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)

The present study has investigated the effect of PMA, an inducer of monocyte differentiation, on HIV expression in a chronically infected promonocyte clone. After acute HIV infection of U937 cells, clones that constitutively expressed varying levels of HIV were isolated by limiting dilution. One clone (U1) produced low levels of HIV but was found to increase its production 20-fold after PMA induction, as detected by reverse transcriptase or A capture. Further characterization of U1 indicated that PMA could induce cellular differentiation and maturation in the clone similar to that in uninfected U937 cells. In addition, functional studies revealed that superoxide anion production from the U1 clone was not different from that of uninfected U937 cells. Electron microscopic studies of U1 indicated that PMA induced endocytotic vesicles containing many HIV particles. These studies provide a model at the clonal level to 1) examine latency or chronicity of HIV infection in monocytes and 2) delineate the signals required for conversion to high level viral expression.
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PMID:Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. 244 97

We studied the effect of human immunodeficiency virus (HIV) infection on the surface-marker expression of the human promonocytic cell line U937. U937 cells persistently produced HIV as detected by reverse transcriptase activity in culture supernatant. Expression of HLA class II antigens on U937/HIV cells was decreased 2- to 10-fold, depending on the Mab used. Class II expression of U937/HIV cells increased approximately two-fold by treatment with r-interferon-gamma. Whereas noninfected U937 cells expressed moderate amounts of lymphocyte function-associated antigen-1 (LFA-1) (CD11a) and minimal amounts of the C3bi receptor (CD11b) and p150/95 (CD11c), U937/HIV cells expressed moderate amounts of C3bi receptor and p150/95 and showed elevated expression of LFA-1 alpha (CD11a) and -beta (CD18) chains. Expression of these adhesion molecules resulted in strongly enhanced phorbolester-induced aggregation of U937/HIV cells compared with the noninfected U937 cells. In addition, almost all U937/HIV cells, but not noninfected U937 cells, intensely stained for cytoplasmic nonspecific esterase activity. The effects of HIV infection on U937 cells strikingly resemble the effects of differentiation-inducing agents, such as PMA and DMSO, on the U937 phenotype. Our finding suggests that HIV infection, apart from down regulating class II expression, induces differentiation of U937 cells.
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PMID:Human immunodeficiency virus infection down-regulates HLA class II expression and induces differentiation in promonocytic U937 cells. 310 23

Modifications of the glutathione (GSH) intracellular level have been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression. In regard to this hypothesis, we have investigated the effects of valproic acid (VPA) on HIV replication. Indeed, it has been recently reported that VPA inhibits the human red blood cell glutathione reductase. In the supernatant of a CEM-SS T-lymphocytic cell line infected with the LAI strain of HIV-1, we observed an increase, in a dose-dependent fashion, of the reverse transcriptase activity after treatment of cells with VPA. VPA also induced HIV expression in the chronically infected monocytic U1 cell line which constitutively expresses low levels of virus, enhanced the HIV-long terminal repeat (LTR)-directed expression of beta-galactosidase in transiently transfected Jurkat T-cells, and potentiated the PMA effect on the LTR transactivation. GSH assays showed that VPA treatment led to a decrease in the intracellular level of this thiol compound in U937 (U1 parent-cell line) and in Jurkat T-cells. Work to understand the molecular mechanism of VPA-induced HIV transcription and expression are now in progress. VPA seems to be an adequate molecule to study the implications of a GSH decrease in the stimulation of HIV replication. However, a modification of the intracellular balance between reduced and oxidized glutathione, rather than a simple reduction of the intracellular glutathione level, could be of importance in the regulation of HIV replication and we are now testing this hypothesis. Finally, these findings already suggest that VPA, which is an anticonvulsive drug frequently prescribed for the management of various seizure disorders, should not be recommended for treatment of epilepsy or other related illnesses in HIV-positive individuals.
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PMID:Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. 751 59

Sixteen biphenyl derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells. 3-Bromo- (4) and 3,3'-dibromo-4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2,2'- bis(methoxycarbonyl)biphenyl (5) demonstrated potent anti-HIV activity with EC50 values of 0.52 and 0.23 micrograms/mL and therapeutic index values of > 190 and > 480, respectively. A comparison of the anti-HIV activity of these biphenyl derivatives suggested that the types of substituents on the phenolic hydroxy groups rather than the number of bromine(s) on the aromatic rings are important to the enhanced anti-HIV activity. Compounds 4 and 5 also showed potent inhibitory activity against HIV-1 reverse transcriptase in a template-primer dependent manner. The site of inhibition of HIV could be related to inhibition of this enzyme. Compounds 4 and 5 did not induce virus expression from the chronic HIV-1-infected cell lines ACH-2 and U1. Furthermore, these two agents did not inhibit an increase in virus production from the chronic HIV-1-infected cell lines when the phorbol ester PMA was present.
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PMID:Anti-AIDS (acquired immune deficiency syndrome) agents. 17. New brominated hexahydroxybiphenyl derivatives as potent anti-HIV agents. 754 78

