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)

1. The double-stranded RNA-dependent 2',5'-oligoadenylate (2-5A) synthetase/ribonuclease L (RNase L) system plays an essential role in the establishment of the antiviral state of a cell exposed to virus infection. 2. Until recently, the application of 2-5A derivatives to reinforce this system seemed to be limited mainly due to the low specificity of RNase L for viral RNA. 3. Two new strategies have been developed which yield a selective antiviral effect of 2-5As at least against human immunodeficiency virus-1 (HIV-1) infection: (i) an "intracellular immunization" approach using 2-5A synthetase cDNA linked to HIV trans-acting response element (TAR) and (ii) inhibition of retroviral reverse transcriptase activity by 2-5A analogues.
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PMID:(2'-5')Oligoadenylate and intracellular immunity against retrovirus infection. 137 26

The proposal that replication of human immunodeficiency virus type 1 (HIV-1), mediated by cell-to-cell transmission of the virus, might bypass de novo reverse transcription was tested by using one-step cell-to-cell and cell-free virus infection systems. Two well characterized reverse transcriptase (RT) inhibitors, azidothymidine at 20 microM and phosphonoformic acid at 100 micrograms/ml, blocked HIV replication completely following both cell-free virus and cell-to-cell transmission infection, as determined from the kinetics of unintegrated viral DNA synthesis and supernatant RT production after virus infection. Our results confirm that de novo reverse transcription is a crucial and mandatory event in HIV-1 replication following cell-to-cell transmission of the virus.
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PMID:De novo reverse transcription is a crucial event in cell-to-cell transmission of human immunodeficiency virus. 137 83

The derivation of ethyl-methanesulfonate (EMS) mutagenized subclones from the CEM T-cell line has been described. These clones expressed CD4 and bound soluble gp120, however, two of the generated clones were markedly reduced in their ability to form syncytia after infection with either gp160-vaccinia vector or cell-free human immunodeficiency virus type 1 (HIV-1). Here, we asked at what stage(s) viral infection is blocked in these cells. Polymerase chain reaction (PCR) analysis revealed that at 6 and 72 h postinfection with HIV-1, cells of the syncytia-deficient clones expressed markedly reduced amounts of viral-specific DNA compared with cells of the parental line or the syncytia-positive clones. Long-term cultures revealed a marked delay in the appearance of reverse transcriptase (RT) activity in the supernatants of these subclones when compared with the parental line and viral replication did not lead to massive cell death. Syncytia formation in HIV-1-infected cultures of the syncytia-deficient subclones was enhanced by tumor necrosis factor alpha (TNF alpha) when added 24 h postinfection. In contrast, pretreatment with TNF alpha for 48 h followed by washing and infection of the cells with HIV-1 augmented syncytia formation of the syncytia-positive subclones, but not of the syncytia-negative subclones. Thus, the EMS-mutagenized subclones may provide a tool to study host cell factors required for the establishment of a productive HIV-1 infection and responsiveness to TNF alpha.
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PMID:Study of viral replication in HIV-1-infected CEM T-cell subclones which are reduced in their ability to form syncytia. 138 Feb 60

Over 50 different commercially available sulfonic acid-containing dyes were analyzed for their ability to prevent HIV-1-induced cell killing and in inhibiting HIV-1 replication. Compounds of remarkably similar structure, but with differing patterns of sulfonic acid group substitutions, had a wide range of potency in inhibiting HIV-1. Chicago sky blue (CSB) was highly effective in the inhibition of HIV-1 with less toxicity to CEM-SS cells than most of the other sulfonated dyes tested. Synthesis of CSB was undertaken to produce a product greater than 98% pure and this compound was used to elucidate the possible mechanisms by which this class of structurally related compounds inhibits HIV-1. Addition of CSB to cells infected at high multiplicity at any time up to 24 h after infection, unlike dideoxycytidine (ddC) or oxathiin carboxanilide (OC), inhibited HIV-1-induced cell killing. Other postinfection time course studies revealed that CSB had to be present for 24 h or longer immediately after infection to be protective. Virus binding to cells occurred in the presence of CSB, but the requirement for virion envelope-cell membrane fusion was delayed. CSB was a potent inhibitor of the reverse transcriptase (RT) of both HIV-1 and HIV-2, although it was less active against HIV-2 in a cell killing-based assay. CSB also inhibited Rauscher and LP-BM5 murine leukemia viruses. CSB appears to disrupt the interaction between viral proteins and cell membranes, both in the fusion step early in the infection cycle and in the development of syncytia in the late stages of virus infection.
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PMID:Sulfonic acid dyes: inhibition of the human immunodeficiency virus and mechanism of action. 151 63

Elucidation of the mechanism by which viral infection induces the appearance of carbohydrate neoantigens is highly important. Results from such studies could be expected to be significant for a general understanding of the regulation of glycosylation, and perhaps especially important for the understanding of glycosylation in cancer. For anti-viral therapy in AIDS, inhibitors of glycosylation enzymes are very promising as their mode of action may preclude evolvement of resistent HIV substrains, which seems to be a common problem with the reverse transcriptase inhibitors presently used. Successful therapy with glycosylation enzyme inhibitors will, however, require the development of more specific and less toxic compounds. If carbohydrate antigens can elicit a neutralizing immune response in vivo, the possibility exists that carbohydrate neoantigens can be utilized in the construction of a vaccine against AIDS.
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PMID:Carbohydrates of human immunodeficiency virus. 152 May 31

