Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel canine retrovirus was isolated from mononuclear cells of the peripheral blood of a leukaemic dog. The main clinical and pathological findings in this dog were lethargy, anorexia, weakness, dyspnoea, severe anaemia, thrombocytopenia and a high white blood cell count, practically all of which were lymphoblasts. The virus was isolated from mononuclear cells obtained from the blood, cocultivated with indicator cells. The virus particles encode a reverse transcriptase with Mg++ preference, have a density in sucrose gradients of 1.16 g ml-1, and induce syncytia in permissive cell cultures such as Himalayan tahr ovary and canine fetal thymus lines. This agent replicates to high titres. The virus exhibits a morphogenesis and morphology typical of lentiviruses. Immunoblotting and competitive radioimmunoassays failed to detect immunological crossreactivity with other representative lentiviruses and oncoviruses of the retrovirus family.
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PMID:Isolation and preliminary characterisation of a novel retrovirus isolated from a leukaemic dog. 137 29

An adult horse infected with a virulent, cell culture-adapted strain of equine infectious anemia virus (EIAV) developed cyclical thrombocytopenia in which the nadir of platelet counts coincided with peak febrile responses. In order to investigate the mechanism of thrombocytopenia during acute febrile episodes, four adult horses were experimentally infected with the wild-type Wyoming strain of EIAV. Platelet counts decreased from baseline as rectal temperature increased. Serum reverse transcriptase activity increased above background levels in all horses, coincident with increase in rectal temperature. All horses developed an EIAV-specific immune response detectable by Western immunoblot by postinfection day 10. Increases in platelet-associated immunoglobulins G and M were detectable by direct fluorescent-antibody test and flow cytometric assay. Viral replication in bone marrow megakaryocytes was not detectable by in situ hybridization. Results suggest an immune-mediated mechanism of thrombocytopenia in horses infected with EIAV. Despite an inability to identify virion particles in association with platelet-bound antibody, the cyclical nature of the thrombocytopenia and the occurrence of a marked cell-free viremia concomitant with fever and thrombocytopenia suggest immune complex deposition on platelets. We propose that clearance of virus and antibody-coated platelets from the peripheral circulation by hepatic Kupffer cells and splenic macrophages may target infectious virus particles, in the form of immune complexes, to host cells most permissive for in vivo viral replication.
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PMID:Immune-mediated thrombocytopenia in horses infected with equine infectious anemia virus. 171 20

We associated HPA 23 (inhibitor of the reverse transcriptase) to cyclosporin A (CSA) for two homosexual patients with positive HIV serology, who had a peripheral thrombocytopenia resistant after alone CSA treatment. HPA 23 was given for 15 days at a dose of 4 mg/kg/day in a 24 hours continuous perfusion. The circulating tungsten blood concentration was about 4.4 micrograms/ml (between 3 and 8.4 micrograms/ml). Even if HPA 23 has frequently been responsible of thrombocytopenia at a dose superior than 2 mg/kg/day and in spite of any CSA activity in single treatment, this association shows a significant platelets increase. But thrombocytopenia reappeared a week after the stay of HPA 23 treatment. So, it is possible that HPA 23 might have, at this circulating blood concentration, an antiviral activity in vitro. In this hypothesis there might be a relation between antiviral replication and autoimmune disorders and, at least, CSA might oppose against the thrombocytopenia induced by HPA 23.
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PMID:[Addition of HPA 23 to cyclosporin in the treatment of thrombopenic purpura in HIV-positive subjects]. 244 94

Ammonium tungsto antimoniate (HPA 23) is a potent inhibitor of nucleic acid polymerases and reverse transcriptases of retroviruses. Its in vivo activity as an HIV inhibitor was previously published. However, its clinical use is limited by pharmacological parameters (short half-life and intravenous administration) and significant side effects (thrombocytopenia). In order to evaluate the place of this drug in the therapeutic strategy of HIV-infected patients, we administered 1.5 mg/kg of HPA 23 in 15 infected patients at various stages of the disease twice a day during 14 days. A significant decrease of reverse transcriptase activity (less than 15% of the initial value) was noticed in 13 patients. This activity remained low at least 6 weeks after the end of the treatment in 8 patients. Thrombocytopenia was the only significant side effect reported and was always transient. This study suggests that HPA 23 can be used as an induction treatment in patients infected by HIV. A maintenance treatment has to be defined, as well as the association to other drugs.
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PMID:Reverse transcriptase activity (RTA) in lymphocyte cultures of HIV-infected patients receiving short treatments of HPA 23. A biological evaluation. 245 97

