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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An RNA-dependent RNA polymerase activity has been demonstrated for spring viremia of carp virus (SVCV). The optimal temperature for in vitro synthesis of RNA was 20 to 25 degrees C. The SVCV enzyme activity was stimulated when the methyl donor S-adenosyl-L-methionine was included in the reaction mixture. S-adenosyl-L-methionine was not particularly effective in stimulating the virion RNA polymerase activity of vesicular stomatitis virus or pike fry rhabdovirus. The 5' nucleotide of the SVCV viral RNA is pppAp.
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PMID:Spring viremia of carp virus RNA and virion-associated transcriptase activity. 56 17

The retroviruses human T-cell lymphotrophic virus-I (HTLV-I) and HTLV-III/LAV (lymphadenopathy-associated virus) are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV). Because HTLV-III infects only humans and chimpanzees, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT) is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.
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PMID:Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine. 346 67

S-Adenosyl-L-methionine (SAM), a methyl donor, and its analogue S-adenyl-L-homocysteine (SAH), an inhibitor of methylation, stimulate the activity of spring viraemia of carp virus (SVCV) virion transcriptase. The stimulation observed for SVCV is analogous to that observed previously (Furuichi, 1974, 1978) for a totally unrelated virus, cytoplasmic polyhedrosis virus (CPV). In the absence of exogenous SAM, RNA with 5'-methylated termini (presumptive GpppAmpAp) was produced, indicating that SVCV has an endogenous methyl donor. Significantly less methylated termini were produced when SVCV nucleocapsids were used to prime in vitro transcription reactions, suggesting that the majority of the endogenous methyl donor is not associated with the nucleocapsid. Partial removal of endogenous methyl donor by preparing nucleocapsids did not have any effect on the degree of stimulation by exogenous SAM or SAH. We conclude from this study that SAH has two effects on SVCV transcription, inhibition of methylation and stimulation of transcription.
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PMID:Stimulation of transcription by S-adenosyl-L-homocysteine and virion-encapsidated methyl donor in spring viraemia of carp virus. 727 15

Sera from 39 out of 40 patients with chronic hepatitis C virus (HCV) infection who had been treated for 60 weeks with interferon alfa-2b proved initially HCV RNA positive by reversed transcriptase polymerase chain reaction (PCR). These patients were analysed for genotype and quantitatively for HCV RNA levels prior to treatment by using a competitive PCR method with colorimetric detection of the amplified products. HCV RNA levels were correlated to outcome of treatment, mode of acquisition, histology and HCV genotype. The median pretreatment HCV RNA level in sustained responders (n = 15) with eradication of the viremia and normalization of serum ALT levels lasting 24 weeks post treatment was significantly lower than that in the combined group of non-sustained responders (n = 9) and non-responders (n = 15), 2.52 x 10(5) vs 8.90 x 10(5) genome equivalents per ml serum, p < 0.0125, respectively. 10 out of 17 patients with HCV RNA levels lower than the median level (5.64 x 10(5) genome equivalents per ml serum) had a sustained response to interferon treatment versus only 5/22 with levels equal to or higher than the median level, p = 0.04. No significant pretreatment differences in median HCV RNA levels according to mode of acquisition, genotype, or liver histology prior to treatment were seen. It is concluded that a low pretreatment HCV RNA level seems to be indicative of a sustained response to interferon alfa-2b treatment, whereas a high level seems to be indicative of a non-sustained or non-response. In the individual patient, however, the levels varied widely irrespective of response category.
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PMID:Serum hepatitis C virus RNA levels in chronic hepatitis C--importance for outcome of interferon alfa-2b treatment. 793 25

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.
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PMID:A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team. 889 68

A reversible target capture viral RNA extraction procedure was combined with a reverse-transcriptase nested polymerase chain reaction (PCR) to develop a capture PCR assay providing a rapid and safe prediction method for circulating bluetongue virus in infected ruminants. This new assay was compared with virus isolation and a recently developed antigen-capture enzyme-linked immunosorbent assay (ELISA) for the detection of bluetongue virus. Eight Warhill crossbred sheep were inoculated subcutaneously with bluetongue virus serotype 10, and blood samples were taken sequentially over a period of 28 days. The capture PCR detected the peak of viremia, as determined by virus isolation and antigen-capture ELISA, from day 5 to day 14 after challenge. The results indicate that the rapid-capture bluetongue virus PCR provides a rapid indicator of samples in which virus can be isolated. In addition, this capture bluetongue virus PCR procedure does not require a lengthy phenol extraction or the use of the highly toxic methyl mercury hydroxide denaturant.
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PMID:Bluetongue virus detection: a safer reverse-transcriptase polymerase chain reaction for prediction of viremia in sheep. 921 Dec 28

