Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of monkey kidney (BSC-40) cells with vaccinia virus strain WR resulted in a marked increase in ribonucleoside diphosphate reductase (EC 1.17.4.1) activity as measured by CDP reduction in cell-free extracts. After a synchronous infection, increased activity was detected at 2 h, peaked at 4 to 5 h, and then declined between 6 and 8 h to the endogenous cellular level. The induction, detectable at 0.5 PFU/cell, correlated strongly with multiplicity of infection to 10 PFU/cell and continued to increase to 50 PFU/cell. It paralleled the previously described induction of viral DNA polymerase and thymidine kinase, suggesting that the reductase may also be a product of early transcription of the viral genome. The inhibition of DNA synthesis throughout infection resulted in prolonged accumulation of reductase activity and delayed and incomplete down-regulation at 8 h, suggesting that repression involves late functions. Rescue of fluorodeoxyuridine-inhibited DNA synthesis with exogenous thymidine restored the normal pattern. Preferential association of the induced reductase with the cytoplasmic sites of vaccinia virus DNA replication (virosomes) was not detected. The induced enzyme is similar in several respects to other eucaryotic ribonucleotide reductases, but is distinct from host cell reductase in response to certain modulators of reductase activity (M. B. Slabaugh and Christopher K. Mathews, J. Virol. 52:501-506, 1984). Full activity required an activator, exogenous reducing equivalents, and iron. Hydroxyurea, EDTA, dATP, and dTTP inhibited CDP reduction, setting this reductase apart from T4 reductase, which is not inhibited by dATP, and from herpesvirus reductase, which requires no activation and is insensitive to deoxyribonucleoside triphosphate inhibition.
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PMID:Vaccinia virus induces ribonucleotide reductase in primate cells. 638 75

Fifteen patients with HBsAg-positive, severe chronic active hepatitis, nine DNA polymerase (DNAP)-positive and six negative were treated with intravenous adenine arabinoside (Ara-A) in a dose of 10 mg/kg/day for five consecutive days during each of two consecutive weeks. Of the DNAP-positive patients, two responded with histological and clinical remission as well as permanent loss of DNAP. However, histological and clinical remission were also observed in patients with unsatisfactory DNAP response and even in DNAP-negative patients. It is suggested that, in addition to its antiviral effect, Ara-A might have another mechanism, such as immunosuppression, that induced histological and clinical remission. Alternatively, the discrepancy of response might relate to the natural course of chronic type B hepatitis. Accordingly, controlled trial is mandatory for assessing the effect of Ara-A or any other agent in the treatment of chronic type B hepatitis.
Infection
PMID:Clinicopathological response of HBsAg-positive chronic active hepatitis to adenine arabinoside: lack of correlation with DNA polymerase response. 649 Jan 67

The DNA polymerase gene of Epstein-Barr virus (EBV) was cloned into baculovirus transfer vector (pBlueBac). The recombinant baculovirus (AcEBP-15) was obtained by cotransfection of Spodoptera frugiperda (Sf9) cells with infectious DNA from Autographa californica multiple nuclear polyhedrin virus (AcMNPV) and pBlueBac plasmid carrying EBV polymerase gene. Infection of Sf9 cells with the recombinant virus produced substantial quantities of the EBV DNA polymerase protein of the expected size (110 kD). The identity of the EBV polymerase 110-kD polypeptide was determined by (a) immunoprecipitation and Western blot analyses with rabbit polyclonal antiserum specific for a synthetic peptide derived from the coding sequence of the polymerase gene; (b) identification of a polypeptide of identical size (110 kD) from EBV-infected cells; (c) measurement of DNA polymerase activity similar to that of the enzyme induced in EBV-infected cells; and (d) neutralization of the enzymatic activity by the rabbit antiserum and inhibition by phosphonoacetic acid. Our results indicate that the baculovirus expression system provides large quantities of functional polymerase suitable for biochemical and structural analyses, thereby furthering our understanding of the mechanism of viral DNA replication and its inhibition by antiviral drugs.
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PMID:Functional characterization of partially purified Epstein-Barr virus DNA polymerase expressed in the baculovirus system. 797 69

