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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary duck hepatocyte (PDH) cultures, congenitally infected with the duck hepatitis B virus (DHBV), were grown on feeder cell layers of irradiated human embryonic lung fibroblasts and then exposed to a number of compounds with recognized or potential antiviral activity. These compounds included conventional antiviral agents, reverse transcriptase inhibitors, compounds with activity to supercoiled-DNA, and DNA-binding agents. Twenty-three compounds were evaluated, and 13 were found to inhibit significantly viral DNA replication. Seven of these compounds (ellipticine, amsacrine, coumermycin A1, Adriamycin, mitozantrone, chloroquine, and neocarzinostatin) acted at the level of viral SC DNA and significantly inhibited production of duck hepatitis B surface antigen (DHBsAg). Conventional agents that inhibited DHBV DNA replication included ganciclovir, acyclovir, bromovinyldeoxyuridine, ribavirin, phosphonoformate, and dideoxyadenosine. Except for dideoxyadenosine, these inhibitors of viral DNA synthesis did not significantly inhibit DHBsAg production. Two additional compounds, novobiocin and nalidixic acid, altered the pattern of viral DNA replication, especially the generation and processing of viral SC DNA, and also inhibited the production of DHBsAg. Several compounds acting at the level of viral SC DNA have now been identified and may offer potential for the management of chronic hepatitis B virus infection.
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PMID:Antiviral strategies in chronic hepatitis B virus infection: II. Inhibition of duck hepatitis B virus in vitro using conventional antiviral agents and supercoiled-DNA active compounds. 169 59

Constructs expressing the core, surface, X, or polymerase proteins of hepatitis B virus were transfected into human cells. In transient assays, only the polymerase inhibited the responses to interferons alpha and gamma (IFN-alpha and -gamma). Stable expression of the polymerase was achieved in the cell line 2fTGH, which carries an IFN-inducible marker gene, by growth under conditions that select for inhibition of the response to IFN-alpha, but the clones grew poorly. When expressed alone, the terminal protein domain of the polymerase gene inhibited the response to IFN-alpha and the reverse transcriptase plus RNase H domains appeared to be toxic. Clones of cells expressing terminal protein alone, selected for the loss of response to IFN-alpha, grew normally and had no detectable response to IFN-alpha, IFN-gamma, or double-stranded RNA. Binding of IFN-alpha to these cells was not impaired but did not lead to activation of the E alpha subunit of the IFN-induced transcription factor E. These observations are of potential importance in relation to the pathogenesis of chronic hepatitis B virus infection and the resistance of such infection to IFN-alpha therapy.
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PMID:Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA. 170 74

The effect of 2',3'-dideoxycytidine, a potent antiviral agent, which, following anabolic phosphorylation, inhibits the reverse transcriptase of the human immunodeficiency virus in vitro, was assessed in 16 Pekin ducks chronically infected with the duck hepatitis B virus. Nine ducks were given 11 mg/m2 of dideoxycytidine intravenously every 6 h, and 7 ducks received no treatment. Serum duck hepatitis B virus deoxyribonucleic acid and deoxyribonucleic acid polymerase activity decreased in every duck treated with dideoxycytidine. The mean inhibition of deoxyribonucleic acid polymerase and duck hepatitis B virus deoxyribonucleic acid on the third day of treatment measured 64% (p less than 0.01) and 73% (p less than 0.01), respectively. The inhibition of deoxyribonucleic acid polymerase persisted after treatment was stopped, and 4 ducks continued to show greater than 50% inhibition 12 days after stopping treatment. Duck hepatitis B virus deoxyribonucleic acid, which was measured in total cellular deoxyribonucleic acid extracted from liver biopsy specimens obtained before and on the last day of treatment with dideoxycytidine, showed an average inhibition of 96% in 3 ducks treated with dideoxycytidine, but showed no decrease in the remaining 5 ducks. Thus, dideoxycytidine has potent antiviral activity against duck hepatitis B virus and warrants further evaluation as an antiviral agent in the treatment of chronic hepatitis B virus infection in humans.
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PMID:Inhibition of duck hepatitis B virus replication by 2',3'-dideoxycytidine. A potent inhibitor of reverse transcriptase. 247 99