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

A commercially available kit, Amplicor, was compared with a locally developed nested reverse-transcriptase (RT) PCR for qualitative detection of HCV-RNA. Sixty-one serum samples from sixty-one patients with liver disease, and 60 samples from 60 hemophiliacs without symptoms, but known to have been heavily exposed to hepatitis C virus, were investigated. There was a high degree of concordance between the two diagnostic tests (97%), the Amplicor kit being slightly more sensitive than the in-house PCR, when evaluated using serial dilutions of samples showing discrepant results. The relationship between viremia and abnormal ALT levels was studied in the two groups of patients. Among those with chronic liver disease, 8.3% of patients with viremia had normal ALT levels, whereas transaminases were normal in 20% of hemophiliacs with viremia. This points to ALT as being a poor marker of ongoing viral replication.
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PMID:Viremia in chronic hepatitis C patients evaluated by the Amplicor RT-PCR, a nested RT-PCR, and transaminase levels. 953 67

Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clinical features have been difficult because of sensitivity and specificity shortcomings of available techniques. We titered the genomic- and minus-strand HCV RNAs by a strand-specific, semiquantitative, genotype-independent reverse-transcriptase polymerase chain reaction (RT-PCR) in the liver tissue of 61 patients with chronic hepatitis C. Findings were correlated with the levels of HCV RNA in the serum, the HCV genotype, the expression of intrahepatic HCV antigens, the histological activity (using separate scores for the lobular and the portal/periportal necroinflammatory activity and for the fibrosis), and the response to interferon alfa (IFN-alpha) treatment. Genomic- and minus-strand HCV RNA were detected in 59 and 57 liver specimens, respectively. The HCV-RNA level in the serum correlated with the genomic-strand, but not with the minus-strand, HCV-RNA titer in the liver. No correlations were found between either strand of the intrahepatic HCV RNA and the level of expression of HCV antigens in the liver, or with the grading/staging of the underlying liver disease. The response to IFN-alpha treatment could be predicted by the serum HCV-RNA level and genotype, but not by the intrahepatic level of genomic- or minus-strand HCV RNA. These results suggest that, although the detection of the minus-strand HCV RNA reliably identifies the presence of replicating HCV in its target organ, the quantitative measurement of viremia remains the clinically meaningful "golden standard" for assessing the level of HCV replication.
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PMID:Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reverse-transcriptase polymerase chain reaction. 991 32

Previous studies have demonstrated the feasibility of implantation of human blood cells or tissues in lethally irradiated mice or rats, radioprotected with SCID mouse bone marrow cells: The Trimera system. In the present study, we describe the development of a mouse Trimera model for human hepatitis B virus (HBV) infection. In this model, viremia is induced by transplantation of ex vivo HBV-infected human liver fragments. Engraftment of the human liver fragments, evaluated by hematoxylin-eosin staining and human serum albumin mRNA expression, was observed in 85% of the transplanted animals 1 month postimplantation. Viremia levels were determined in these mice by measuring serum HBV DNA using polymerase chain reaction (PCR), followed by dot-blot hybridization. HBV DNA is first detected 8 days after liver transplantation. Viremia attains a peak between days 18 and 25 when HBV infection is observed in 85% of the transplanted animals. The HBV-Trimera model was used to evaluate the therapeutic effects of human polyclonal anti-HBs antibodies (Hepatect) and of two reverse-transcriptase inhibitors, lamivudine (3TC) and beta-L-5-fluoro-2',3'-dideoxycytidine (beta-L-5FddC). Treatment of HBV-Trimera mice with these drugs effectively reduced both the percentage of infected animals and the viral load in their sera. Treatment cessation resulted in rebound of viral load, indicating HBV replication upon drug withdrawal. These results show that the HBV-Trimera model represents a novel experimental tool for simulating human HBV infection and evaluating potential anti-HBV therapeutic agents.
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PMID:The hepatitis B virus-trimera mouse: a model for human HBV infection and evaluation of anti-HBV therapeutic agents. 991 35


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