The acidic carboxy-terminal 89-amino acid fragment of bacteriophage T4 gene 32 protein was expressed in Escherichia coli to high levels from an inducible plasmid construct. Infection of induced cells by wild-type T4 phage results in impaired phage DNA synthesis. The time at which DNA synthesis begins and the diminution in DNA synthesis rates correlate with the amount of carboxy-terminal peptide that accumulates intracellularly prior to infection. Correspondingly, when induced cells are infected with viable phage containing a small deletion near the carboxy-terminus of 32 protein (delta PR201), the inhibition of phage DNA synthesis was much more severe. The mutant 32 protein competes less well against overproduced wild-type acid peptide than does wild-type 32 protein. The purified acid peptide, when used as the attached ligand for affinity chromatography, binds several T4 proteins from phage-infected cells, including 43 protein (T4 DNA polymerase), Dda protein (a DNA helicase), and UvsX protein (a Rec-like recombination protein). Furthermore, at 50- to 100-fold molar excess of acid peptide over intact 32 protein, phage DNA synthesis was specifically inhibited at the initiation step in an in vitro 5-protein DNA replication experiment. We propose that one or more phage replication proteins are titrated as non-productive protein-protein complexes at a site away from the DNA template. This implies that the carboxy-terminal domain of 32 protein is involved in an obligate step of replication machine assembly when the protein is properly attached to ssDNA in the vicinity of a primer-template junction. The assembly defect we observe is strikingly similar to the repression, or "squelching", of the activity of certain eukaryotic transcriptional activators.
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PMID:Assembly of the bacteriophage T4 replication machine requires the acidic carboxy terminus of gene 32 protein. 842 54

Most human megakaryocytes (MGKs) express the CD4 antigen on their surface. Approximately 25% have a CD4 receptor density comparable to that of CD4+ T cells (Basch et al, Proc Natl Acad Sci USA 87:8085, 1990). In these studies, we show: (1) the presence of mRNA for CD4 in human MGKs; (2) the binding of human immunodeficiency virus-1 (HIV-1) to human MGKs; (3) the inhibition of binding by anti-CD4 (Leu3a) antibody or rCD4; (4) the infection of a human MGK line, CHRF-288 with HIV-1; and (5) inhibition of infection with anti-CD4. Human MGKs have mRNA for CD4 as shown by in situ hybridization with an RNA probe synthesized from a 3-kb cDNA sequence of plasmid pSP65.T4.8 containing the full-length CD4 sequence. MGKs (23% +/- 17%) bound HIV-1, as determined by anti-gp120 and anti-CD41 staining. Binding to human MGKs could be inhibited 55% to 75% with anti-CD4 or rCD4, respectively. Infection of a CD4+ MGK line (CHRF-288) could be accomplished with HIV-1, as determined by proviral DNA polymerase chain reaction and p24 production. Preincubation with anti-CD4 inhibited apparent proviral DNA infection by 100% and p24 production by 65% to 70%. Thus, human MGKs have a CD4 receptor capable of binding HIV-1. Using this receptor, HIV-1 can infect cells representative of the MGK lineage.
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PMID:Human megakaryocytes have a CD4 molecule capable of binding human immunodeficiency virus-1. 849 Jan 76

Infection with hepatitis B virus can result in asymptomatic seroconversion with viral clearance, fulminant hepatic failure and death, or chronic, typically lifelong, transmissible infection. The mechanism(s) of viral persistence are poorly understood but viral clearance and fulminant hepatic failure are generally thought to result from co-ordinated and effective and abnormally vigorous immune responses, respectively, whereas viral persistence results from immunological failure in addition to poorly characterized viral factors promoting persistence. This paper proposes (1) that the predominant viral factor(s) promoting persistence of hepatitis B virus are homeostatic mechanism(s) responsible for modulating its replication and mutation and (2) that chronic hepatitis B results when these mechanisms are successful and other outcomes occur when these homeostatic mechanism(s) fail. Furthermore, it is proposed that seroconversion (e.g. from HBsAg to anti HBsAg positivity), when it occurs, is a consequence facilitated by restricted viral antigenic diversity and reduced viral replication rather than a proximate cause of it. The specific homeostatic mechanisms proposed--negative feedback inhibition of hepatitis B virus DNA polymerase/reverse transcriptase mediated by HBs antigen and a hepatitis B virus DNA polymerase fidelity modulating function of HBeAg--are consistent with the available data and resolve many paradoxical clinical observations. But, more importantly, this model has clear implications for therapy, including the rational design of drugs and therapeutic vaccines.
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PMID:Hepatitis B virus replication and mutation are autoregulated by interactions between surface antigen and HBeAg and the HBV DNA polymerase: a functional model with therapeutic implications. 904 82

