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 "stromal" or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3-specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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PMID:Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma. 137 43

Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2',3'-dideoxy-3'-azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5'-triphosphate moieties. GM-CSF increased the levels of AZT-5'-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5'-triphosphate/thymidine-5'-triphosphate. In contrast, M-CSF-induced increases in AZT-5'-triphosphate were roughly matched by increases in thymidine-5'-triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5'-triphosphate were associated with parallel increases in the levels of deoxycytidine-5'-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5'-triphosphate/deoxycytidine-5'-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.
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PMID:Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages. 137 54

Bone marrow (BM) stromal fibroblasts produce hematopoietic growth factors (HGFs) in response to inflammatory mediators such as tumor necrosis factor-alpha or interleukin-1 alpha (IL-1 alpha). In the absence of such inflammatory stimuli, production of HGFs by BM stromal cells has been problematic and controversial. In vivo, however, basal hematopoiesis maintains blood counts within a normal homeostatic range even in the absence of inflammation, and HGFs are required for progenitor cell differentiation in vitro. To better ascertain the contribution of BM stromal fibroblasts to basal hematopoiesis, we therefore studied HGF production in quiescent BM stromal fibroblasts by three sensitive assays: serum-free bioassay, enzyme-linked immunosorbent assay, and reverse transcriptase polymerase chain reaction. Stromal fibroblasts were cultured in the presence or absence of normal human serum to determine if serum factor(s) present in the noninflammatory (basal) state induce secretion of HGFs. Human serum was found to induce or enhance transcription and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhance secretion of constitutively expressed IL-6. In contrast, no secretion of either granulocyte-CSF (G-CSF) or IL-3 was found. These data indicate that factors in normal human serum are active in enhancing GM-CSF and IL-6 production by stromal fibroblasts and suggest that these growth factors contribute to the maintainance of normal, basal hematopoiesis in vivo.
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PMID:Bone marrow stromal fibroblasts secrete interleukin-6 and granulocyte-macrophage colony-stimulating factor in the absence of inflammatory stimulation: demonstration by serum-free bioassay, enzyme-linked immunosorbent assay, and reverse transcriptase polymerase chain reaction. 138 Dec 37

Monocytes cultured 7 to 10 days in recombinant human macrophage CSF (MCSF) were greater than 400-fold more susceptible to HIV infection than an equal number of cells cultured in medium alone. Levels of reverse transcriptase activity and p24 Ag in culture fluids of monocytes treated with MCSF 1 wk before and continuously after HIV infection were significantly greater than those of control cells cultured without MCSF. HIV-induced cytopathic effects in the MCSF-treated cultures also increased in both frequency and extent. At any given viral inoculum, the frequency of HIV-infected cells, the level of HIV mRNA/infected cell, and the level of proviral DNA/infected culture in MCSF-treated monocyte cultures were dramatically greater than those in control cultures. These differences were directly related to MCSF concentration to a maximum between 750 and 1000 U/ml MCSF, and were evident at all time points examined through 5 wk. None of the preceding effects was observed when MCSF was added at the time of or 1 wk after HIV infection. These data suggest that the predominant effect of MCSF for control of HIV infection is on the monocyte itself, not the virus. If these in vitro observations extend to the HIV-infected patient, then the variable levels of MCSF in tissue or blood may determine both the susceptibility of macrophages to virus infection and the extent of virus replication in infected cells.
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PMID:Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. 170 95

Infection due to the human immunodeficiency virus (HIV) has been complicated by the development of acute nonlymphocytic leukemia in five patients whose cases have previously been reported; other manifestations, including preleukemia, myelofibrosis, and myeloid hyperplasia, have also been reported in patients infected with HIV. We report the sixth case of an HIV-infected patient who developed acute myelomonocytic leukemia; HIV infection was documented by tests for serum antibodies (enzyme-linked immunosorbent assay and western blotting), by a markedly elevated p24 antigen level in plasma, and by cultures of CSF and peripheral blood that were positive for HIV. Furthermore, myelomonoblasts that were cultured without the addition of growth factors displayed evidence of HIV replication through the presence of p24 antigen and reverse transcriptase activity, both of which lasted for 4 weeks in the supernatant fluid of the cell cultures. This case report provides the first data indicating that HIV may infect myelomonoblasts in vivo and represents the sixth reported case of an association between HIV infection and pure acute nonlymphocytic leukemia.
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PMID:Relationship between acute myelomonoblastic leukemia and infection due to human immunodeficiency virus. 190 61

