Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Antisera to a peptide representing the extreme carboxy terminus of the hepatitis delta virus antigen (HDAg) open reading frame (residues 197 to 211) recognized only the large (p27 delta) and not the small (p24 delta) form of HDAg in immunoblots of infected liver extracts, thereby providing direct proof that p27 delta and p24 delta differ in their carboxyl-terminal sequence and that p27 delta results from mutation within the stop codon terminating translation of p24 delta. Reactions with other peptide antisera demonstrated that multiple smaller virus-specified proteins were carboxy-terminally truncated forms of HDAg, and immunoprecipitation studies suggested that different forms of HDAg were present as heterologous complexes within the liver extract.
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PMID:Immunoblot analysis demonstrates that the large and small forms of hepatitis delta virus antigen have different C-terminal amino acid sequences. 173 Sep 40

A trimer of hepatitis delta virus (HDV) cDNA in a retrovirus expression vector was transfected into subclone of the PLC/PRF/5 human hepatoma cell line, and a stable cell line (H1 delta 9) was clonally selected that supported the synthesis of both genomic and antigenomic sense HDV RNA. The H1 delta 9 cell line also expressed hepatitis delta antigen (HDAg) in cell nuclei in three distinct morphological patterns, including patterns typically seen in HDV-infected livers. HDAg expression was restricted to the smaller (p24) of the two HDAg-associated polypeptides in early passages of the H1 delta 9 cell line, but continuous passage of the cells resulted in increasing of expression of the larger (p27) HDAg-specific polypeptide. Passage of the H1 delta 9 cells also led to sustained expression of monomeric HDV RNA and a reduction in the levels of dimeric- and trimeric-HDV RNA. This was accompanied by an attenuation of virus-related cytotoxicity which was a feature of early cell passage numbers. HDV RNA replication in these cells was resistant to actinomycin D suggesting that replication was not dependent on continued expression from the transfected HDV cDNA and thus was likely to be self-sustaining.
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PMID:Hepatitis delta virus RNA, protein synthesis and associated cytotoxicity in a stably transfected cell line. 216 31

Hepatitis A virus is an enteric picornavirus. Its genome is a single stranded RNA molecule of positive-strand polarity of 7478 bases. This sequence codes for a polyprotein which is processed to give rise to viral proteins VP-1, VP-2, VP-3 and others. Hepatitis B virus, a major worldwide infectious and cancer promoting agent contains a DNA genome of 3226 base pairs that replicates by a reverse transcriptase via an RNA intermediate. Extensive sequencing and expression experiments have revealed four major genes named surface, core, polymerase and X which are coded in more than one reading frame. Furthermore, within a frame, proteins are expressed from multiple initiation codons resulting in several related products. The viral genome of hepatitis C virus (nonA-nonB), an elusive major infectious agent, has recently been cloned. This genome is a single positive-stranded RNA of at least 10,000 bases which codes for several antigens, some of them associated specifically with nonA-nonB hepatitis infections. The hepatitis D (delta) viral agent, an infectious agent requiring a hepadnarious for propagation, contains a covalently closed circular single-stranded RNA genome of 1167 nucleotides. This genome encodes the protein p24 and p27 that bind specifically to antisera from patients with chronic hepatitis D infections.
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PMID:Hepatitis A, B, C, D and E viruses: structure of their genomes and general properties. 222 69

