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)

Mitsuya and Broder [Proc. Natl. Acad. Sci. USA 83:1911-1915 (1986)] demonstrated that every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside containing the 2',3'-dideoxyribose configuration, when evaluated against human immunodeficiency virus (HIV) in vitro, significantly suppressed both the infectivity and the cytopathic effect of the virus, with 2',3'-dideoxycytidine (ddCyd) being the most potent of the series (total antiviral protection at 0.5-1.0 microM). We have compared three factors likely to be of significance in determining the pharmacological activity of these compounds, i.e., (i) their abilities to influence pool sizes of physiological deoxynucleoside-5'-triphosphates, (ii) their capacity to generate the corresponding 2',3'-dideoxynucleoside-5'-triphosphates, and (iii) the effectiveness of these nucleoside-5'-triphosphates as inhibitors of HIV reverse transcriptase. In MOLT-4 cells (a human T cell line), ddCyd was the compound most efficiently converted to its 5'-triphosphate, whereas 2',3'-dideoxyguanosine and 2',3'-dideoxythymidine were the compounds least efficiently converted, generating levels of their corresponding 5'-triphosphates less than 0.1% of that seen with ddCyd when these nucleosides were compared on an equimolar basis (5 microM). The 3'-azido analogue of 2',3'-dideoxythymidine fell intermediate between these two extremes. As inhibitors of HIV reverse transcriptase, however, all the 5'-triphosphates, with the exception of 2',3'-dideoxyinosine-5'-triphosphate, fell within a narrow range of activity (Ki, 0.10-0.26 microM), affinities some 40-60 fold greater than those of the corresponding physiological 2'-deoxynucleoside-5'-triphosphates. Significant alterations in pool sizes of physiological 2'-deoxynucleoside-5'-triphosphates were not observed at pharmacologically effective drug levels. The relative ability of 2',3'-dideoxynucleosides to generate 5'-triphosphates intracellularly thus correlates much more closely than do the other two factors examined, in capacity to block HIV replication. These studies support the conclusion that, for purposes of design of new compounds of this general class, factors influencing efficiency of nucleotide formation and degradation (e.g., membrane transport mechanisms, affinities for nucleoside kinases and for nucleotide kinases and phosphatases) may be of equal or even greater importance than differences in the relative abilities of the resultant 2',3'-dideoxynucleoside-5'-triphosphates to inhibit the viral reverse transcriptase.
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PMID:Factors determining the activity of 2',3'-dideoxynucleosides in suppressing human immunodeficiency virus in vitro. 245 90

Three different assay systems for monitoring the production of human immunodeficiency virus (HIV) in infected cells were compared. These were (1) a reverse transcriptase assay (RTA), (2) an indirect immunofluorescence assay (IFA), and (3) an enzyme immunoassay (EIA) for detecting HIV antigen in vitro. MOLT-4 subclone 1 cells were infected with serial dilutions of the HTLV-IIIB strain of HIV. Six days after infection, production of HIV was examined by the three methods. EIA was most sensitive showing 64-fold higher sensitivity than RTA, which in turn was fourfold more sensitive than IFA. We applied EIA for detecting HIV in the lymphocyte cultures derived from 18 HIV-seropositive persons. By means of the three systems HIV was isolated from lymphocyte cultures derived from one of nine (11%) asymptomatic persons and from five of nine (56%) symptomatic patients. Interestingly, it was noticed that four samples of lymphocytes did not allow the isolation of HIV but gave positive results by EIA only. Thus, the detection rate of HIV was increased by the application of EIA, to three of nine (33%) persons in the asymptomatic group and to seven of nine (78%) patients in the symptomatic group. Possible use of this assay system for following the development of acquired immunodeficiency syndrome is discussed.
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PMID:Detection of human immunodeficiency virus (HIV) in cultures of lymphocytes from HIV-seropositive persons with special reference to an enzyme immunoassay. 247 39

