UMLS:C0019158 - FACTA Search

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

After the discovery of HDV there have been significant advances in the understanding of the biology and disease of HDV infection. Analyses at the molecular level have revealed several fascinating features (ribozyme activity, RNA-dependent RNA polymerase activity of RNA polymerase II, HDAg isoprenylation, and RNA editing) that are of significant interest. Intensive investigation of the ribozyme elements has yielded important insights in both functional and structural features. However, there is information lacking about other aspects of the HDV replication cycle including the specific nature of the interaction between HDAg and HDV RNA, the function of HDAg in HDV RNA replication, transcription by RNA polymerase II, and the mechanisms of HDV RNA editing and its regulation. Further study of these and other aspects of the HDV replication cycle will continue to enrich our understanding of basic biology. Evaluation of the mechanisms of HDV disease remains an important goal in the study of this agent. Although both acute and chronic disease are commonly associated with unfavorable outcomes, it is clear that chronic infection is associated with a broad spectrum of disease. The interactions between HDV, HBV, and the host are necessarily complex, and it is likely that each contribute factors that influence disease and outcome. Recent analyses of HDV genotypes have suggested that disease variations may be associated with viral genetic factors. Consistent with the obligate role of HBV in the HDV life cycle, HBV replication is also an important determinant of HDV disease. It is still unclear if interactions between specific genotypes or variants of HBV and HDV influence disease. Recent data also suggest that infection with multiple hepatitis viruses (HBV, HDV, and HCV) can influence the severity of disease. It remains to be seen whether coinfection with the recently discovered hepatitis G virus is associated with altered disease patterns. Further advances in our understanding HDV disease and possible therapeutic approaches will rely on a combination of additional studies at the molecular, genetic, epidemiologic, and clinical levels. These studies will continue to elaborate the model of HDV infection and disease that can ultimately be tested by experimental infection of chimpanzees and woodchucks.
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PMID:Hepatitis delta virus. Genetics and pathogenesis. 879 82

When the small form of the delta antigen (deltaAg-S) was expressed from a cDNA expression plasmid and subsequently detected by immunofluorescence, it was found localized to the nucleoli. However, if the cDNA was cotransfected with a cDNA expressing a mutated hepatitis delta virus (HDV) genome that could only replicate by using the deltaAg-S provided by the first plasmid, then most of the deltaAg-S was redistributed to the nucleoplasm, largely to specific discrete nucleoplasmic sites or speckles; this pattern was stable for at least 50 days after transfection. These speckles coincided with those detected with an antibody to SC35, an essential non-small nuclear ribonucleoprotein splicing factor. Others have shown that SC35 speckles correspond to active sites of DNA-directed transcription by RNA polymerase II and also of RNA processing. We also found, in contrast to the cotransfections with the mutant HDV and the deltaAg-S provided in trans, that cells transfected with wild-type HDV showed a variable pattern of staining. The SC35-like speckle pattern of accumulation of delta antigen deltaAg was maintained for only 6 days, after which the pattern began to change. By 18 days posttransfection, a variety of different deltaAg staining patterns were observed. This pattern of change occurs at a time when the large form of the delta antigen deltaAg-L appears and HDV RNA synthesis begins to shut down. Our studies therefore support the interpretation that HDV RNA and deltaAg-S accumulate at SC35 speckle sites in the nucleoplasm. We speculate that these may be the sites at which HDV RNA is transcribed by RNA polymerase II and/or sites of HDV RNA processing. Furthermore, when deltaAg-L, as well as other mutant deltaAg accumulate, the speckle association is disrupted, thereby stopping HDV RNA replication.
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PMID:Redistribution of the delta antigens in cells replicating the genome of hepatitis delta virus. 889 31

We provide the first report, to our knowledge, of a helper-independent system for rescuing a segmented, negative-strand RNA genome virus entirely from cloned cDNAs. Plasmids were constructed containing full-length cDNA copies of the three Bunyamwera bunyavirus RNA genome segments flanked by bacteriophage T7 promoter and hepatitis delta virus ribozyme sequences. When cells expressing both bacteriophage T7 RNA polymerase and recombinant Bunyamwera bunyavirus proteins were transfected with these plasmids, full-length antigenome RNAs were transcribed intracellularly, and these in turn were replicated and packaged into infectious bunyavirus particles. The resulting progeny virus contained specific genetic tags characteristic of the parental cDNA clones. Reassortant viruses containing two genome segments of Bunyamwera bunyavirus and one segment of Maguari bunyavirus were also produced following transfection of appropriate plasmids. This accomplishment will allow the full application of recombinant DNA technology to manipulate the bunyavirus genome.
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PMID:Rescue of a segmented negative-strand RNA virus entirely from cloned complementary DNAs. 898 23