The hepatitis B virus is a member of an unusual family of noncytopathogenic, hepatotropic DNA viruses--the hepadnaviruses. The complete virus comprises a lipoprotein coat, the hepatitis B surface antigen, enveloping a nucleocapsid core that contains a small, circular DNA molecule. Four open reading frames have been identified on the hepatitis B virus DNA genome. They encode seven proteins, including a hepatitis B virus DNA polymerase molecule with reverse transcriptase activity. The replication of the virus resembles that of retroviruses and occurs predominantly but not exclusively in hepatocytes. Virus variants involving genomic mutations have been identified. Testing for hepatitis B surface antigen permits detection of many but not all acutely infected patients. Diagnosis of acute infection rests on the identification of IgM antibodies to the hepatitis B core antigen. Antibody to hepatitis B surface antigen appears in serum during the convalescent phase of hepatitis B virus infection. It is the neutralizing, protective antibody largely responsible for immunity to reinfection. In persistent infection hepatitis B surface antigen is present, antibody to hepatitis B core antigen is predominantly an IgG antibody, antibody to hepatitis B surface antigen is not detectable or is present in very low titers and viral replication may be active. Persistent infection leads to an asymptomatic carrier state, chronic hepatitis, cirrhosis and hepatocellular carcinoma. No specific treatment exists for acute hepatitis B virus infection. Current data indicate that approximately 50% of adults who have chronic infection achieve virologic, biochemical and histologic remission from treatment with alpha-2b-interferon.
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PMID:Hepatitis B today: clinical and diagnostic overview. 832 12

Hepatitis-associated aplastic anemia (HAAA) is an uncommon disorder that usually is not due to hepatitis A or B virus infection. Hepatitis C virus (HCV) seropositivity is infrequently observed in aplastic anemia (AA) patients who have not been extensively transfused. However, HCV seropositivity may not be detected until several weeks or months after viral infection and AA patients may exhibit defective humoral immunity. Therefore, we evaluated sera from AA patients for the presence of HCV viremia using a reverse transcriptase polymerase chain reaction (RT-PCR) based assay and several serologic assays for HCV antibodies. Serum samples from 90 AA patients who presented to the UCLA Medical Center between March 1984 and February 1990 were analyzed. Overall, 17 patients were found to have HCV viremia by RT-PCR assay, of whom 14 had a positive second-generation HCV enzyme immunoassay (EIA-2) and only 6 were EIA-1 reactive. The frequency of HCV viremia increased with the duration of time between diagnosis and sample procurement, and the number of blood products transfused prior to sampling (P = 0.026). No patient who received fewer than 20 U of blood products or who was sampled less than 20 days after diagnosis had a positive HCV RT-PCR result. Of four patients with hepatitis-associated AA (HAAA), one who was sampled 23 days after diagnosis had hepatitis C viremia and a reactive EIA-2 assay. Therefore, the high frequency of HCV viremia in this patient population is most likely due to transfusion with contaminated blood products prior to the introduction of routine blood donor screening for HCV.
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PMID:Hepatitis C virus infection in acquired aplastic anemia. 962 79

The routes of hepatitis B virus and hepatitis C virus transmission are quite similar and coexistence of both viruses in one patient is not a rare phenomenon. Until now, the natural course of liver diseases induced by coinfections has not been well documented and the mechanisms of interaction between the two viruses and the human host have not been fully clarified. We report the case of a patient suffering from chronic hepatitis due to hepatitis C virus who developed an acute hepatitis B virus superinfection. Serum hepatitis C virus ribonucleic acid became undetectable by reverse transcriptase/polymerase chain reaction at diagnosis of acute hepatitis B virus infection. At the same time, there was a striking increase in the serum concentrations of the antibodies against C22 and C33c hepatitis C virus antigens. Four months after clinical resolution of the acute hepatitis, hepatitis B surface antigen was undetectable in serum and three months later antibodies against hepatitis B surface antigen appeared. Two years after acute hepatitis B virus infection, the patient has had no relapse of markers for viral replication of hepatitis B virus. Transaminases are within the reference range and hepatitis C virus ribonucleic acid is undetectable in both serum and liver tissue. We hypothesize that acute hepatitis B virus infection stimulated a specific humoral response against hepatitis C virus as well as triggering non-specific defense mechanisms which finally eliminated both viruses.
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PMID:Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection. 1084 91