We established an improved non-radioactive in situ hybridization (ISH) method to detect mRNA of cytokines in cell preparations and tissues. Via this method we could demonstrate various cytokines in stimulated peripheral blood mononuclear cells (PBMC), lymphoid cell lines and human lymphoid tissues. The probes for the in situ hybridization were made by labelling cytokine-specific PCR products with digoxigenin (Dig) in a repeated PCR. This resulted in an intrinsic labelling of the probe with several Dig-UTP molecules. Incorporation of Dig-11-dUTPs was shown on ethidium bromide-stained agarose gels by a higher molecular weight of the PCR products with incorporated Dig-dUTPs when compared to control PCR products without digoxigenin. Cytospin-centrifuged cells of PHA-stimulated PBMC or lymphoid cell lines and frozen sections of various human lymphoid tissues were hybridized with the Dig-labelled cytokine probes and the hybridized probes were detected immuno-histochemically. In this way, we detected and localized cytokine mRNAs (IL-2, IL-4, IL-6, IL-8, IL-10) in PBMC, in the human T-cell line Jurkat, in the follicular lymphoma cell line DoHH2, and in human lymph nodes and tonsils. The in situ hybridization had a high sensitivity as the results correlated closely with the detection of cytokine mRNA by reverse transcriptase-PCR (RT-PCR) data from the same samples. We showed that Jurkat and DoHH2 cells produce several cytokines constitutively and that, after activation with the phorbol ester PMA, expression of several cytokine mRNAS was enhanced.
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PMID:An improved, sensitive, non-radioactive in situ hybridization method for the detection of cytokine mRNAs. 765 59

Integrins comprise a superfamily of alpha beta heterodimers that serve as cell signaling as well as adhesion molecules. We demonstrate that the alpha 3 beta 1 and alpha 6 beta 1 integrins are laminin/merosin receptors expressed in human thymocytes. By reverse transcriptase-PCR analysis, we determined that the alpha 3A beta 1, but not the alpha 3B beta 1, cytoplasmic structural variant of alpha 3 beta 1 is expressed in thymocytes. In contrast, both alpha 6A beta 1 and alpha 6B beta 1 cytoplasmic structural variants of alpha 6 beta 1 are expressed. A small percentage (10 to 15%) of human thymocytes bind to immobilized laminin, and even fewer (3 to 5%) bind to merosin, the laminin isoform normally present in the thymus. This binding, however, can be increased to 39 to 41% after activation of thymocytes with Mn2+ (or PMA). Binding to either laminin or merosin is completely inhibited by anti-beta 1 mAb or by a mixture of anti-alpha 3 and anti-alpha 6 mAbs, indicating that both alpha 3 beta 1 and alpha 6 beta 1 participate in thymocyte adhesion to the laminin family of extracellular matrix proteins. The protein kinase C inhibitors, calphostin C and staurosporine, inhibit Mn(2+)-enhanced thymocyte binding, suggesting that protein kinase C activity is crucial for the binding. Furthermore, the data indicate that at least two divalent cation binding sites serve to regulate integrin binding activity. Finally, we show that both immobilized laminin and merosin have costimulatory function for anti-CD3-induced thymocyte proliferation, and both anti-alpha 3 and anti-alpha 6 mAbs can block this proliferative response. The cooperative function of alpha 3 beta 1 and alpha 6 beta 1 evidenced in the laminin/merosin binding and proliferation assays suggests that thymocyte-merosin interactions may play an important role in thymic T cell development.
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PMID:Alpha 3 beta 1 and alpha 6 beta 1 integrins mediate laminin/merosin binding and function as costimulatory molecules for human thymocyte proliferation. 781 63

Interleukin-3 (IL-3), a cytokine known to be produced by activated T lymphocytes, mast cells, eosinophils and neutrophils, is a potent stimulator of normal haemopoiesis, particularly megakaryocytopoiesis. However, it remains unknown whether leukaemic megakaryoblasts can produce IL-3 and whether IL-3 is involved in the pathological process of megakaryoblastic leukaemia. In this study, several human leukaemia cell lines with or without megakaryocytic features, the DAMI, MEG-01, HEL, K562, HL-60 and U937, were chosen as the models. It was first demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) and indirect immunofluorescence assay that IL-3 was expressed in DAMI and MEG-01 cells, but not in other cell lines, although two erythroleukaemic cells, the HEL and K562, also possess some megakaryocytic features. Interestingly, the mRNA for IL-3 receptor was detected in nearly all the cell lines except K562 cells, suggesting that expression of IL-3 and its receptor may be dissociated in most of the cell lines and that co-expression of IL-3 and its receptor exists in megakaryoblastic cell lines, the DAMI and MEG-01. Of the cell lines which did not express IL-3 under unstimulated condition, only HEL cells were able to express IL-3 mRNA after treatment with PMA for 72 h. Furthermore, the proliferation of DAMI and MEG-01 cells could be enhanced in the presence of IL-3 and suppressed by the anti-IL-3 antibody and the IL-3 antisense oligodexyonucleotides (ODNs). These findings indicate that IL-3, as an autocrine growth factor, is involved in the growth of some megakaryocytic leukaemia cell lines.
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PMID:Interleukin-3 is an autocrine growth factor of human megakaryoblasts, the DAMI and MEG-01 cells. 781 61

