

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Hepatitis B surface antigen (HBsAg) particles consist predominantly of a glycoprotein of 226 amino acids which bears the B-cell epitopes important for the induction of protective antibody responses in humans. It has been clearly shown that the region between residues 120 and 150 of the S protein represents the a determinants common to all hepatitis B virus (HBV) isolates and is exposed on the surface of the HBV particle. Anti-α antibodies protect adults against the majority of infections irrespective of the subtype of the wild-type virus. Occasional examples of infection positive for anti-HBs antibodies have been associated with the emergence of HBV variants. In particular, asymptomatic infections have been described in vaccinated children, an observation which is associated with an amino acid change in a domain critical for anti-HBs binding. Variation in amino acid sequence is also found within the preS amino terminal extensions of the S protein, although these do not correlate with subtypic variations among the S-antigenic domains. There is no direct evidence that preS determinants per se may stimulate a protective immune response in humans, although the hepatocyte attachment domain is located in the preSl region which is conserved between HBV isolates. The inclusion of preS specificities augments anti-HBs responses in an experimental animal; however, at the present time it is unclear as to how this may best be exploited in improving hepatitis B vaccines for human use. Variability in HBV envelope proteins has implications for the design of vaccination programmes and the diagnosis of HBV infections; however, the low frequency of HBV variants emerging in the face of increasing levels of herd immunity to hepatitis B at the present time means that the extension of immunization programmes using existing vaccines remains a priority

ISSN:0300-5526    

DOI:10.1159/000150412

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Clearance of hepatitis B virus (HBV) infection requires an effective T-cell-dependent humoral response that is often defective in HBV carriers and in immunosuppressed patients. We have shown in mice and humans that bone marrow (BM)-derived memory cells, capable of producing antibodies to the HBV envelope and nucleocapsid antigens, are transferable from BM donors (BMD) to their recipients. BMD BALB/c mice were immunized with recombinant HBV surface antigen (HBsAg), and BM from anti-HBs-positive donors was transplanted to irradiated recipient mice, who seroconverted to anti-HBs within 30 days of bone marrow transplantation (BMT), and responded to booster vaccination. In a similar manner, 19/26 human BM recipients, who received their HLA-matched BM from BMDs immunized once with HBsAg, seroconverted within several weeks after BMT. Antibodies to HBsAg were also observed in 3 recipients of peripheral blood lymphocytes (PBL) obtained from HLA-matched immunized human donors. Finally, clearance of HBsAg and HBV DNA was observed in an HBsAg carrier with leukemia who received BMT from his HLA-matched anti-HBc+/anti-HBs+ brother. These results indicate that adoptive transfer of immunity to HBV may be achieved through immunization of BM or PBL donors against HBV.

ISSN:0300-5526    

DOI:10.1159/000150413

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Recent studies in Xenopus oocytes and other systems have led to an understanding of the HBV capsid, or core particle, assembly process. Nascent HBV core polypeptides rapidly dimerize. Accumulation of free dimers to a signature concentration (∼0.8 µM) then triggers a highly cooperative capsid assembly reaction. This dimer-to-capsid transition is accompanied by a switch from HBe to HBc antigenicity and appears to be nucleated by interaction between core protein and RNA: deletion of a protamine-like RNA binding domain at the C-terminus of the core protein markedly increases the concentration of dimers needed to drive capsid assembly. The simple assembly pathway seen for HBV capsids mirrors that of R17 bacteriopha

ISSN:0300-5526    

DOI:10.1159/000150414

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

HBV core (HBc) particle is one of the most intensively studied particulate carriers for the insertion of foreign peptide sequences. Recombinant HBc protein expressed from the cloned gene undergoes the correct folding in a large variety of bacterial, yeast, insect and mammalian cells. Unique assembly properties and shape of 30/34-nm HBc particles allow substantial insertions into their primary structure without loss of their capsid-forming ability. N- and C-terminal regions, as well as the immunodominant loop in the middle of the molecule are widely accepted as targets for the introduction of foreign epitopes, ensuring retention and even enhancement of the original immunological activity of inserted sequences. Special sets of display vectors have been constructed on the basis of the cloned HBc gene. Epitope sequences of viral (BLV, FeLV, FMDV, HBV, HCV, HIV-1, HRV2, MCMV, PV-1, SIV) and nonviral (human chorionic gonadotropin) origin have been studied as model display moieties.

ISSN:0300-5526    

DOI:10.1159/000150415

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Variation in viral genomes is dependent upon rates of polymerase error and the relative influence of selection pressures. For HBV, it appears that there is substantial immune pressure in keeping with the immunopathogenesis; the ability of the virus to persist is probably linked with this process. As the viral genome is small, mutants may have multiple effects, particularly apparent within regions that have overlapping functions, such as the encapsidation signal and the X gene. Here, an attempt has been made to correlate variation within the pre-core/core gene with clinical progression and response to interferon and to put forward hypotheses to show the relationship of these mutations to the immune response. Their effects on overlapping regions are also discussed. Little is currently known about the functional importance of mutations within and around the X gene, but it is likely that this will prove a fruitful area of research.

ISSN:0300-5526    

DOI:10.1159/000150416

出版商:S. Karger AG    

年代:1995

数据来源: Karger