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)

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

Simian retroviruses closely related to human T-cell leukemia virus (HTLV) were isolated by establishing virus-producing lymphoid cell lines from 7 species of non-human primates. By co-cultivation with human umbilical cord-blood cells and/or in the presence of interleukin-2, lymphoid cell lines were successfully established from the chimpanzee. African green monkey, pig-tailed macaque, red-faced macaque, Formosan monkey, Japanese monkey and bonnet monkey that had antibodies against HTLV antigens. These cell lines reacted with human sera of ATL patients and monoclonal antibodies against p19 and p24 of HTLV antigens. Cellular DNAs contained the provirus sequences homologous to HTLV-I by Southern blot hybridization. Moreover, they produced extracellular type-C virus particles and RNA-dependent DNA polymerase. All of these lymphoid line cells had Tac antigen, interleukin-2 receptor, and those of chimpanzee and red-faced macaque had helper/induced T-cell markers, while those derived from African green monkey had suppressor/cytotoxic T-cell markers. Furthermore, simian HTLV-related viruses of pig-tailed macaque, red-faced macaque and Japanese monkey were transmitted to human lymphocytes on co-cultivation.
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PMID:Isolation of simian retroviruses closely related to human T-cell leukemia virus by establishment of lymphoid cell lines from various non-human primates. 257 38

A retrovirus isolated from experimentally induced sheep lung carcinoma (SPCTV) was propagated in chronically infected Himalayan tahr ovarian cells and in normal sheep lung cells. Follow-up of infection of the cells with SPCTV showed the appearance of syncytium, plaque formation, partial recovery and the establishment of a chronic infection. Virus-associated reverse transcriptase activity in the medium fluctuated but remained at a constantly high level at the stage of chronic infection. Stages of type-C virus morphogenesis were demonstrated by electron microscopy. The viral genome was detected in both the nucleus and cytoplasm by in situ hybridization. Chronically infected cells formed colonies when plated in soft agar. Following subcutaneous inoculation of chronically infected cells (of fibroblast origin) into nude mice, lymphoid tumors developed at the site of inoculation and in vital organs.
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PMID:Transforming potential of a retrovirus isolated from lung carcinoma of sheep. 258 Aug 2

The 2',3'-dideoxynucleosides (ddNs) are currently undergoing clinical evaluation as antiretroviral agents in HIV-infected individuals. When phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate analogues with reverse transcriptase, thereby inhibiting HIV replication. These nucleoside analogues can also inhibit, by chain-terminating additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl transferase (TdT). To determine the effect of possible intracellular chain-terminating additions of ddNMPs by TdT, we exposed a series of TdT-positive and TdT-negative cell lines to 2',3'-dideoxyadenosine (ddA), a representative ddN. At ddA concentrations 25-fold higher than required for inhibition of HIV replication, progressive dose-related cytotoxicity was observed in the TdT-positive cell lines. This was accentuated by the adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the intracellular generation of ddATP from ddA. A central role of TdT in mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell line rendered TdT positive by infection with a TdT cDNA-containing retroviral vector. After a 48-hour continuous exposure period to 250 mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the TdT-negative parental line, whereas 90% cell death was observed in the TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic cells (six cases). We conclude that ddA/CF selectively damages TdT-positive cells, presumably by chain-terminating additions of ddAMP, and that this may have therapeutic relevance in TdT-positive malignant disease.
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PMID:2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells. 283 1

A lymphoid cell line CK-a was established from peripheral blood of an infant with acute lymphoblastic leukemia of non-T, non-B cell type with mediastinal tumor. The CK-a cells were positive for surface immunoglobulins, Epstein-Barr virus-specific nuclear antigen, HLA-DR and Leu 12 antigens, and negative for sheep erythrocyte-rosette-receptor, and Leu 1, 2, 3 and 4 antigens. Budding particles were detected in electron micrographs of ultrathin sections of the CK-a cells. In the culture media of CK-a cells, particles with a buoyant density of 1.16 g/ml and labeled with [3H]uridine and [35S]methionine but not with [3H]thymidine were found to carry reverse transcriptase activity which preferred Mg2+ to Mn2+. Enveloped particles of 80 to 120 nm in diameter were detected in the fractions at 1.16 g/ml by electron microscopy. Thus, the particles had properties compatible with a definition of Retroviridae, and were tentatively named CK virus (CKV). The genome size of CKV RNA determined by agarose-acrylamide composite gel electrophoresis was 6.1 +/- 0.2 kb. Immune electroblotting assay detected antibody reactive with a CKV protein with a molecular weight of 67,000 in the serum of the patient, but not in sera of an adult T cell leukemia patient and healthy controls. No syncytia were formed by mixed cultures of CK-a and XC cells.
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PMID:Retrovirus produced by a lymphoid cell line from an infant with acute lymphoblastic leukemia. 288 14