An important aspect of human immunodeficiency virus (HIV-1) infection is the regulation of its expression by nuclear factor kappa B (NF-kappa B) through redox-controlled signal transduction pathways. In this study, we demonstrate that iron chelation by deferoxamine (DFO) protects against the cytotoxic and reactivating effects of hydrogen peroxide (H2O2). These protective effects were observed both in lymphocytic (ACH-2) and promonocytic (U1) cells latently infected by HIV-1. Concomitantly, NF-kappa B activation by H2O2, when followed by gel retardation assay, was decreased in the DFO-treated U1 and ACH-2 cells. This latter DFO-mediated effect was specific, as DFO did not clearly affect AP-1 DNA-binding activity when studied after H2O2-induced stress. More importantly, DFO protected against the H2O2-induced activation of HIV-1 as evidenced by reverse transcriptase activity in the supernatant. DFO also protected against PMA-induced NF-kappa B activation as well as TNF-alpha-induced HIV-1 activation. Furthermore, DFO attenuated the p24 response in PBMC infected with HIV-1 and stimulated with IL-2. These different effects of DFO were obtained at DFO concentrations lower than 5 microM. Other chemically unrelated iron chelators also provided protection against cytotoxicity, NF-kappa B activation, and HIV-1 activation in U1 cells challenged with H2O2.
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PMID:Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. 855 2

Acute HIV-1 infection of H9 and C8166 cultures has been shown to be suppressed by certain flavonoids, and evidence for inhibition of HIV-1 protease, integrase, and reverse transcriptase by flavonoids also exists. The present aim was to determine whether flavonoids inhibit HIV-1 activation in models of latent infection. By screening flavonoids from six different classes, three structurally related compounds (chrysin, acacetin, and apigenin) were identified that inhibited HIV expression in TNF-alpha-treated OM-10.1 cultures. The three compounds had favorable potencies against HIV activation in relation to their growth inhibitory effects (therapeutic index 5-10). Chrysin also inhibited HIV expression in response to PMA in OM-10.1 cells, in ACH-2 cells stimulated with either TNF-alpha or PMA, and in 8E5 cultures. Furthermore, return to viral latency in OM-10.1 cells previously exposed to TNF-alpha occurred over a shorter time interval when chrysin was added. The inhibition of HIV activation was not dependent on preincubation with flavonoids relative to TNF, and was characterized by a lack of HIV RNA accumulation by Northern analysis. Gel-shift experiments revealed that NF-kappa B activation after TNF-alpha treatment was not inhibited by these agents, suggesting that some other critical factor(s) needed for viral transcription was being affected. These findings indicate that flavonoids inhibit HIV-1 activation via a novel mechanism, and that these agents are potential candidates for therapeutic strategies aimed at maintaining a cellular state of HIV-1 latency.
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PMID:Inhibition of HIV activation in latently infected cells by flavonoid compounds. 882 17

Protein kinase C (PKC) appears to play a role in replication of human immunodeficiency virus type 1 (HIV-1). PKC is a family of at least 12 isozymes. In this study, we investigated a role of Ca(2+)-dependent PKC isozymes (alpha, beta, and gamma) in activation of latent HIV-1 in U1, a chronically infected promonocytic cell line, using polyclonal rabbit anti-PKC isozyme antibodies as specific inhibitors. Antibodies were introduced intracellularly by electroporation and then cells were stimulated with PMA. HIV-1 production was measured as p24 antigen using ELISA and reverse transcriptase activity. Anti-PKC beta antibody significantly inhibited PMA-induced HIV-1 production, whereas antibodies against PKC alpha and gamma had no significant effect. Furthermore, anti-PKC beta antibody inhibited PMA-induced activation of NF-kappa B and HIV-1 LTR. Preincubation of anti-PKC beta antibody with its antigenic peptide reversed the inhibitory effect of anti-PKC beta antibody. This study suggest that PKC beta plays a role in PMA-induced activation of latent HIV-1.
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PMID:Role of protein kinase C-beta isozyme in activation of latent human immunodeficiency virus type 1 in promonocytic U1 cells by phorbol-12-myristate acetate. 889 Nov 15


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