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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD8+ CTL responses constitute a critical component for vaccines developed to eliminate intracellular pathogens. One approach to achieve broad CTL diversity is based on genetically linking immunogenic peptides from multiple proteins to form poly-epitope Ags. To address the influence of flanking residues on class I Ag presentation, H-2d-restricted HIV-1 and mouse hepatitis virus CTL epitopes were linked via various spacer residues. The resulting 20 to 31 amino acid peptides were expressed using recombinant vaccinia viruses to monitor both CTL recognition and induction. Our data indicate that recognition is profoundly influenced by the nature of intervening residues forming carboxyl-terminal flanks for one and amino-terminal flanks for the other epitope. Flanking amino acids with aromatic (tyrosine), basic (lysine), and small aliphatic side chains (alanine) supported efficient CTL recognition of both epitopes. By contrast, acidic and helix breaking residues (glycine, proline) specifically inhibited recognition of the adjacent amino-terminal epitope. Flanking residues inhibitory for recognition were also detrimental for CTL induction, suggesting similar processing mechanisms in vitro and in vivo. The ratios of peptide-specific CTL precursors primed by the tandem epitopes varied up to 50-fold depending on molecular context. These data demonstrate a substantial role of carboxyl-flanking residues in governing the efficiency of class I Ag presentation both in vitro and in vivo. The dramatic influence of flanking residues on the hierarchy of CTL responses indicates that CTL induction by poly-epitope Ags can be optimized by strategically linking epitopes via selection of appropriate spacer residues.
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PMID:Flanking residues alter antigenicity and immunogenicity of multi-unit CTL epitopes. 887 18

Hepatitis delta virus (HDV) encodes two isoforms of its principal gene product, hepatitis delta antigen (HDAg). These two forms play distinctive and complementary roles in viral replication. Here we report that the large (LHDAg), but not the small (SHDAg), isoform of HDAg has the capacity to activate the expression of cotransfected genes driven by a variety of promoters, including the pre-S, S, and C promoters of hepatitis B virus. Mutational analysis of the C-terminal 19 amino acids unique to LHDAg shows that changing prolines to alanines in the two PXXP motifs in this region specifically ablates the activation function without abolishing another activity of LHDAg, namely, its ability to inhibit HDV RNA synthesis. However, C-terminal truncations that also disrupt these PXXP motifs only slightly diminished the activation function, indicating that the proline mutations were not acting by inactivating potential SH3 interactions that could be mediated by these motifs. Mutation of the isoprenylated cysteine to serine decreases but does not abolish the activation activity, and overexpression of SHDAg does not interfere with the transactivation function of LHDAg. Although the mechanism and biological significance of this activity of LHDAg remain unknown, the presence of this activity serves as yet another marker that functionally distinguishes this protein from the closely related isoform SHDAg.
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PMID:Activation of heterologous gene expression by the large isoform of hepatitis delta antigen. 949 64

The pre-S envelope protein of duck hepatitis B virus (DHBV) contains a region, Asp-Asp-Pro-Leu-Leu (DDPLL), that is specifically required for virus assembly and secretion (Lenhoff and Summers, J Virol 1994;68:4565-4571). We found that amino acids 201 to 205 of the pre-S envelope protein of woodchuck hepatitis virus (WHV) form a conserved amino acid cluster, Gly-Asp-Pro-Ala-Leu (GDPAL), which resembles the DDPLL sequence of DHBV. To determine whether the GDPAL region was functionally equivalent to the DDPLL region, we deleted this region from the pre-S protein of WHV or mutated individual amino acids within the region. The mutant DNA was transfected into human hepatoma cell line Huh7, and the medium was assayed for virion production by immunoprecipitation and Southern blot analysis. We found that an in-frame deletion of this small region inhibited virion formation, suggesting that the GDPAL region of the pre-S envelope protein was required for virus assembly and/or secretion of WHV. Individual replacement of alanine 204, leucine 205, or serine 206 with other amino acid residues did not affect virus production. However, substitution of either aspartic acid 202 with valine or proline 203 with leucine dramatically inhibited WHV production. Furthermore, the GDPAL mutants were individually tested for their abilities to complement a pre-S1 defective genome. The results showed that the GDPAL region functioned as part of the pre-S1 protein but was not required to function as part of the pre-S2 protein.
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PMID:The GDPAL region of the pre-S1 envelope protein is important for morphogenesis of woodchuck hepatitis virus. 958 99