A patient with common variable hypogammaglobulinemia (CVH) who presented with recurrent sinopulmonary infections, nodular lymphoid hyperplasia of the small bowel, and intestinal giardiasis was studied. A diffuse lymphocytic lymphoma with small bowel, skin, and hepatic involvement subsequently developed in the patient. Light microscopy of the tumor revealed tissue infiltration with mononuclear cells having the morphologic features of T-lymphocytes. The malignant lymphocytes had characteristics of T-suppressor/cytotoxic cells as established by the absence of surface immunoglobulin and Leu 3 surface markers, and the presence of OKT3 and OKT8 surface markers. Peripheral blood lymphocyte studies revealed an increased number of T-suppressor cells, a reversal of the helper-suppressor ratio, and a generalized state of hyporesponsiveness to mitogen and antigen stimulation. No evidence of retroviral reverse transcriptase activity was detected in cultures of peripheral blood lymphocytes. The association between CVH and a lymphoma composed of cells with T-suppressor/cytotoxic surface markers has not been previously reported. The postulated role of T-suppressor cells in the failure of immunoglobulin synthesis in some forms of CVH suggests that the finding of a T-suppressor/cytotoxic cell lymphoma complicating CVH may be more than fortuitous.
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PMID:Common variable hypogammaglobulinemia complicated by an unusual T-suppressor/cytotoxic cell lymphoma. 294 34

Simian acquired immunodeficiency syndrome is a fatal immunosuppressive disease caused by type D retroviruses such as simian acquired immunodeficiency syndrome retrovirus type 1 (SRV-1). The disease is characterized by generalized lymphadenopathy, opportunistic infections, and lymphoid depletion with defects in both humoral and cell-mediated immunity. To understand how SRV-1 infection relates to the immune defect, we studied in vivo-infected lymphocytes from SRV-1-positive macaques with and without clinical signs of immunosuppressive disease. B and T helper/inducer and T suppressor/cytotoxic lymphocytes were purified by panning or by flow cytometry. Neutrophils were purified by dextran sedimentation, and platelets were purified by low-speed centrifugation. In vitro infection studies were also done with HUT78, H9, K562, rhesus lung fibroblast, rhesus monkey kidney, and bat lung cells. SRV-1 in lymphocytes or culture supernatants was detected by the induction of syncytia in cocultivated Raji cells and was confirmed by immunofluorescence, electron microscopy, or reverse transcriptase assay. We found that B and T helper/inducer lymphocytes were infected in all animals tested. The number of infected T suppressor/cytotoxic cells was generally lower than that of the other cell subsets, and not all animals in this subset had SRV-1 infections. All other cells exposed in vitro to SRV-1, except bat lung cells, were able to be infected. These findings show that SRV-1 has a broad cell tropism for lymphoid and nonlymphoid cell types.
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PMID:Simian retrovirus D serogroup 1 has a broad cellular tropism for lymphoid and nonlymphoid cells. 296 65

Infection of normal peripheral blood T cells by the acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV) was evaluated in long-term cultures of helper-inducer T cells (T4 cells). Cells that were inoculated with ARV and maintained in medium supplemented with interleukin-2 remained productively infected with this virus for more than 4 months in culture, although they showed no cytopathic effects characteristic of acute ARV infection. The presence of replicating virus was demonstrated by reverse transcriptase activity of culture fluids and by viral antigens and budding particles detected on cells by immunofluorescence and electron microscopy. Virus produced in these cultures remained infectious and could induce cytopathic effects and viral antigens in uninfected lymphoid cells. The finding that normal lymphocytes may be productively infected by an AIDS retrovirus in the absence of cell death suggests that a range of biologic effects may occur after infection in vivo.
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PMID:Persistent noncytopathic infection of normal human T lymphocytes with AIDS-associated retrovirus. 299 22

Three human T-lymphotropic viruses have been isolated and characterized in the past 5 years. The ability to culture target cells with T-cell growth factor and sensitive detection systems for the virally encoded polymerase reverse transcriptase permitted isolation of HTLV-I, which is strongly linked to the cause of adult T-cell leukemia and associated with other lymphoid malignancies in endemic areas. The same techniques, using a permissive human tumor cell line, allowed the isolation and characterization of HTLV-III/lymphadenopathy-associated virus, which is implicated as the primary cause of the acquired immunodeficiency syndrome (AIDS). This virus shares some features with HTLV-I and HTLV-II, such as additional genes not found in most retroviruses. One gene codes for a transcriptional activator protein and may be a feature of a larger group of related retroviruses. The clear identification of the primary cause of AIDS has resulted in the development of specific immunologic reagents, preventive and therapeutic proposals, and comprehensive identification of the clinical diseases associated with this virus.
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PMID:A human T-lymphotropic retrovirus (HTLV-III) as the cause of the acquired immunodeficiency syndrome. 299 99

DNA from human T-lymphoid (Molt-4) and hamster kidney (BHK-21) cells infected with the T-lymphotropic simian foamy virus LK-3 was shown to be infectious, when assayed by transfection of BHK-21 cells. The proviral genome was further characterized by blot hybridization to a specific cDNA probe, which had been prepared by reverse transcription in vitro using viral RNA and RNA-dependent DNA polymerase present in cytoplasmic extracts of infected BHK-21 cells. This probe hybridized to a DNA species of 14 kbp in extracts from LK-3-infected diploid human fibroblasts, Molt-4 and BHK-21 cells, whereas no hybridization occurred with DNA from the respective uninfected controls. No integrated proviral DNA could be demonstrated, and the 14 kbp DNA was shown not to represent circular DNA. The patterns of restriction endonuclease and S1 nuclease fragments indicated a unique configuration of linear double-stranded DNA containing a single-stranded section separating two subunits one of which may be sufficient to transmit LK-3 by transfection with DNA.
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PMID:Detection and characterization of infectious DNA intermediates of a primary foamy virus. 301 32


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