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)

Acquired immunodeficiency syndrome (AIDS) is caused by infection with a pathogenic human retrovirus known as human immunodeficiency virus (HIV). Approximately 1 million people are currently infected with HIV in the United States, with 8 to 10 million infected individuals worldwide. The virus is transmitted predominantly through genital sexual contact, although orogenital spread has been rarely reported. Heterosexual transmission has been most common in the Third World, whereas male homosexual transmission has predominated in the United States and western Europe. Transmission through homosexual contact has been steadily declining over the past 5 years as transmission through illicit intravenous drug use and promiscuous unprotected heterosexual activity has increased. Sexually transmitted diseases that cause inflammatory or ulcerative lesions of the genital tract act as important cofactors in increasing the risk of transmission through sexual contact. Perinatal transmission of HIV occurs in approximately 30% of infants born to infected mothers. Transmission to infants through breast-feeding has also been documented. Health care workers have been infected with HIV through accidental high-risk percutaneous or mucous membrane exposures, albeit at a low transmission rate of 0.3%. Infection of patients by infected health care professionals is a rare event, having been reported only once in 10 years of the epidemic. Infection with HIV results in a chronic lifelong infection. The major targets for HIV are CD4+ T-helper lymphocytes and cells of monocyte/macrophage lineage. Infection of the T-helper lymphocyte ultimately results in the death of the cell. Over time (measured in years), a progressive destruction of the T-helper lymphocyte population occurs, which results in profound immune suppression. Infection of monocytes/macrophages is not cidal, but these cells do have functional alterations as a result of the infection, which may contribute to the immune deficiency. In addition, chronically infected tissue macrophages may act as an important reservoir for HIV, particularly in the central nervous system. Infection of the T-helper lymphocytes and monocytes/macrophages is mediated through attachment of HIV through a specific binding interaction between CD4 expressed in the plasma membrane of these cells and a surface glycoprotein on the virus, gp120. Once the virus nucleocapsid (core particle) enters the cytoplasm of the target cell, the viral RNA genome is reverse transcribed by a reverse transcriptase enzyme into proviral DNA. This proviral DNA migrates into the nucleus where it integrates into the host cellular genome, which results in a chronically infected cell.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:AIDS: Part I. 139 37

Recombinant human growth hormone (rhGH) was administered to mice to determine its effect on hematopoiesis. BALB/c mice and mice with severe combined immune deficiency (SCID), which lack T cells and B cells, were administered intraperitoneal injections of rhGH for 7 days. Upon analysis, both strains of mice exhibited an increase in splenic and bone marrow hematopoietic progenitor cell content and cellularity, indicating that rhGH can act as a hematopoietic growth factor. C57BL/6 mice were then placed on azidothymidine (AZT). AZT is a reverse transcriptase inhibitor currently used as a treatment for acquired immune deficiency syndrome (AIDS), but which also produces significant myelotoxic effects. Treatment of mice with rhGH partially counteracted the myelosuppressive properties of AZT. Bone marrow cellularity, hematocrit values, white blood cell counts, and splenic hematopoietic progenitor cell content were all significantly increased if rhGH (20 micrograms injected intraperitoneally every other day) was concurrently administered with AZT. Administration of ovine GH (ovGH), which, unlike rhGH, has no effect on murine prolactin receptors, also prevented the erythroid-suppressive effects of AZT in mice, but had no significant effect on granulocyte counts. Thus, the effects of GH are mediated at least in part through GH receptors in vivo. Additionally, when mice were initially myelosuppressed by several weeks of AZT treatment, the subsequent administration of ovGH resulted in an increase in splenic hematopoietic progenitor cells. No significant pathologic effects were observed in mice receiving either repeated rhGH or ovGH injections. Thus, GH exerts significant direct hematopoietic growth-promoting effects in vivo and may be of potential clinical use to promote hematopoiesis in the face of myelotoxic therapy.
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PMID:Growth hormone exerts hematopoietic growth-promoting effects in vivo and partially counteracts the myelosuppressive effects of azidothymidine. 152 Aug 71

Human immune deficiency virus (HIV) replicates by conversion of the RNA genome into the double-stranded DNA provirus. The reverse transcriptase is not the only enzymatic function crucial in DNA-provirus synthesis. A viral-coded RNase H activity which specifically degrades RNA in RNA-DNA hybrids has been shown to be essential as well. Here we demonstrate that the HIV-reverse transcriptase which consists of a two-polypeptide complex, p66 and p51, copurifies with an RNase H activity which exhibits properties of a processive exonuclease. Only the p66 molecule, not p51, is active as polymerase as evidenced by activated gel analysis. p66 exhibits RNase H activity when precipitated as immune complex by a monoclonal antibody raised against a bacterially expressed carboxy-terminal portion of p66. The monoclonal antibody which does not interfere with enzyme activity also precipitates a second population of molecules with RNase H activity which is of low mol. wt, p15. This RNase H appears therefore to be derived from the carboxy terminus of p66 during processing to the p51 polypeptide. It exhibits low template-binding ability and is of a non-processing mode of action which may be due to the absence of the reverse transcriptase domain. These results lend experimental support to the hypothesis that the RNase H gene maps at the carboxy terminus of the reverse transcriptase. Since both RNase H populations are virus-coded they may be essential for retrovirus replication in general and useful targets for chemotherapeutic agents.
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PMID:Identification and characterization of HIV-specific RNase H by monoclonal antibody. 245 83