The drug 3'-azido-3'-deoxythymidine (AZT), a synthetic thymidine analogue, has been used clinically in the management of acquired immune deficiency syndrome (AIDS). The drug is an effective antiviral agent due to its ability to block reverse transcriptase activity. This action of AZT was demonstrated in the Rauscher leukemia virus (RLV)-induced murine erythroleukemia model system. Unfortunately, associated with AZT has been the development of hematopoietic toxicity manifested by anemia, neutropenia, and overall bone marrow suppression. Hematopoietic growth factors (GM-CSF, erythropoietin), cytokines (interleukin-1), and agents known to potentiate hematopoiesis (lithium) have been demonstrated to modulate drug and/or radiation-induced hematopoietic toxicity. We report the results of further studies designed to investigate the ability of GM-CSF, erythropoietin, interleukin-1, and lithium to modulate AZT toxicity on murine hematopoietic granulocyte-macrophage (CFU-GM), megakaryocytic (CFU-Meg), and erythroid (BFU-E) progenitors cultured from bone marrow and spleen cells from mice infected with RLV. Hematopoietic progenitors from either normal or RLV-infected animals when exposed to AZT demonstrated concentration-dependent toxicity and differed for each progenitor with BFU-E being the most sensitive (ID50 concentration, 5 x 10(-9) M) and CFU-GM the least sensitive (ID50 concentration, 5 x 10(-5) M). As has been previously demonstrated using normal murine hematopoietic progenitors, when cultured with RLV-infected marrow or spleen cells, addition of GM-CSF, Meg-CSF or erythropoietin failed to inhibit AZT toxicity in vitro on CFU-GM, CFU-Meg, and BFU-E, respectively. However, in the presence of interleukin-1 (recombinant human IL-1 alpha, 30 ngm) or lithium chloride (ultra-pure, 1.0 mM), AZT toxicity CFU-GM, CFU-Meg, and BFU-E cultured from RLV-infected marrow or spleen cells was reduced. These results further demonstrate interleukin-1 and lithium are effective in modulating the toxic action of AZT on hematopoietic progenitors and that RLV-infected animals serve as a useful viral model system to study the effect of agents capable of modulating hematopoiesis in the presence of the anti-viral drug AZT.
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PMID:Effect of interleukin-1, GM-CSF, erythropoietin, and lithium on the toxicity associated with 3'-azido-3'-deoxythymidine (AZT) in vitro on hematopoietic progenitors (CFU-GM, CFU-MEG, and BFU-E) using murine retrovirus-infected hematopoietic cells. 194 Jun 11

Feline immunodeficiency virus (FIV; formerly, feline T-lymphotropic lentivirus) is a typical lentivirus resembling human and simian immunodeficiency viruses in morphologic features, protein structure, and reverse transcriptase enzyme. It is antigenically dissimilar, however. The virus is tropic for primary and permanent feline T-lymphoblastoid cells and Crandell feline kidney cells. The virus did not grow in other permanent feline non-lymphoblastoid cells that were tested, or in lymphoid and non-lymphoid cells from man, dogs, mice, and sheep. During short-term inoculation studies in cats, the feline immunodeficiency-like syndrome found in nature was not experimentally induced, but a distinct primary phase of infection was observed. Fever and neutropenia were observed 4 to 5 weeks after inoculation; fever lasted several days, and neutropenia persisted from 1 to 9 weeks. Generalized lymphadenopathy that persisted for 2 to 9 months appeared at the same time. Antibodies to FIV appeared 2 weeks after inoculation and then plateaued. Virus was reisolated from the blood of all infected cats within 4 to 5 weeks after inoculation and persisted indefinitely in the face of humoral antibody response. Virus was recovered from blood, plasma, CSF and saliva, but not from colostrum or milk. Contact transmission was achieved slowly in one colony of naturally infected cats, but not between experimentally infected and susceptible specific-pathogen-free cats kept together for periods as long as 4 to 14 months. The infection was transmitted readily, however, by parenteral inoculation with blood, plasma, or infective cell culture fluids. In utero and lactogenic transmission were not observed in kittens born to naturally or experimentally infected queens. Lymphadenopathy observed during the initial stage of FIV infection was ascribed to lymphoid hyperplasia and follicular dysplasia. A myeloproliferative disorder was observed in 1 cat with experimentally induced infection.
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PMID:Pathogenesis of experimentally induced feline immunodeficiency virus infection in cats. 245 96

