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)

Previous work has shown that the hepatitis B x antigen (HBxAg) and antibodies directed against the polymerase of hepatitis B virus (anti-pol) are early markers of hepatitis B virus (HBV) replication in natural infections. The present study was carried out to test the hypothesis that the appearance of one or both of these markers signaled reactivation in chronic carriers with liver disease who were treated with alpha-interferon (IFN). The results show that HBV DNA decreased among the patients who responded to therapy, and that among these responders, neither HBxAg nor anti-pol became detectable in serum for 12 months after treatment, in contrast to controls. Hence, the loss of HBxAg and anti-pol correlate with decreased levels of HBV DNA in response to IFN therapy. However, different patterns of HBxAg and anti-pol were observed among alpha-IFN-treated HBV carrier patients who were also chronically infected with the hepatitis delta virus (HDV). The treatment of such patients often resulted in the loss of HDV RNA from serum and delta antigen from liver. Most of these patients had increased levels of HBV DNA in serum. HBxAg and/or anti-pol also became detectable in patients who lost markers of HDV, implying that the suppression of HDV by IFN is accompanied by the appearance of early markers of HBV reactivation in some of the treated patients.
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PMID:Hepatitis B x antigen and polymerase antibodies in the serum of hepatitis B carriers with or without hepatitis delta virus infection. Effects of interferon treatment. 150 Jun 93

We have studied antibodies (anti-pol antibody) against the polymerase gene product of hepatitis B virus by solid-phase enzyme immunoassay using synthetic peptides coded for by this gene. Sera from six patients with acute hepatitis B, 112 chronic hepatitis B virus carriers and six healthy individuals with naturally acquired immunity to hepatitis B virus were tested for anti-pol antibody. In acute hepatitis B virus infection, anti-pol antibody was detected in three of six patients. In chronic hepatitis B virus infection, anti-pol antibody was detected in 17 of 29 (59%), in 23 of 33 (70%) of cirrhotic patients and in 18 of 24 (75%) patients with cirrhosis complicated by hepatocellular carcinoma, compared with 4 of 19 (21%) asymptomatic carriers and 2 of 7 (29%) patients with chronic persistent hepatitis. Titers of anti-pol antibody were higher in cirrhotic patients with and without hepatocellular carcinoma than in patients with chronic active hepatitis. The presence of anti-pol antibody, however, had no relationship with hepatitis B virus-associated DNA polymerase activities and other viral replicative markers. As for sera from six healthy individuals with naturally acquired immunity to hepatitis B virus, two (33%) were positive for anti-pol antibody. These results indicate that the immune response toward the polymerase gene product is induced during acute and chronic hepatitis B virus infection. In chronic hepatitis B virus infection, anti-pol antibody may serve as a new marker indicative of a long period of hepatitis B virus-induced hepatitis.
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PMID:Detection of antibodies against the polymerase gene product in hepatitis B virus infection. 239 Oct 62

Antibodies against synthetic peptides derived from the polymerase gene of the hepatitis B virus (HBV) were present in 80% of renal dialysis patients infected with HBV and in woodchucks infected with woodchuck hepatitis virus (WHV). Polymerase antibody (anti-pol) appeared as the earliest marker of both HBV and WHV infections in approximately half of the individuals tested, suggesting that these antibodies were generated following early viral replication in the liver during the incubation period and prior to the appearance of virus in the blood. Many HBV- or WHV-infected individuals negative for surface antigen throughout infection also had anti-pol, but anti-pol appeared only after anti-surface, anti-core and/or anti-e. The presence of anti-pol did not correlate with other serologic markers of HBV or WHV infection, nor did it correlate with histologically confirmed hepatitis in woodchucks. However, there was a significant correlation between the presence of anti-pol and elevated liver enzyme levels in the sera of renal dialysis patients. In several cases, anti-pol was the sole marker of infection, suggesting that underlying infection and low levels of virus replication were present. Most individuals with anti-pol had antibodies to one of the three synthetic peptides, suggesting it may be immunodominant in natural infections. In human populations, groups with a high frequency of HBV infection have a high frequency of polymerase antibodies, and groups with a low frequency of HBV infection have a low frequency of polymerase antibodies. A standard assay for the detection of polymerase antibodies is described, and possible clinical applications are discussed.
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PMID:Presence of antibodies to the polymerase gene product(s) of hepatitis B and woodchuck hepatitis virus in natural and experimental infections. 335 82