On the basis of the complete nucleotide sequence of the single-stranded, covalently closed circular hepatitis delta virus RNA genome (K.-S. Wang, Q.-L. Choo, A. J. Weiner, J.-H. Ou, R. C. Najarian, R. M. Thayer, G. T. Mullenbach, K. J. Denniston, J. L. Gerin, and M. Houghton, Nature [London] 323:508-514, 1986 [Author's correction, 328:456, 1987]), five long open reading frames (ORFs) encoding polypeptides containing a methionine proximal to the amino terminus were expressed in bacteria. Only polypeptides encoded by the antigenomic ORF5 cross-reacted with antisera obtained from patients with hepatitis delta virus infections. Immunological analysis of viral extracts and the recombinant ORF5 polypeptides synthesized in bacteria and yeast cells revealed that ORF5 encodes the immunogenic epitope(s) shared by both hepatitis delta viral polypeptides p27 delta and p24 delta and probably represents the complete structural gene for p27 delta and p24 delta. We also present evidence that ORF5 encodes the hepatitis delta antigen, an antigen originally found in the nuclei of hepatocytes of infected individuals (M. Rizzetto, M. G. Canese, S. Arico, O. Crivelli, F. Bonino, C. G. Trepo, and G. Verme, Gut 18:997-1003, 1977). A comparison of the primary structure of the predicted hepatitis delta antigen polypeptides with that of the core antigen of the hepatitis B virus shows that these polypeptides are very dissimilar.
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PMID:A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta. 244 91

The relationships among the core antigen polypeptides of hepatitis B virus (HBV) and ground squirrel hepatitis virus (GSHV) were studied using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and tryptic peptide mapping. The major core antigen polypeptides of liver-derived HBV (p22) and GSHV (p20.5) shared 56% of the spots in their peptide maps. Comparison of hepatitis B core antigen (HBcAg) p19 or ground squirrel hepatitis core antigen (GSHcAg) p16.5 with their respective major polypeptides indicated that these components probably resulted from cleavage of the major polypeptide of each virus. Other polypeptides smaller than the major component of each virus were often faint on polyacrylamide gels and probably resulted from the cleavage or degradation of components larger than p22 of HBcAg or p20.5 of GSHcAg, since their peptide maps contained spots unique to these high-molecular-weight components. p26 of GSHcAg and p27.5 of HBcAg shared approximately two-thirds of the spots on their peptide maps with those of their respective major core polypeptides. Furthermore, p37.5 of GSHcAg and p40 of HBcAg shared about 60% homology with their respective major polypeptides, and also shared many of the spots that were unique to p26 of GSHcAg or p27.5 of HBcAg but were not found in the peptide map of their respective core antigen polypeptides. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis bands larger than 40,000 daltons were variably present, and peptide mapping indicated that these were aggregates of various smaller core antigen-associated polypeptides. The results suggest that p40 of HBcAg and p37.5 of GSHcAg are the largest unique polypeptides in these core particles, and that they are encoded for by the genome of each virus. That a subset of the spots unique to p40 or p37.5 was also found in p27.5 of HBcAg or p26 of GSHcAg, respectively, as compared to the major core polypeptides, also suggests that p27.5 and p26 are unique proteins encoded by the genome of each virus. It is proposed that the core antigen gene of each virus is larger than that which would encode the major polypeptide of each virus, and that the genetic organizations of the core genes of HBV and GSHV are very similar.
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PMID:Core particles of hepatitis B virus and ground squirrel hepatitis virus. I. Relationship between hepatitis B core antigen- and ground squirrel hepatitis core antigen-associated polypeptides by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and tryptic peptide mapping. 710 37