3'-azido-3'-deoxythymidine is a thymidine analogue with an in vitro as well as in vivo efficacy towards HIV-mediated infection. Zidovudine exerts its action, following an intracellular three-step phosphorylation, through viral reverse transcriptase inhibition. Its half-life is approximately one hour. Oral biodisponibility is 65%, and passage through blood-brain barrier results in therapeutic levels is CSF. Clinical evaluation has enabled demonstration of a beneficial effect on survival of stage IV AIDS patients, when treated after a PCP episode. In this setting, aggregate survival ratios reach 73% after one year of follow-up, and 41% after 2 years. In addition, zidovudine activity has been demonstrated in treatment of HIV-induced thrombopenias as well as HIV-related central nervous system disorders. Presently, zidovudine therapeutic evaluation proceeds through the following main axes: dosage tuning (either by lowering of standard dose, and/or dose interval modification); combination with other antiviral therapies; lastly, patient treatment et an early stage of disease.
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PMID:[Zidovudine. The current status of its evaluation]. 269 36

A plant lignan, 3'-O-methyl nordihydroguaiaretic acid (3'-O-methyl NDGA, denoted Malachi 4:5-6 or Mal.4; molecular weigth 316), was isolated from Larrea tridentata and found to be able to inhibit human immunodeficiency virus (HIV) Tat-regulated transactivation in vivo, induce protection of lymphoblastoid CEM-SS cells from HIV (strain IIIB) killing, and suppress the replication of five HIV-1 strains (WM, MN, VS, JR-CSF, and IIIB) in mitogen-stimulated peripheral blood mononuclear cells, all in a dose-dependent manner. Mal.4 inhibits both basal transcription and Tat-regulated transactivation in vitro. The target of Mal.4 has been localized to nucleotides -87 to -40 of the HIV long terminal repeat. Mal.4 directly and specifically interferes with the binding of Sp1 to Sp1 sites in the HIV long terminal repeat. By inhibiting proviral expression, Mal.4 may be able to interrupt the life cycles of both wild-type and reverse transcriptase or protease mutant viruses in HIV-infected patients.
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PMID:Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans. 747 72

Several mutations are associated with resistance to zidovudine (3'-azido-3'-deoxythymidine, AZT) in cultured human immunodeficiency virus type 1 (HIV-1) isolates. Little is known as to what extent drug resistance occurs in vivo and whether its development within the CNS differs from that in peripheral blood. We therefore performed comparative nucleotide sequence analysis of the HIV-1 reverse transcriptase (RT) gene in proviral DNA obtained from blood and CSF of three patients, all of whom had progressed to AIDS under long-term zidovudine treatment. Six to 11 individual proviral copies per patient and compartment were analyzed by polymerase chain reaction (PCR)-mediated direct sequencing. In all samples, mutations associated with zidovudine resistance could be identified. They occurred in multiple HIV-1 copies in both blood and CSF, indicating that molecular determinants of resistance are reflected in most individual proviruses in vivo. Comparable positions and frequencies of mutations in isolates derived from both compartments do not argue for independent development of zidovudine resistance in CSF.
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PMID:In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1-infected patients. 750 98


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