MT-4 cells persistently infected with human immunodeficiency virus type 1 (HIV-1) (MT-4/HIV-1) were recently isolated (K. Ikuta, C. Morita, M. Nakai, N. Yamamoto, and S. Kato, Japan. J. Cancer Res. (Gann), 79, 418-423, 1988). Mouse hybridoma cell clones producing monoclonal antibodies (MoAbs) to HIV-1 gag p24 and p18, and pol reverse transcriptase (RT) were isolated by using this MT-4/HIV-1 cell line for the screening of MoAb production by the immunofluorescence (IF) test. By indirect IF tests of acetone-fixed cells with these MoAbs, the IF intensities in MT-4/HIV-1 cells were found to be higher than those in the other HIV-1 infected cells, such as MOLT-4/HIV-1, HL-60/HIV-1, and U937/HIV-1 cells. Cell surface expression of the HIV-1 gag p24 and p18 antigens examined by IF and radioimmune techniques with these MoAbs revealed the p24 and p18 antigens to be expressed strongly on the cell surface of MT-4/HIV-1 cells and faintly on the cell surface of MOLT-4/HIV-1 cells, respectively. However, monoclonal antibody isolated in the present study failed to detect pol RT antigen on the surface of MT-4/HIV-1 cells. These results indicate that the gag p24 and p18 antigens are expressed, at least in part, on the surface of HIV-1-infected cells.
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PMID:Expression of human immunodeficiency virus type 1 (HIV-1) gag antigens on the surface of a cell line persistently infected with HIV-1 that highly expresses HIV-1 antigens. 249 13

Soybean saponins isolated from soybean seeds were investigated for their antiviral activity on HIV in vitro, using an HTLV-I-carrying cell line, MT-4. Saponin B1 completely inhibited HIV-induced cytopathic effects and virus-specific antigen expression 6 days after infection at concentrations greater than 0.5 mg/ml. Saponin B2 also inhibited HIV infection, although less potently. Both saponin B1 and B2 had no direct effect on the reverse transcriptase activity of HIV. Saponin B1 also inhibited HIV-induced cell fusion in the MOLT-4 cell system. The results of this study suggest that soybean saponins, especially saponin B1, have inhibitory activity against HIV infection.
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PMID:Inhibitory effect of glycosides like saponin from soybean on the infectivity of HIV in vitro. 257 82

The effect of tumor necrosis factor (TNF) on the replication of human immunodeficiency virus type 1 (HIV-1) was investigated in several T4 lymphocyte cell lines. TNF markedly enhanced the cytopathogenicity of HIV-1, virion-associated reverse transcriptase (RT) activity in the cell culture supernatant, and viral antigen expression in MOLT-4 cells as early as 3 days after HIV-1 infection. A slight increase in RT activity was also observed in the supernatant of H9 cell cultures exposed to TNF. However, TNF did not increase either RT activity in MT-4 cell supernatants or viral antigen expression in HUT-78 cells. Thus, TNF is able to stimulate the replication of HIV-1 in de novo infected T4 cells although not all T4 cells seem to be sensitive to this stimulatory effect.
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PMID:Tumor necrosis factor enhances replication of human immunodeficiency virus (HIV) in vitro. 291 52

Large plaque-inducing clones were obtained from small plaque-inducing parental clones of human immunodeficiency virus (HIV) by the plaque-cloning method. The cloned HIVs that formed large and small plaques were studied as follows: 1) infectivity was determined by the ratio of plaque-forming units (PFU) to reverse transcriptase (RT) activity; 2) viral growth was assessed by the amount (RT activity) of virus after infection; and 3) HIV long terminal repeat (LTR)-linked gene expression of the viruses was measured by chloramphenicol acetyltransferase (CAT) assay using persistently infected MOLT-4 cells. Results showed that clones producing large plaques showed similar or slightly lower infectivity but higher virus production, faster viral growth, and higher gene expression activity than clones producing small plaques. These analyses revealed that clones producing large plaques could replicate more rapidly than those producing small plaques. Restriction enzyme map analysis of these cloned viruses showed that they were also genetically different. These results suggest that the changes in the biological features observed here might be due to mutation during the cloning procedure.
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PMID:Emergence of large plaque-producing clones of human immunodeficiency virus (HIV) in vitro. 292 4

An extract of culture medium of Lentinus edodes mycelia (LEM) was prepared. This was further fractionated by 50% ethanol precipitation and both the resulting product, E-P-LEM, and LEM were studied to evaluate their effect on the activity of human immunodeficiency virus (HIV) in vitro. The experiments were performed using either a cell-free infection system with MT-4 cells, or a cell-to-cell infection system with MOLT-4 cells, which induces multinucleated giant cells very efficiently. E-P-LEM almost completely blocked both the cytopathic effect of giant cell formation and specific antigen expression due to HIV, whereas LEM before ethanol precipitation blocked the expression of HIV antigen in MT-4 cells only at a high concentration. Pretreatment of the virus with E-P-LEM before infection blocked HIV infection in the target cells. Thus, the inhibitory effect of LEM and E-P-LEM on HIV could be due to a blocking of the initial stages of HIV infection. Moreover, reverse transcriptase activity of avian myeloblastosis virus was inhibited.
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PMID:Inhibition (in vitro) of replication and of the cytopathic effect of human immunodeficiency virus by an extract of the culture medium of Lentinus edodes mycelia. 317 37