Although the hepatitis delta virus genome contains multiple open reading frames, only one of these reading frames is known to be expressed during replication of the virus. This open reading frame encodes two distinct molecular species of hepatitis delta antigen (HDAg), p24 delta and p27 delta, depending on the location of the stop codon which terminates translation. We found antibody specific for p27 delta to be capable of precipitating p24 delta in extracts of infected liver, indicating that p27 delta and p24 delta form heterologous complexes in vivo. After cross-linking with 0.05% glutaraldehyde, specific HDAg dimers were detected in antigen prepared from both the liver and serum of an HDV-infected woodchuck carrier of woodchuck hepatitis virus. Guanidine HCl-denatured HDAg extracted from liver and dialyzed against phosphate-buffered saline sedimented in rate-zonal sucrose density gradients as 15S multimeric complexes. These 15S multimers were stable in the presence of 1.2% Nonidet P-40. After RNase digestion, the 15S complex was reduced to a 12S complex without associated RNA, while boiling for 3 min in 1% sodium dodecyl sulfate-0.5% 2-mercaptoethanol further reduced the 15S complex to 3S HDAg monomers. In the absence of glutaraldehyde cross-linking, HDAg extracted from liver migrated as monomer species in reducing and nonreducing gels, suggesting that the conserved cysteine residue present in p27 delta does not play a role in the formation of either dimers or multimers. On the other hand, an amino-terminal chymotrypsin-digested HDAg fragment, with a predicted length of 81 or less amino acids, retained the ability to form dimers, consistent with the hypothesis that a coiled-coil motif present between residues 27 and 58 may play a role in HDAg protein interactions in vivo.
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PMID:Hepatitis delta virus antigen forms dimers and multimeric complexes in vivo. 767 57

Hepatitis delta virus is a satellite of the hepatitis B virus which provides the surface antigen for the viral coat. The genome of the hepatitis delta virus consists of a single-stranded, circular RNA of 1679 nucleotides which forms a rod structure due to a high extent of self homology and which replicates via synthesis of an antigenomic RNA in a rolling circle mechanism similar to plant viroids. The antigenomic RNA contains the open reading frame for the delta-antigen which exists in two isoforms, p24 and p27. The formation of these two isoforms is explained by RNA editing at nucleotide 1012 which changes the stop translation codon UAG at amino acid residue 196 into the codon UGG for tryptophan and extends the open reading frame for the synthesis of p27. In order to investigate whether the editing occurs cotranscriptionally during RNA replication or is a posttranscriptional base modification in the genomic or antigenomic RNA, replication defective deletion mutants of the HDV genome were constructed and expressed in COS-7 cells. Editing was demonstrated in non-replicating fragments of genomic HDV RNA but not in antigenomic HDV RNA fragments. The sequences from nucleotide position 337-1200 of the genomic RNA were sufficient to enable low levels of editing. Editing at position 1012 required the opposite strand of the RNA rod from nucleotide position 337-783. Replicating circular HDV RNA was much more efficiently edited than non-replicating full length genomic HDV RNA. Expression of delta-antigen in trans did not complement the low editing efficiency of replication defective genomic HDV RNA. These results demonstrate posttranscriptional U to C editing in the genomic HDV RNA and exclude misincorporation during HDV RNA replication as the editing mechanism. The minimal structural requirements for HDV RNA editing reside between nucleotide position 337-1200.
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PMID:Requirements for editing in the genomic RNA of hepatitis delta virus. 774 56

The coronavirus mouse hepatitis virus-A59 (MHV-A59) encodes a serine-like proteinase (3C-like proteinase or 3CLpro) in ORF 1a of gene 1 between nucleotides 10,209 and 11,114. We previously have demonstrated that proteins expressed in vitro from a cDNA clone of the 3CLpro region possess proteinase activity, and that the proteinase is able to cleave substrate in trans. We sought to determine if the 27-kDa in vitro cleavage product (p27) was an active form of the 3CLpro and whether this was consistent with the 3CLpro expressed in virus-infected cells. Antibodies directed against the 3CLpro domain detected 27-kDa MHV proteins in vitro and in MHV-A59-infected cells. The 27-kDa proteins were able to cleave substrate in trans without other protein cofactors or supplemental membranes, and the p27 proteinase activity was retained after purification by immunoprecipitation and gel electrophoresis. When p27 was expressed in vitro with portions of the amino-and carboxy-terminal flanking domains (MP1 and MP2), p27 was not liberated by cls cleavage. The proteolytic activity of the 27-kDa proteins was inhibited by a variety of cysteine and serine proteinase inhibitors, and was eliminated by the cysteine proteinase inhibitor E64d. These results indicate that the 27-kDa protein is a mature proteinase in MHV-A59-infected cells, and that appropriate processing of this molecule occurs in vitro.
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PMID:Intracellular and in vitro-translated 27-kDa proteins contain the 3C-like proteinase activity of the coronavirus MHV-A59. 880 21