The mouse hepatitis virus (MHV) membrane (M) protein contains only O-linked oligosaccharides. We have used this protein as a model to study the structural requirements for O-glycosylation. We show that MHV M is modified by the addition of a single oligosaccharide side chain at the cluster of 4 hydroxylamino acids present at its extreme amino terminus and identified Thr at position 5 as the functional acceptor site. The hydroxylamino acid cluster, which is quite conserved among O-glycosylated coronavirus M proteins, is not in itself sufficient for O-glycosylation. Downstream amino acids are required to introduce a functional O-glycosylation site into a foreign protein. In a mutagenic analysis O-glycosylation was found to be sensitive to some particular changes but no unique sequence motif for O-glycosylation could be identified. Expression of mutant M proteins in cells revealed that substitution of any 1 residue was tolerated, conceivably due to the occurrence of multiple UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc transferases). Indeed, MHV M served as a substrate for GalNac-T1, -T2, and -T3, as was demonstrated using an in situ glycosylation assay based on the co-expression of endoplasmic reticulum-retained forms of the GalNAc transferases with endoplasmic reticulum-resident MHV M mutants. The GalNAc transferases were found to have largely overlapping, but distinct substrate specificities. The requirement for a threonine as acceptor rather than a serine residue and the requirement for a proline residue three positions downstream of the acceptor site were found to be distinctive features.
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PMID:Structural requirements for O-glycosylation of the mouse hepatitis virus membrane protein. 979 8

The N-terminal region of the hepatitis-C virus (HCV) core protein is rich in basic residues, while the C-terminal end of the protein comprises of a stretch of hydrophobic amino acids. Between these two extremes is an amphipathic region with two predicted alpha-helical segments. This region embodies Leu or hydrophobic residues in positions of heptad repeats and is possibly capable of self-association. To investigate this possibility, the core sequence was divided into two fragments and expressed separately as recombinant proteins. Recombinant proteins with the N-terminal fragment remained as monomers even at high concentrations in SDS/PAGE. Recombinant protein with the C-terminal fragment appeared largely monomeric on denaturing gels but some oligomers were also detected. Furthermore, proline mutations in either one of the predicted alpha helices adversely affected the observed oligomerization. The self-association capacity of the core protein C-terminal region was further supported by results from a yeast two-hybrid system. To affirm our conclusion, a peptide covering the heptad repeats and the predicted alpha helices was synthesized. Data from mass spectrometry and gel-filtration chromatography concluded that this peptide readily self-associated into the homodimer. Therefore, our results suggest that the oligomerization motifs of the HCV core protein may not be limited to the previously suggested N-terminal region.
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PMID:Self-association of the C-terminal domain of the hepatitis-C virus core protein. 985 97

We determined full-length nucleotide sequence of hepatitis B virus (HBV) genome in sera from 40 Japanese patients with HBsAg-positive hepatocellular carcinoma (HCC), in order to obtain information on HCC-specific characteristics, if any, of the HBV genome. Direct sequencing of the long distance PCR products starting from 50 microliters of serum samples revealed that 95% of our isolates were of genotype C, and that mutations and deletions/insertions were very common. With respect to envelope protein genes, deletions and missense mutations were frequent in preS2, and the determinant a domain of HBsAg was rich in "antibody-escape" mutations. Within the precore/core region, the most remarkable mutation was the replacement of proline of wild type by other amino acids at codon 130 of the core gene, which was found in 58% of our isolates, while precore-stop mutation was found in 45%. Most interestingly, however, about 90% of our isolates had mutations at nt positions 1762 (A-to-T) and 1764 (G-to-A) within the core promoter, which had been implicated in "e-suppressive" phenotype of HBV genome. G-to-A at nt 1613 and C-to-T at nt 1653 within enhancer II and T-to-C/A at nt 1753 within core promoter were also evident: 38%, 53%, and 40%, respectively. It was interesting that some of the characteristics observed in our isolates form HCC patients had been previously implicated in fulminant hepatitis and/or acute exacerbation of chronic hepatitis.
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PMID:Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: comparative analysis of 40 full-length isolates. 993 Jan 89