To develop vector systems that combine high transcription activity with biologically safe delivery vehicles, we have explored the use of RNA replication to amplify mRNAs, by using flock house virus (FHV) as a model system. The FHV RNA replicase is encoded in the larger of the two segments that comprise the viral positive-sense RNA genome. A cDNA copy of this self-replicating RNA was precisely positioned between a promoter site for cellular RNA polymerase II and a cDNA encoding a self-cleaving ribozyme from hepatitis delta virus. Transfection of this plasmid into cultured BHK cells resulted in prolonged, autonomous FHV RNA replication in the cytoplasm and substantial amplification of the RNA replicon. The replicase also amplified RNA transcribed from a second plasmid of similar design that contained a cDNA copy of the other FHV genome segment. These results constitute a significant step toward the harnessing of nodaviral RNA replication as the basis of a versatile vector system.
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PMID:Replication of flock house virus RNAs from primary transcripts made in cells by RNA polymerase II. 906 Jul 3

In the presence of an RNA- temperature-sensitive (ts) mutant helper virus, two coronavirus mouse hepatitis virus (MHV) defective interfering (DI) RNAs complemented each other, resulting in the assembly of MHV particles; we used this ability to complement as a means to study coronavirus assembly. One of the two DI RNAs was DIssA, a naturally occurring self-replicating DI RNA encoding N protein and the gene 1 proteins that encode RNA polymerase function; DIssA supports the replication and transcription of other non-self-replicating DI RNAs. The other DI was a genetically engineered DI RNA that encoded sM and M proteins. Coinfection of these two DIs at the nonpermissive temperature for the ts helper virus resulted in replication and transcription of both DI RNAs but not in synthesis of the helper virus RNAs. MHV particles containing DI RNAs, N protein, and M protein, all of which were exclusively derived from the two DI RNAs, were released from the coinfected cells; the amount of sM protein was below the limits of detection. Analyses of DI RNAs with mutations in the two envelope protein genes demonstrated that M and sM proteins appeared to be required for assembly and release of MHV particles that contained DI RNAs and N protein, while S protein was not required for assembly and release of MHV particles.
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PMID:Assembled coronavirus from complementation of two defective interfering RNAs. 909 69

Chronic inflammatory states frequently lead to the increased production of nitric oxide (NO) via inducible NO synthase (NOS-2). In addition, NO may produce mutagenesis through several mechanisms such as DNA oxidation, DNA deamination, and the formation of N-nitroso compounds. As there is a strong association between human hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC), we were interested in whether human HCV hepatitis leads to induction of NOS-2 and if the mutation repair system of p53/p21 was upregulated. Reverse transcriptase-polymerase chain reaction (RT-PCR) for human NOS-2 message was performed on RNA samples from both liver biopsies and whole liver from HCV-positive and control patients (normal liver from hepatic resections for metastases). Immunohistochemistry (IHC) for p53 and Western blot analysis for p21 were also performed on the whole liver samples. From the liver biopsies, 60% of HCV-positive patients expressed NOS-2 by RT-PCR. Looking at the whole liver samples, 100% of the HCV-positive patients expressed NOS-2 vs 12.5% in the normal samples. p53 was not detected in either group but there was upregulation of p21 over baseline expression in a number of the HCV-positive patients. Human HCV hepatitis leads to consistent upregulation of hepatic NOS-2 message, but message is not predictably present in "normal" human liver. There is also induction of p21 in some patients with HCV hepatitis. Chronic expression of NO in HCV hepatitis may play a role in DNA mutagenesis and the development of HCC.
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PMID:Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. 922

Analysis of the variable chains (V alpha/V beta) of the specific T cell receptor (TCR) of organ-infiltrating T cells may provide further insights into the pathogenesis of many infectious diseases, malignancies, and autoimmune disorders. To determine the TCR V beta repertoire of these small T cell populations antigen-independent in vitro expansion is necessary but may select for certain T cell subpopulations. In this study various antigen independent T cell activation protocols were used to stimulate peripheral blood mononuclear cells (PBMC) of six healthy blood donors, and TCR V beta molecules were analyzed by flow cytometry and semiquantitative reverse-transcriptase polymerase chain reaction. In addition, the analysis of in vitro expanded liver-infiltrating T cells and autologous peripheral blood T cells derived from five patients with autoimmune hepatitis but none of six controls revealed a selective overexpression of single TCR V beta molecules in the liver tissue. In contrast to freshly isolated PBMC, no preferential expansion of single TCR V beta families was observed using phytohemagglutinin, anti-CD3 antibodies, or oxidative stress for antigen-independent T cell activation. In conclusion, antigen-independent T cell activation offers the chance to analyze small populations of organ-infiltrating T cells without skewing the TCR V beta repertoire.
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PMID:Antigen-independent in vitro expansion of T cells does not affect the T cell receptor V beta repertoire. 935 7