Feline immunodeficiency virus (FIV), formerly called feline T-lymphotropic lentivirus, causes an immune deficiency in cats that is very similar to the acquired immune deficiency syndrome in humans (N. C. Pedersen, E. M. Ho, M. L. Brown, and J. K. Yamamoto, Science 235:790-793, 1987). We have examined the reverse transcriptase of this virus to determine whether it is similar enough to the reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1) to enable its use as a model for chemotherapy for acquired immune deficiency syndrome. The FIV reverse transcriptase is similar to that of HIV-1 in sensitivity to the noncompetitive inhibitor phosphonoformate (Ki, 0.3 microM) and relative insensitivity to phosphonoacetate. This enzyme was also sensitive to two competitive inhibitors, the 5'-triphosphates of 2', 3'-dideoxythymidine (Ki, 3.4 nM) and 3'-azido-3'-deoxythymidine (AZT; Ki, 6.2 nM). The ratios of Ki/Km for these two competitive inhibitors are similar to the ratios calculated from previously reported data for the HIV-1 enzyme assayed under identical conditions. In contrast, the FIV enzyme is different from the reverse transcriptase of avian myeloblastosis virus in sensitivity to those inhibitors. The replication of FIV in Crandell feline kidney cells was inhibited by AZT; virus production was inhibited more than 95% by 1.0 microM AZT.
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PMID:Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. 247 68

Since the detection of antibodies against the human immune deficiency virus (HIV) does not definitely prove HIV infection in hemophiliacs, virus detection was attempted by virus isolation from the peripheral blood monocytes (PBL), by demonstration of p24 antigen and decline of p24 antibody, and by detection of viral DNA by the polymerase chain reaction (PCR). Virus isolation was optimized by immediate coculture of PBL and by replacement of the reverse transcriptase test by the p24 antigen test, whereas the elimination of CD8+ lymphocytes proved to be unnecessary. Virus detection was dependent on the clinical stage of the illness. Virus isolation in 70 of 211 patients (33%) was more sensitive than detection of p24 antigen or decline of p24 antibody. PCR was performed in 25 patients and indicated infection in all of 15 isolation-positive cases and in 6 of 10 patients from whom virus was not isolated. Changes from negative to positive virus culture and from a weakly fusiogenic to a highly fusiogenic isolate were often accompanied by a progression of the disease. The results suggest that reactivation of HIV occurs when immune deficiency has become manifest. Apparently virus isolation detects only the virus already reactivated in vivo, whereas the PCR may also detect latent virus.
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PMID:Comparison of different methods for detecting human immune deficiency virus in human immunodeficiency virus-seropositive hemophiliacs. 268 96

Lymphadenopathy associated virus ( LAV ) has been isolated from patients with the acquired immunodeficiency syndrome (AIDS) or lymphadenopathy syndrome. Since the immune deficiency in AIDS seems to be primarily related to the defect of the helper-inducer T lymphocyte subset, the possibility that LAV is selectively tropic for this subset was investigated. Fractionation of T lymphocytes was achieved by cellular affinity chromatography with monoclonal antibodies. In a hemophilic patient who was a healthy carrier of LAV , reverse transcriptase activity and virus particles detected by electron microscopy were found only in cultures of helper-inducer lymphocytes. When infected with LAV in vitro, lymphocyte subsets from normal individuals yielded similar results. Virus production was associated with impaired proliferation, modulation of T3-T4 cell markers, and the appearance of cytopathic effects. The results provide evidence for the involvement of LAV in AIDS.
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PMID:Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. 632 60

Several lines of evidence indicate that an impairment of EBV-specific immune responses may contribute to the pathogenesis of Hodgkin's disease (HD). At present, however, it is not clear whether a defective immunity to EBV is a characteristic restricted to EBV-associated HD cases or a more generalized phenomenon, part of the inherent immune deficiency of HD patients. In this study, we have addressed this issue by analyzing EBV-specific responses in infiltrating T lymphocytes (TILs) from one HD biopsy, where the virus was confined to a small proportion of apparently normal lymphocytes. TIL cultures were established using low amounts of recombinant interleukin 2 and in the absence of specific stimulation, conditions that preferentially induce the proliferation of in vivo activated T cells. An EBV-specific cytotoxic component was revealed by the capacity of these TILs to lyse autologous EBV-positive lymphoblastoid cell lines (LCLs) obtained by spontaneous transformation from the lesion but not HLA-mismatched LCLs and autologous phytohemagglutinin blasts. This cytotoxic activity closely resembled that of EBV-specific memory T cells, which may be reactivated from the blood lymphocytes of healthy donors by in vitro stimulation with autologous LCLs. The use of a panel of appropriately HLA-matched B95.8-transformed LCLs as targets in standard 51Cr release assays revealed EBV-specific cytotoxic responses to be restricted mainly through the A11 and B44 HLA alleles with a minor HLA-A26-restricted component. Using autologous fibroblasts infected with recombinant vaccinia viruses expressing the EBV latent antigens, the TIL culture was shown to recognize latent membrane protein 2 and, to a lesser extent, EBV-encoded nuclear antigen 6. In addition, a strong proliferative response was induced by coculture of TILs with autologous but not with allogeneic LCLs or autologous phytohemagglutinin blasts. Six CD4-positive, EBV-specific T-cell clones were isolated by limiting dilution. The study of cytokine mRNA expression, carried out by reverse transcriptase-assisted PCR, revealed that three of these T-cell clones expressed a Th0 phenotype, whereas 1 had a Th2 phenotype. These findings are consistent with the presence in this HD lesion of an ongoing immune response against EBV-carrying cells and suggest that the complex immune deficiency that characterizes HD patients probably does not include a generalized, constitutional defect of EBV-specific T-cell responses.
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PMID:Identification and characterization of an Epstein-Barr virus-specific T-cell response in the pathologic tissue of a patient with Hodgkin's disease. 762 78