Hepatitis B genotype D (HBV/D) is the most widespread genotype and exists as at least five subgenotypes (HBV/D1-D5). However, little is known about the association of virological characteristics with clinical differences among HBV/D subgenotypes. To investigate the virological characteristics of these subgenotypes and their clinical implications, we selected a cohort of 109 genotype D infected individuals from the state of West Bengal, India, including 68 HBsAg positive patients and 41 with occult HBV infection. Among the HBsAg positive subjects 28 had chronic hepatitis B virus infection, 40 were asymptomatic carriers based on clinical examination, liver function test and ultrasonograph results. Overall, HBV/D1 was found in 17%, HBV/D2 in 29%, HBV/D3 in 34% and HBV/D5 in 20% of the cases. HBV/D1 was significantly associated with chronic liver disease (P = 0.01), and in this subgenotype A1896 (PreC mutations) were most common. Although BCP mutations (A/C1753 and T1762/A1764) were found to be frequently associated with HBV/D2 (33% and 33%) and D5 (47% and 59%), no apparent clinical correlation was observed. On the other hand, occult HBV infection was significantly associated with HBV/D3 infection, along with low level of BCP and PreC mutations and several non-synonymous substitutions in the catalytic reverse transcriptase (RT) domain of polymerase gene. Similar nucleotide substitutions in the surface (S) gene region were observed from both northern and eastern Indian HBV/D3 isolates. In conclusion, HBV/D subgenotypes differ in their mutational patterns in the S, polymerase and the BCP/PreC regions that may influence their clinical outcomes.
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PMID:Subgenotypes of hepatitis B virus genotype D (D1, D2, D3 and D5) in India: differential pattern of mutations, liver injury and occult HBV infection. 1945 42

Although an estimated 1 million persons in the United States are chronically infected with hepatitis B virus, the prevalence of hepatitis B has declined since the implementation of a national vaccination program. Hepatitis B virus is transmitted in blood and secretions. Acute infection may cause nonspecific symptoms, such as fatigue, poor appetite, nausea, vomiting, abdominal pain, low-grade fever, jaundice, and dark urine; and clinical signs, such as hepatomegaly and splenomegaly. Fewer than 5 percent of adults acutely infected with hepatitis B virus progress to chronic infection. The diagnosis of hepatitis B virus infection requires the evaluation of the patient's blood for hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody. The goals of treatment for chronic hepatitis B virus infection are to reduce inflammation of the liver and to prevent complications by suppressing viral replication. Treatment options include pegylated interferon alfa-2a administered subcutaneously or oral antiviral agents (nucleotide reverse transcriptase inhibitors). Persons with chronic hepatitis B virus infection should be monitored for disease activity with liver enzyme tests and hepatitis B virus DNA levels; considered for liver biopsy; and entered into a surveillance program for hepatocellular carcinoma.
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PMID:Hepatitis B: diagnosis and treatment. 2038 72

A novel polymerase chain reaction (PCR)-Luminex assay was developed for rapid, accurate, and high-throughput detection of the most important hepatitis B virus (HBV) variants, including those with reverse transcriptase (RT) domain L180M, M204I/V, A181T/V/S, I233V and N236T mutations associated with resistance to lamivudine (LAM) or adefovir (ADV). Using mixtures of mutant and wild-type HBV, this method was sufficiently sensitive for detecting 10(3)HBV ml(-1) and could detect minor mutants when they comprised 5% of the total viral population. Comparison of the PCR-Luminex assay with INNO-LiPA for detecting clinical LAM- or ADV-resistant chronic hepatitis B virus infection in 64 patients confirmed the following: the 2 methods were 97.9% (48 of 49) and 93.3% (14 of 15) concordant for detecting LAM- or ADV-resistance mutations, respectively. The agreement with direct sequencing was 70.3% (45 of 64). The PCR-Luminex assay or multi-analyte suspension array can detect simultaneously and efficiently minor populations HBV mutants early during infection in many clinical samples. It is a simple, cost-effective method for resistance surveillance or selecting appropriate antiviral agents and initiating timely rescue treatment before the development drug-resistance related virus or biochemical breakthrough.
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PMID:Detection of lamivudine- or adefovir-resistant hepatitis B virus mutations by a liquid array. 2151 43

Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
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PMID:Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. 2612 70


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