The capacities to induce the synthesis of hepatitis B virus (HBV) unit-length DNA were compared for two HBV DNAs with an overall sequence diversity of about 10%. They had been cloned from serum (DNA2) and from a hepatocellular carcinoma (DNA4), respectively. As a major difference, DNA4 carries a translational stop signal preventing the synthesis of precore protein. Progeny DNA yields obtained after transfection with respective pregenome transcription units allocated DNA2 to a low-replicator and DNA4 to a high-replicator phenotype. Cotransfection of DNA2 interfered with progeny DNA synthesis induced by DNA4. By mutual exchange of restriction fragments, the region on the viral genome responsible for the differing replicator phenotypes was confined to a sequence comprising the 3'-terminal part of the X gene, core promoter, encapsidation signal epsilon, precore/core gene, and 5'-terminal part of the pol gene. Point mutations in DNA2 abolishing proper expression of the precore gene strongly enhanced the yield of progeny DNA, whereas cotransfection of a precore expression plasmid with DNA4 or with the mutated DNA2 substantially lowered the amount of progeny DNA. Hence, precore expression acts as an inhibitory principle for HBV replication. The same stop mutation as in DNA4 has been found to arise frequently in virus carriers. Loss of precore expression and concomitant conversion to a more severe hepatitis, as observed in the course of a chronic infection, thus can be explained by a relaxation of replication-level control.
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PMID:Precore-mediated inhibition of hepatitis B virus progeny DNA synthesis. 851 Feb 4

We present evidence for a novel member of the hepadnavirus family that is endemic in wild arctic ground squirrels (Spermophylus parryi kennicotti) in Alaska. This virus, designated arctic squirrel hepatitis virus (ASHV), was initially detected in the livers of animals bearing large hepatic nodules by nucleic acid hybridization with hepadnavirus probes and in plasma by cross-reactivity with antibodies to hepadnavirus surface and core antigens. The complete nucleotide sequence of the 3,302-bp-long ASHV genome was determined and compared with those of ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus (WHV); all sequences were organized into four open reading frames, designated pre-C/C, pre-S/S, pol, and X. Despite roughly equivalent variability among the three rodent hepadnaviruses (around 16% base and 19% amino acid exchanges), ASHV appeared to be more closely related to GSHV than to WHV in phylogenetic analysis. Accordingly, preliminary studies of the pathology of ASHV infection suggested that ASHV may be a less efficient oncogenic agent than WHV. About one-third of aged animals maintained in captivity, including virus-infected as well as uninfected squirrels, developed large liver nodules, consisting of hepatocellular adenomas or carcinomas or nonmalignant lesions characterized by drastic microvesicular steatosis. ASHV-infected arctic ground squirrels may serve as a new model with which to analyze the contribution of hepadnavirus- and host-specific determinants to liver pathology and tumorigenesis.
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PMID:A new hepadnavirus endemic in arctic ground squirrels in Alaska. 867 41

DNA vaccine candidates for foot-and-mouth disease (FMD) were engineered to produce FMD virus (FMDV) particles that were noninfectious in cell culture or animals. The prototype plasmid, pWRM, contains a cytomegalovirus immediate-early promoter-driven genome-length type A12 cDNA followed by the bovine growth hormone polyadenylation site. BHK cells transfected with this plasmid produced virus, but the specific infectivity of pWRM was much lower than that achieved with in vitro-generated RNA genomes. To improve the infectivity of the plasmid, a cDNA encoding the hepatitis delta virus ribozyme was added to the 3' end of the FMDV cDNA. The resulting plasmid, pWRMH, exhibited slightly increased infectivity in cell culture and produced virus when inoculated into suckling mice. A third plasmid, pWRMHX, was created by removal of the sequences encoding the cell binding site found in capsid protein VP1 of pWRMH. Although cells transfected with pWRMHX produced viral capsids, this plasmid was not lethal in suckling mice, indicating that particles lacking the cell binding site were not able to initiate secondary infectious cycles. Swine inoculated with pWRMHX did not show any signs of disease and produced neutralizing antibodies to FMDV, and 20% of the vaccinated animals were protected from challenge. A derivative of pWRMHX, pWRMHX-pol-, harboring a mutation designed to inactivate the viral polymerase was much less immunogenic, indicating that immunogenicity of pWRMHX resulted, in part, from amplification of the viral genome in the animal.
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PMID:Plasmid DNA encoding replicating foot-and-mouth disease virus genomes induces antiviral immune responses in swine. 931 23