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), an inhibitor of glycoprotein processing, has been shown to inhibit the human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured cells. In contrast to reverse transcriptase inhibitors, castanospermine targets host enzymes. We have analyzed castanospermine in murine systems, using cultured cells as well as live animals. Plaque formation by Rauscher murine leukemia virus (RLV) was inhibited with a median inhibitory concentration (IC50) of 2 micrograms/ml. RLV-exposed BALB/c mice treated with a 20 day course of castanospermine starting 4 h postinoculation showed a dose-dependent inhibition of splenomegaly. Oral castanospermine therapy given to chronically RLV-infected mice prolonged median survival from 36 to 94 days when compared to untreated controls (p = 0.007). Castanospermine was better tolerated orally than intraperitoneally at the same dose. Toxic effects included weight loss, lethargy, and dose-dependent thrombocytopenia. At the highest intraperitoneal dose, lymphoid depletion occurred in thymus, spleen, and lymph nodes. We conclude that castanospermine is an active antiviral agent in animals and that prolonged oral administration is tolerable; however, when compared to 3'-azido-3'-deoxythymidine in the same murine system, castanospermine was less active and more toxic.
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PMID:In vivo analysis of castanospermine, a candidate antiretroviral agent. 249 48

Zidovudine (Retrovir) is the only drug found to be useful for managing human immunodeficiency virus (HIV) infection in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The drug is virostatic, ie, it prevents replication of HIV by inhibiting the enzyme reverse transcriptase. Zidovudine is well tolerated and provides short-term benefits by improving the quality of life and extending survival time. It is expensive and can be toxic, however, so its use requires close supervision. Zidovudine at present is approved only for patients with documented Pneumocystis carinii pneumonia or with a CD4 count below 200/mm3. Other probable indications include HIV wasting syndrome, HIV dementia complex, oral candidiasis, Kaposi's sarcoma, the presence of early markers of HIV infection, and HIV-related symptomatic thrombocytopenia. A stepwise approach to initiating zidovudine therapy should include detailed counseling and close surveillance.
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PMID:Zidovudine for treating AIDS. What physicians need to know. 266 55

A 3-month-old male infant presented with pallor, hepatomegaly (4.5 cm), splenomegaly (1.5 cm), anaemia (Hb 6 g/dl) and thrombocytopenia (16 X 10(9)/l). A liver biopsy was diagnostic for Langerhans cell histiocytosis (histiocytosis X). The patient's lymphocytes, co-cultured with neonatal lymphocytes, were positive for virus-like particles without reverse transcriptase activity. The hepatomegaly diminished after 6 months and a second liver biopsy showed decreased histiocytic infiltration. A second viral blood culture remained negative. After 14 months, the hepatomegaly had disappeared completely and there were no more abnormal haematological or clinical findings.
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PMID:Spontaneous healing of Langerhans cell histiocytosis (histiocytosis X). 326 42

Suramin sodium is a reverse transcriptase inhibitor with in vitro activity against the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). Ninety-eight patients with AIDS manifest as opportunistic infections (n = 38), AIDS with Kaposi's sarcoma (n = 38), AIDS-related complex (n = 20), or AIDS-associated non-Hodgkin's lymphoma (NHL) (n = 2) were treated with suramin sodium at 0.5, 1.0, or 1.5 g/wk for six weeks followed by maintenance therapy with 0.5 or 1.0 g/wk. Of 72 patients who were HIV culture positive before therapy and were assessable for subsequent HIV culture 40% became culture negative during treatment, with no apparent correlation between virus recovery and serum suramin concentration. No immunologic improvement was noted. One complete clinical remission was noted in a patient with Kaposi's sarcoma and stage IV NHL. Seven minor clinical responses were also noted. Toxic reactions were generally reversible, and included fever (78%), rash (48%), malaise (43%), nausea (34%), neurologic symptoms (33%), and vomiting (20%). Suramin-induced neutropenia was noted in 26%, thrombocytopenia in 12%, a serum creatinine level of 180 mumol/L or higher (greater than or equal to 2.1 mg/dL) in 12%, liver dysfunction in 14%, and clinical and/or laboratory evidence of adrenal insufficiency in 23%. Sixteen patients died while receiving suramin or within three weeks of discontinuation of drug therapy due to infection (n = 6), hepatic failure (n = 3), pulmonary Kaposi's sarcoma (n = 2), AIDS encephalitis (n = 2), AIDS-associated NHL (n = 1), iatrogenic hemo-pneumothorax (n = 1), or pulmonary disease of uncertain etiology. Suramin as currently administered cannot be recommended as effective therapy for AIDS.
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PMID:Suramin therapy in AIDS and related disorders. Report of the US Suramin Working Group. 365 Mar 39