The coronavirus, mouse hepatitis virus strain A59 (MHV), expresses a chymotrypsin-like cysteine proteinase (3CLpro) within the gene 1 polyprotein. The MHV 3CLpro is similar to the picornavirus 3C proteinases in the relative location of confirmed catalytic histidine and cysteine residues and in the predicted use of Q/(S, A, G) dipeptide cleavage sites. However, less is known concerning the participation of aspartic acid or glutamic acid residues in catalysis by the coronavirus 3C-like proteinases or of the precise coding sequence of 3CLpro within the gene 1 polyprotein. In this study, aspartic acid residues in MHV 3CLpro were mutated and the mutant proteinases were tested for activity in an in vitro trans cleavage assay. MHV 3CLpro was not inactivated by substitutions at Asp3386 (D53) or Asp3398 (D65), demonstrating that they were not catalytic residues. MHV 3CLpro was able to cleave at a glutamine-glycine (QG3607-8) dipeptide within the 3CLpro domain upstream from the predicted carboxy-terminal QS3636-6 cleavage site of 3CLpro. The predicted full-length 3CLpro (S3334 to Q3635) had an apparent mass of 27 kDa, identical to the p27 3CLpro in cells, whereas the truncated proteinase (S3334 to Q3607) had an apparent mass of 24 kDa. This 28-amino-acid carboxy-terminal truncation of 3CLpro rendered it inactive in a trans cleavage assay. Thus, MHV 3CLpro was able to cleave at a site within the putative full-length proteinase, but the entire predicted 3CLpro domain was required for activity. These studies suggest that the coronavirus 3CL-proteinases may have a substantially different structure and catalytic mechanism that other 3C-like proteinases.
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PMID:Determinants of mouse hepatitis virus 3C-like proteinase activity. 914 89

The replicase of mouse hepatitis virus strain JHM (MHV-JHM) is encoded by two overlapping open reading frames, ORF1a and ORF1b, which are translated to produce a 750-kDa precursor polyprotein. The polyprotein is proposed to be processed by viral proteinases to generate the functional replicase complex. To date, only the MHV-JHM amino-terminal proteins p28 and p72, which is processed to p65, have been identified. To further elucidate the biogenesis of the MHV-JHM replicase, we cloned and expressed five regions of ORF1a in bacteria and prepared rabbit antisera to each region. Using the immune sera to immunoprecipitate radiolabeled proteins from MHV-JHM infected cells, we determined that the MHV-JHM ORF1a is initially processed to generate p28, p72, p250, and p150. Pulse-chase analysis revealed that these intermediates are further processed to generate p65, p210, p40, p27, the MHV 3C-like proteinase, and p15. A putative replicase complex consisting of p250, p210, p40, p150, and a large protein (> 300 kDa) coprecipitate from infected cells disrupted with NP-40, indicating that these proteins are closely associated even after initial proteolytic processing. Immunofluorescence studies revealed punctate labeling of ORF1a proteins in the perinuclear region of infected cells, consistent with a membrane-association of the replicase complex. Furthermore, in vitro transcription/translation studies of the MHV-JHM 3Cpro and flanking hydrophobic domains confirm that 3C protease activity is significantly enhanced in the presence of canine microsomal membranes. Overall, our results demonstrate that the MHV-JHM ORF1a polyprotein: (1) is processed into more than 10 protein intermediates and products, (2) requires membranes for efficient biogenesis, and (3) is detected in discrete membranous regions in the cytoplasm of infected cells.
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PMID:Processing of the coronavirus MHV-JHM polymerase polyprotein: identification of precursors and proteolytic products spanning 400 kilodaltons of ORF1a. 951 67


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