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

RNA polymerase II is implicated in the RNA-templated RNA synthesis during replication of viroids and Hepatitis Delta Virus (HDV); however, neither the RNA template nor protein factor requirements for this process are well defined. We have developed an in vitro transcription system based on HeLa cell nuclear extract (NE), in which a segment of antigenomic RNA corresponding to the left-hand tip region of the HDV rod-like structure serves as a template for efficient and highly specific RNA synthesis. Accumulation of the unique RNA product is highly sensitive to alpha-amanitin in HeLa NE and only partially sensitive to this drug in NE from PMG cells that contain an allele of the alpha-amanitin-resistant subunit of pol II, strongly suggesting pol II involvement in this reaction. Detailed analysis of the RNA product revealed that it represents a chimeric molecule composed of a newly synthesized transcript covalently attached to the 5' half of the RNA template. Selection of the start site for transcription is remarkably specific and depends on the secondary structure of the RNA template, rather than on its primary sequence. Some features of this reaction resemble the RNA cleavage-extension process observed for pol II-arrested complexes in vitro. A possible involvement of the described reaction in HDV replication is discussed.
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PMID:Specific HDV RNA-templated transcription by pol II in vitro. 1066 97

Cellular DNA-dependent RNA polymerase II (pol II) has been postulated to carry out RNA-dependent RNA replication and transcription of hepatitis delta virus (HDV) RNA, generating a full-length (1.7-kb) RNA genome and a subgenomic-length (0.8-kb) mRNA. However, the supporting evidence for this hypothesis was ambiguous because the previous experiments relied on DNA-templated transcription to initiate HDV RNA synthesis. Furthermore, there is no evidence that the same cellular enzyme is involved in the synthesis of both RNA species. In this study, we used a novel HDV RNA-based transfection approach, devoid of any artificial HDV cDNA intermediates, to determine the enzymatic and metabolic requirements for the synthesis of these two RNA species. We showed that HDV subgenomic mRNA transcription was inhibited by a low concentration of alpha-amanitin (<3 microgram/ml) and could be partially restored by an alpha-amanitin-resistant mutant pol II; however, surprisingly, the synthesis of the full-length (1.7-kb) antigenomic RNA was not affected by alpha-amanitin to a concentration higher than 25 microgram/ml. By several other criteria, such as the differing requirement for the de novo-synthesized hepatitis delta antigen and temperature dependence, we further showed that the metabolic requirements of subgenomic HDV mRNA synthesis are different from those for the synthesis of genomic-length HDV RNA and cellular pol II transcripts. The synthesis of the two HDV RNA species could also be uncoupled under several different conditions. These findings provide strong evidence that pol II, or proteins derived from pol II transcripts, is involved in mRNA transcription from the HDV RNA template. In contrast, the synthesis of the 1.7-kb HDV antigenomic RNA appears not to be dependent on pol II. These results reveal that there are distinct molecular mechanisms for the synthesis of these two RNA species.
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PMID:RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. 1091 85

Replication of the genome of hepatitis delta virus (HDV) requires RNA-directed RNA synthesis using a host polymerase(s). This manuscript reviews the relevant published evidence. It also provides two new studies, both of which made use of transiently transfected Huh7 cells undergoing HDV RNA-directed RNA synthesis. For the first study, RNA transcription inhibitors were added to the transfected cells for periods of 1 to 2 days, after which assays of the effects on the accumulation of processed unit-length genomic HDV RNA were performed. For the second study, nuclei were isolated at 6 days after transfection, and then in vitro runoff transcription was used to assay the effects of RNA transcription inhibitors. Overall, the data support the interpretation that HDV transcription does not require host polymerase I or III (pol I or III) but at least primarily involves an enzyme resembling pol II.
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PMID:Host RNA polymerase requirements for transcription of the human hepatitis delta virus genome. 1158 84


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