Encephalitozoonidae are microsporidia associated with human infections including hepatitis, encephalitis, conjunctivitis, and disseminated disease. Microsporidia produce a small resistant spore containing a polar tube which serves as a unique vehicle of infection. Polar tube proteins (PTPs) from Encephalitozoon hellem. Encephalitozoon (Septata) intestinalis, and Encephalitozoon cuniculi were purified to homogeneity by HPLC. By SDS-PAGE, the Mr of E. hellem PTP was 55 kDa, while the Mr of E. intestinalis and E. cuniculi PTP was 45 kDa. Polyclonal rabbit antiserum to these purified PTPs localized to polar filaments by immunogold electron microscopy and immunofluorescence, and demonstrated cross-reactivity by both immunoblotting and immunogold electron microscopy. These PTPs have similar solubility properties, hydrophobicity, and proline content to a 43-kDa PTP we have previously purified from Glugea americanus, a fish microsporidium. As the polar tube is critical in the transmission of this organism, further study of PTPs may lead to the development of new therapeutic strategies and diagnostic tests.
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PMID:Polar tube proteins of microsporidia of the family encephalitozoonidae. 1018 55

The S protein of hepatitis B virus is the principal component of virus envelope and the primary target of anti-HBs response. Mutants or variants that escape neutralization by anti-HBs have been selected during immunoprophylaxis of HBV after birth and liver transplantation. We investigated a case of a Korean child who was vaccinated at birth against hepatitis B and also given hepatitis B immunoglobulin, but nevertheless later became infected with the virus. Hepatitis B virus-specific deoxyribonucleic acid covering the region of genome encoding the predominant "a" determinant of hepatitis surface antigen was amplified using polymerase chain reaction, and the nucleotide sequence was determined. We present for the first time in Korea the independent emergence of an escape mutant with substitution of arginine for glycine at amino acid 145 and proline for glutamate at amino acid 120 in "a" determinant after immunization.
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PMID:Emergence of vaccine-induced escape mutant of hepatitis B virus with multiple surface gene mutations in a Korean child. 1141 Jul 1

The effects of different doses of Interferon alpha 2b (IFN alpha 2b), alone and in combination with praziquantel (PZQ), on hepatic schistosomiasis were tested. An experimental murine model of hepatic schistosomiasis was used. Four parameters were assessed; hepatic fibrosis by estimation of OH-proline content/g dry weight liver, hepatocyte proliferative activity by the PCNA/LI, schistosomal egg load by digesting parts of the liver by KOH and hepatocyte function by measuring parenchymal liver enzyme levels. IFN alpha 2b was found to increase hepatic fibrosis in a dose dependent manner both alone and in combination with PZQ. An augmentation of the regenerative activity of the liver was observed. A reduction in the number of the granulomas and egg counts was observed only when PZQ was added. However, no effect on the size of the granulomas was observed apart from the normal process of modulation. Caution should be exercised when treating patients with concomitant hepatic schistosomiasis and hepatitis with IFN alpha 2b as it increases both hepatocyte regenerative activity and hepatic fibrosis; two main components of cirrhosis.
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PMID:Parasitological, pathological and functional studies on the effects of IFN alpha 2b in murine hepatic schistosomiasis. 1141 37

MS is an autoimmune CNS demyelinating disease in which infection appears to be an important pathogenic factor. Molecular mimicry, the cross-activation of autoreactive T cells by mimic peptides from infectious agents, is a possible explanation for infection-induced autoimmunity. Infection of mice with a non-pathogenic strain of Theiler's murine encephalomyelitis virus (TMEV) engineered to express an epitope from Haemophilus influenzae (HI) sharing 6/13 amino acids with the dominant proteolipid protein (PLP) epitope, PLP139-151, can induce CNS autoimmune disease. Here we demonstrate that another PLP139-151 mimic sequence derived from murine hepatitis virus (MHV) which shares only 3/13 amino acids with PLP139-151 can also induce CNS autoimmune disease, but only when delivered by genetically engineered TMEV, not by immunization with the MHV peptide. Further, we demonstrate the importance of proline at the secondary MHC class II contact residue for effective cross-reactivity, as addition of this amino acid to the native MHV sequence increases its ability to cross-activate PLP139-151-specific autoreactive T cells, while substitution of proline in the HI mimic peptide has the opposite effect. This study describes a structural requirement for potential PLP139-151 mimic peptides, and provides further evidence for infection-induced molecular mimicry in the pathogenesis of autoimmune disease.
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PMID:Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139-151 mimic peptide derived from murine hepatitis virus. 1698 Nov 79


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