Interleukin-11 (IL-11), a newly-identified cytokine produced by stromal cells, elevates platelet counts in neonatal rats in vivo and synergizes in vitro with IL-3 in supporting murine megakaryocyte colony formation and stimulating hematopoietic stem cells. Megakaryocytopoiesis is also enhanced by other colony-stimulating factors (CSFs), including IL-3, IL-6, and Steel factor (SLF). Dysregulation of neonatal thrombopoiesis predisposes newborns to develop thrombocytopenia during sepsis, despite increased circulating pools of committed thrombopoietic progenitors in newborn cord blood compared with adult. We previously reported reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), and IL-3 from stimulated cord mononuclear cells, but increased expression of SLF in human umbilical vein endothelial cells (HUVEC). Therefore, we hypothesized that IL-3, IL-6, and SLF might modulate megakaryocytopoiesis by inducing IL-11 expression, and newborns might express altered levels of IL-11 mRNA expression during activated conditions, contributing to the difference in circulating colony-forming unit-megakaryocyte (CFU-Meg) cord and adult blood. Phorbol myristate acetate (PMA) induced a twofold greater increase in IL-11 mRNA expression in neonatal fibroblasts (NFb) compared with adult fibroblasts (AFb), and a 3.6-fold greater increase in HUVEC than human adult aorta endothelial cells (HAEC) by Northern blot analysis. PMA also induced a threefold greater increase in IL-11 protein production in NFb than AFb. Physiologic agonists IL-1 alpha, transforming growth factor-beta 1 (TGF-beta 1), and TGF-beta 2 triggered upregulation of IL-11 mRNA expression in both NFb and AFb. However, IL-3, IL-6, PIXY321 (a GM-CSF-IL-3 fusion protein), and SLF failed to upregulate IL-11 mRNA expression from the basal level, while macrophage-colony stimulating factor (M-CSF) mRNA was significantly induced. These data suggest that the hematopoietic effect of IL-6, SLF, and IL-3 on megakaryocytopoiesis is probably not mediated by secondary IL-11 mRNA expression. Similarly, inflammatory agonists IL-1 beta, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) alone did not upregulate IL-11 expression from the basal level in endothelial cells, whereas intracellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 were strongly induced. Minimal basal IL-11 expression was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in NFb, AFb, HUVEC and HAEC. The quantitative RT-PCR assay also verified that IL-1 beta and TNF-alpha-stimulated HUVEC and HAEC, and IL-3- and IL-6-stimulated NFb and AFb only expressed minimal levels of IL-11 mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells. 752 67

A putative retrovirus was isolated from a dog with a severe, acquired immunodeficiency-like syndrome. The haematological abnormalities and immunological deficiencies included anaemia, leucopenia (lymphopenia and neutropenia), thrombocytopenia, decreased humoral immunity, and ineffective T-cell responses in-vitro. The necropsy findings included generalized lymphoid depletion, severe bone marrow hypoplasia, plasmacytic infiltrates in lymphoid and non-lymphoid organs, and severe secondary infections. Supernates of peripheral blood mononuclear cell cultures from the affected dog contained an agent with manganese-dependent reverse transcriptase (RT) activity that sedimented at a density of 1.122 g/ml. RT activity was also found post-mortem in extracts prepared from the bone marrow, lymph nodes, and small intestine. The lymph nodes and small intestine expressed a 3.8 kb mRNA that was recognized by a bovine leukaemia virus (BLV) pol DNA probe by Northern blotting. DNA isolated from the lymph nodes and small intestine from the affected dog showed distinct band patterns by Southern analysis, suggesting an exogenous retrovirus. The retrovirus could be propagated in normal canine peripheral blood mononuclear cells or short-term canine lymphocyte cell lines in-vitro, and was cytopathogenic for cells of canine, but not human, origin. These results suggest the existence of a pathogenic canine retrovirus capable of producing disease of the type associated with retroviruses in other species.
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PMID:Retrovirus-like activity in an immunosuppressed dog: pathological and immunological findings. 753 63


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