Phosphorothioate antisense oligodeoxynucleotide against HIV-1 rev (S-ODN-rev) inhibits virus-induced cytopathic effects (CPE) in acute infection and inhibits the expression of HIV-1 core protein, p24, in chronically infected cells in vitro. HIV-1 reverse transcriptase activity was not affected by S-ODN-rev at the high concentrations of 5-25 microM, which were 250-1250 times higher than the concentration required to achieve 100% HIV-1-induced CPE inhibition. [32P]-labeled S-ODN-rev was rapidly uptaken by MOLT-4 cells, whereas [32P]-SO-ODN-rev and [32P]-O-ODN-rev were not. In the observation of FITC-S-ODN-rev-treated MOLT-4 cells by a confocal laser scanning microscope, diffuse fluorescence was apparently observed in the cytoplasm. Interestingly, fluorescence signals were accumulated in the nuclear region of chronically infected MOLT-4/HIV-1 cells 60 min after incubation. FITC-labeled homooligomer, FITC-S-dC20 and FIT-C-S-dT20, also accumulated in the nucleus of MOLT-4/HIV-1 cells, but weak fluorescence was observed on the cell membrane and in the cytoplasm of the FITC-S-random treated MOLT-4/HIV-1 and MOLT-4 cells.
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PMID:Anti-human immunodeficiency virus type 1 activity of phosphorothioate analogs of oligodeoxynucleotides: penetration and localization of oligodeoxynucleotides in HIV-1-infected MOLT-4 cells. 752 75

Three flavans, daphnodorins A, B and C isolated from Dahpne odora THUNB. were tested for their abilities to inhibit human immunodeficiency virus type 1 (HIV-1(IIIB)) replication in MT-4 cells. The effective concentrations (EC50) of daphnodorins A, B and C against HIV-1-induced cytolysis were 0.26 +/- 0.08, 1.8 +/- 0.6 and 3.6 +/- 0.5 micrograms/ml, respectively. Also these three compounds showed inhibitory effects of p24 antigen in human peripheral blood lymphocytes. As compared with 2',3'-dideoxycytidine 5'-triphosphate (DDC-TP), daphnodorin A and daphnodorin C had relatively weak inhibitory effects on the reverse transcriptase of HIV-1, while daphnodorin B did not show any inhibitory effect at concentrations up to 1000 micrograms/ml. These three compounds showed marked inhibitory effects on syncytium formation between HIV-1(IIIB)-infected and uninfected MOLT-4 (clone 8) cells at 3-30 micrograms/ml without inducing cytotoxicity. The concentrations of the compounds blocking syncytium formation were consistent with the effective concentrations (EC50) against HIV-induced cytolysis of MT-4 cells. These results, differing from reverse transcriptase inhibitors, suggest that the daphnodorins exert their anti-HIV-1 activity through inhibition of early events of viral replication including adsorption of the virions to the cells or the subsequent entry.
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PMID:Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by daphnodorins. 752 15

The in vitro effect of human natural interferon alpha (IFN-alpha) on cell contact-mediated human immunodeficiency virus type 1 (HIV-1) transmission from epithelial cells to lymphocytes was examined. This type of infection is most likely to occur when the mucosal linings of the reproductive or digestive organs serve as latent viral reservoirs and HIV-1 invades the host through the basolateral surface of polarized epithelia upon contact with intraepithelial lymphocytes. The cell-to-cell infection model consisted of target MOLT-4 T lymphocytes exposed for various time periods to chronically HIV-1-infected intestinal monolayers (I407/YH5) in the presence of log10 dilutions of IFN (range 10(5)-10(-2) IU/ml). Concurrent measurements of resulting productive infection from MOLT-4 revealed that complete inhibition of reverse transcriptase activity was prevented by doses starting from 1 IU, whereas the cessation of p24 production occurred at 1000 IU of IFN present at inoculation. The results indicate that IFN can efficiently prevent not only cell-free but also cell-mediated HIV-1 infection--an important means of viral spread in vivo pertinent to HIV-1 transmission resulting from mucosa-lymphocyte interaction.
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PMID:Inhibitory effect of natural interferon alpha on human immunodeficiency virus type 1 transmission from epithelial cells to lymphocytes in vitro. 767 77


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