BHRF1, one of many Epstein-Barr virus (EBV)-encoded proteins, shows strong functional homology to the human bcl-2 proto-oncogene product, a protein involved in the pathogenesis of a subset of B-cell lymphomas, ie, follicle center cell lymphomas (FCCL). We have investigated the presence of possible latent and lytic transcripts of BHRF1 using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay in a group of EBV-associated B-cell lymphomas in patients with (N = 5) or without overt immunodeficiency (N = 4), in T-cell lymphomas (N = 9), and in cases of Hodgkin's disease (N = 6). BHRF1 transcription was found consistently in EBV-associated (ie, diffuse EBER 1/2-positive) B-cell lymphomas in patients with or without immune deficiency, whereas in EBV-associated T-cell lymphomas or in EBV-associated Hodgkin's disease, BHRF1 transcription was only detected in two T-cell lymphomas and one case of Hodgkin's disease, which also harbored EBER 1/2-positive reactive cells. Moreover, weak BHRF1 signals were found in two T-cell lymphomas where EBER 1/2 expression was detected mainly in sporadic reactive lymphocytes and in one reactive tonsil with sporadic EBER 1/2-positive lymphocytes. BHRF1 transcripts were found to be generated by the C or W promoter (associated with viral latency) and/or by the H promoter (associated with the virus lytic cycle). In all cases with H promoter-derived BHRF1 transcripts, transcripts encoding ZEBRA were also detected, suggesting a reactivation of the virus lytic cycle. Analysis of other EBV genes revealed transcription of BARFO in all tested EBV-harboring tissues. Transcription of EBNA1 and LMP1 was usually detected, whereas EBNA2 transcription was found exclusively in B-cell lymphomas in immunocompromised patients. These data demonstrate that BHRF1 transcripts are exclusively found in EBV-associated B-cell lymphomas. When BHRF1 transcripts are detected in T-cell lymphomas or in Hodgkin's disease, it is probably due to the presence of reactive EBER 1/2-positive lymphocytes. The consistent transcription of BHRF1 in EBV-associated B-cell lymphomas suggests a possible pathogenic role for this gene product in EBV-positive B-cell lymphomas analogous to bcl-2.
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PMID:BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. 765 18

A series of substituted 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones and related compounds 1-73 were synthesized and evaluated for their ability to inhibit reverse transcriptase (RT) of the human immune deficiency virus 1 (HIV-1) and replication of HIV-1 in MT2 cells. The antiviral activity of these compounds depends on the stereoselective configuration of the substituent in position 9b. Structure-activity studies were done within these series of compounds to determine the optimum substituents for antiviral activity. The most potent inhibitors were found in the class of 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones bearing a phenyl ring system in position 9b optionally substituted with one or two methyl groups or a chlorine atom in position 8. The most active analogues (R)-(+)-1, (R)-(+)-6, (R)-(+)-13, (R)-(+)-26, and (R)-(+)-53 inhibit the HIV-1 RT with an IC50 between 16 and 300 nM and an IC50 between 10 and 392 nM in MT2 cells, respectively.
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PMID:Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones and related compounds with anti-HIV-1 activity. 768 9

Confidence in the efficacy of using antiretroviral drugs to treat HIV infection has grown in the past year as a result of the prolonged survival of those randomly allocated to receive an additional drug in comparative controlled trials. HIV remains, however, the only serious infectious disease for which antimicrobial treatment is deliberately delayed. This is because infected subjects can often be symptomless for more than a decade in the absence of any treatment, and results from trials with the nucleoside analogue reverse transcriptase inhibitor zidovudine have failed to show any evidence for extended survival in those beginning treatment early compared with those who deferred treatment. The new confidence in currently available treatments, and in the prospects for new ones, inevitably leads to renewed questioning of the current strategy of waiting for signs of immune deficiency before electing to intervene. A new randomised controlled trial comparing strategies of early and deferred treatment is required to assess whether the time has come for intervention immediately after HIV has been diagnosed.
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PMID:Will we ever know when to treat HIV infection? 880 55


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