A complete cDNA clone of the genome (15,246 nucleotides) of the paramyxovirus SV5 was constructed from cDNAs such that an anti-genome RNA could be transcribed by T7 RNA polymerase and the correct 3' end generated by cleavage using hepatitis delta virus ribozyme. The plasmid encoding the antigenome sequence was transfected into cells previously infected with recombinant vaccinia virus that expressed T7 RNA polymerase, together with helper plasmids that expressed the viral replication proteins, NP, P, and L, under the control of the T7 polymerase promoter. Rescue of the RNA genome from DNA was demonstrated by recovering SV5 with the tag restriction sites introduced into the DNA clone, using RT-PCR of the genome RNA and nucleotide sequencing. Rescue of SV5 from DNA did not require expression of the viral V protein as a helper plasmid, suggesting that V protein is not essential for initial replication. The infectious cDNA of SV5 was also manipulated to express green fluorescent protein (GFP) under the control of SV5 transcriptional start and stop signals introduced between the HN and L genes. The amount of GFP that was expressed varied depending on the nature of the newly introduced transcription signals.
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PMID:Recovery of infectious SV5 from cloned DNA and expression of a foreign gene. 935 37

A recently discovered non-A-E hepatitis virus has been designated as hepatitis G virus (HGV) and identified as a new member of the Flaviviridae family. Infection by this virus is thought to be associated with blood-borne hepatitis and usually in the presence of hepatitis C or hepatitis B virus (HBV) infection. In this study, the presence of HGV-RNA in serum or plasma and the prevalence of antibodies against an HGV envelope protein (E2) were investigated in patients undergoing chronic hemodialysis using a sensitive reverse-transcriptase polymerase chain reaction and an enzyme-linked immunosorbent assay, respectively. HGV-RNA was detected in 19 of 112 patients investigated (17%) and anti-E2 antibodies were detected in 15 of 106 patients studied (14.2%). With the exception of two patients, the appearance of anti-E2 is associated with the clearance of serum HGV-RNA. The total prevalence of current (HGV-RNA positivity) and/or past (anti-E2 positivity) HGV infection in this patient population is thus 28.6% (32 of 112 patients were positive for serum HGV-RNA and/or anti-E2 antibodies). In apparently healthy blood donors, serum HGV-RNA was detected in four of 358 individuals (1.12%) and anti-E2 was not detected in 50 individuals investigated. From the 19 patients with serum HGV-RNA positivity, nine were coinfected with other hepatitis viruses (seven with HBV; one with HBV, hepatitis C virus [HCV], and hepatitis D virus; and one with HBV and cytomegalovirus). Thirteen of 15 patients with anti-E2 positivity (10 were positive for only anti-E2 and three were also positive for anti-HBc) had no detectable HGV-RNA. In two patients, both HGV-RNA and anti-E2 antibodies were concomitantly present (both patients were coinfected with HCV or HBV). Of the HGV-infected patients, only three who were coinfected with HBV showed elevated serum alanine aminotransferase levels. The serum HCV-RNA and/or anti-HCV were detected in five (4.5%) of 112 patients. From these findings, we conclude that there is a high prevalence of HGV infection (28.6%) compared with HCV (4.5%) in patients undergoing hemodialysis in our hospital. However, approximately 50% of patients had spontaneously lost the viremia and developed anti-HGV-E2 antibodies. We confirm that HGV infection alone is not associated with elevated serum transaminases, and the appearance of anti-HGV-E2 is usually accompanied with clearance of serum HGV-RNA. In contrast to the results of our previous study, the majority of patients infected with HGV are not coinfected with HCV, indicating that HGV is capable of independent transmission. It is likely that there is a preferential HGV acquisition in the hemodialysis unit. The clinical significance of long-term infection with HGV remains to be established.
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PMID:High prevalence of hepatitis G virus infection compared with hepatitis C virus infection in patients undergoing chronic hemodialysis. 946 14

Hepatitis delta virus (HDV) contains a circular, viroid-like RNA and the hepatitis delta antigen (HDAg) protein. The viral RNA is replicated via RNA-dependent RNA synthesis, which is thought to be mediated by host DNA-dependent RNA polymerase II (pol II). The precise mechanism of HDV RNA replication using RNA as a template remains to be elucidated, though it is clear that HDAg is involved. We demonstrate here that both SP1-activated and basal pol II transcription are inhibited by HDAg. This inhibitory effect of HDAg was observed in vivo in transient cotransfection assays as well as in vitro in HeLa nuclear extracts with purified, recombinant HDAg. The in vitro inhibition of pol II transcription could be reversed with excess HeLa nuclear extracts. Furthermore, HDAg specifically inhibited pol II-mediated transcription but not pol I- or III-mediated transcription. These results provide support for the model in which HDAg participates in a complex with host cell pol II transcription factors to mediate pol II-dependent HDV RNA replication, concomitantly cellular pol II transcription.
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PMID:Inhibition of Cellular RNA polymerase II transcription by delta antigen of hepatitis delta virus. 970 11

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