Transmission of human immunodeficiency virus (HIV) and mortality was studied among infants of infected women in Zimbabwe. Of 367 infants born to HIV-infected women, 72 (19.6%) died compared with 20 (5.4%) of 372 infants of uninfected women (P < .01). Infection by HIV DNA polymerase chain reaction among infants who survived >7 days and died within 2 years could be assessed in 87% (58/67) of infants of infected women and 83% (5/6) of infants of uninfected women; transmission occurred in 40 of 58 infants. Among 27 infected infants tested at birth, 19 (70%), 5 (19%), and 3 (11%) were apparently infected via in utero, intrapartum or early postpartum, and late postpartum transmission, respectively. The majority of HIV-infected infants who died in the first 2 years of life were likely to have acquired in utero infection.
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PMID:Mortality in the first 2 years among infants born to human immunodeficiency virus-infected women in Harare, Zimbabwe. 965 29

This report describes the antigenic and nucleotide characterization of a herpes-like virus that has been isolated from the adrenal tissues of neonatal Pacific harbor seals. Infection with this virus has been previously implicated as a major cause of death of animals undergoing rehabilitation. Comparison and phylogenetic analysis of sequenced fragments of the DNA polymerase, glycoprotein B and glycoprotein D genes, and immunofluorescence assay using herpesvirus-specific monoclonal antibodies, demonstrated close similarity of the Pacific harbor seal herpesvirus to European isolates of phocid herpesvirus-1 (PHV-1) and other alpha-herpesviruses affecting terrestrial carnivores.
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PMID:Antigenic and nucleotide characterization of a herpesvirus isolated from Pacific harbor seals (Phoca vitulina richardsii). 985 89

Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting. Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease. Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of CMV to ganciclovir is related to mutations in the UL97 region of the viral genome and/or mutations in the viral DNA polymerase. Resistance to foscarnet and cidofovir is associated with mutations in the viral DNA polymerase. Antiviral susceptibility of CMV strains containing DNA polymerase mutations is dependent on the region of the DNA polymerase where the mutations are located. Some DNA polymerase mutant viruses are cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition that specific UL97 and UL54 mutations are associated with resistance to antiviral agents has led to the development of molecular methods for detection of mutant viruses. This article reviews the mechanisms of resistance of CMV to antiviral agents, the laboratory methods for detection of resistant CMV, and the clinical aspects of infections caused by antiviral-resistant CMV.
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PMID:Resistance of human cytomegalovirus to antiviral drugs. 1019 60

Infection of cells with viable or UV-inactivated murine cytomegalovirus (MCMV) increased the IFN-inducible 204 gene at both the mRNA and the protein levels. The activity of a reporter gene driven by the mouse Ifi204 promoter induced following virus infection showed that this increase was due to transcriptional activation. Moreover, FACS analysis of infected mouse embryo fibroblasts (MEF) stably transfected with a p204-dominant-negative mutant (p204dmMEF) revealed that they do not accumulate at the G1/S border in the same way as infected MEF transfected with the empty vector (neoMEF). MCMV DNA synthesis is significantly delayed (144 h in p204dmMEF vs 72 h in neoMEF), due to retarded expression of viral genes, namely, IE1 and DNA polymerase, as shown by Western blot comparison of p204dmMEF and neoMEF extracts. These results demonstrate that MCMV may exploit the Ifi204 gene to regulate the cell cycle and enhance its DNA synthesis.
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PMID:The interferon-inducible 204 gene is transcriptionally activated by mouse cytomegalovirus and is required for its replication. 1148 93


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