A new class of membrane-active ether lipid (EL) analogs of platelet-activating factor were studied for in vitro anti-HIV-1 activity. Human T-cell (CEM-ss) monolayers or suspension cultures were used to determine effects of structural modifications of Type A phosphorus-containing and Type B nonphosphorus EL analogs on (a) the inhibitory concentration50 (IC50) for HIV-1 syncytial plaque formation and cell growth, and, (b) virus budding at the cell plasma membrane. Results indicate that representative Type A and Type B EL inhibit HIV-1 but not herpes simplex virus type 2 plaque formation when added before or up to 2 days after viral infection. Anti-HIV-1 activity does not involve direct inactivation of virus infectivity. Type A EL (IC50 range = 0.2-1.4 microM) with alkyoxy, alkylthio, or alkyamido substitution at glycerol position 1 and ethoxy or methoxy substitution at position 2, and Type B compounds (IC50 range = 0.33-0.63 microM) with an inverse choline or nitrogen heterocyclic substitution at position 3 have selective activity against HIV-1-infected T-cells. EL treatment of HIV-1-infected cells is associated with subsequent release of reverse transcriptase activity, but infectious virus production is inhibited with time after infection. Electron microscopic examination of HIV-1-infected and EL-treated cells revealed absence of detectable budding virus at the plasma membrane but presence of intracytoplasmic vacuolar virus particles. In summary, these data suggest that EL analogs are a novel class of agents that induce defective intracytoplasmic vacuolar HIV-1 formation in T-cells. Being membrane interactive, EL are ideally suited for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs.
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PMID:Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation. 169 29

Adult C57BL/10 mice (H-2b Fv-1b) inoculated with LP-BM5 murine leukemia virus develop a disease which has many features in common with human acquired immunodeficiency syndrome (AIDS), in particular abnormal lymphoproliferation and severe immunodeficiency. In the present study, we examined the possibility that this murine AIDS (MAIDS) model would be useful for evaluating antiretrovirus drugs in vivo through the use of a well-defined antiretrovirus drug, the reverse transcriptase (RT) inhibitor (H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. St. Claire, S. Nusinoff-Lehrman, R.C. Gallo, D. Bolognesi, D.W. Barry, and S. Broder, Proc. Natl. Acad. Sci. USA 82:7096-7100, 1985) 3'-azido-3'-deoxythymidine (AZT). We evaluated the effect of AZT treatment on de novo virus infection as well as on the induction of immunodeficiency by various parameters, including RT activity in serum, splenomegaly, proliferative responses against alloantigens and mitogens, soluble-antigen-presenting cell activity, and immunoglobulin G levels in serum. Our results demonstrated that AZT treatment of C57BL/10 mice infected with LP-BM5 murine leukemia virus efficiently prevented the induction of immunodeficiency if started at the time of virus inoculation. Starting AZT treatment 1 week later provided only a partial protective effect. Starting AZT treatment 2 weeks later was associated with suppression of RT activity in serum but no prevention of immunosuppression. This MAIDS model may allow rapid and cost-effective screening for antiretrovirus drugs targeted against retroviral functions shared between human AIDS and MAIDS, such as those encoded by gag, pol, or env.
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PMID:3'-Azido-3'-deoxythymidine prevents induction of murine acquired immunodeficiency syndrome in C57BL/10 mice infected with LP-BM5 murine leukemia viruses, a possible animal model for antiretroviral drug screening. 169 56

Transduction of cellular oncogenes by retroviruses is thought to be a multistep process, involving transcriptional activation of a cellular gene by upstream proviral integration and joining of cellular DNA to retroviral transcriptional signals, followed by copackaging and recombination with a helper virus genome during reverse transcription. To examine the molecular mechanism of the reverse transcriptase-mediated recombination, we introduced into mouse fibroblast cells a variety of constructs in which the neo selectable marker was joined to flanking retroviruslike or cell-like sequences. After superinfection and copackaging with a replication-competent Mo-MuLVsupF virus, the formation of recombinant neo transducing viruses was assessed in a second round of virus infection by the ability to confer G418 resistance to infected cells. Our results showed that recombinant neo proviruses were generated from neo RNA containing either a 5' or 3' retroviral end, implying that one recombination event with helper virus RNA was sufficient to incorporate the neo gene into proviral DNA. Recombination occurred with an apparent frequency of 10(-4) to 10(-5) per replication cycle in the absence of homology between the two recombining partners. This frequency, however, increased at least 100-fold if homology was provided at the site of recombination. Our results support the hypothesis that neo-transducing viruses arise via reverse transcriptase-mediated recombination of RNA rather than by recombination proceeding through DNA intermediates. Unexpectedly, removal of the retroviral packaging site psi reduced the number of neo recombinants only slightly. Our data indicated that although RNAs lacking the psi site are poorly packaged into virions, those RNAs that are included in the virions undergo frequent recombination, even if there is no selection for recombination. Many of the neo recombinants formed with the psi- constructs had undergone additional recombinations and often incorporated the psi site from the helper RNA.
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PMID:Transduction of cellular neo mRNA by retrovirus-mediated recombination. 170 Aug 24

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

Malignant lymphomas were observed in 38% (9 of 24) of simian immunodeficiency virus (SIV)-infected cynomolgus monkeys (Macaca fascicularis) 5 to 15 months after inoculation with SIV strain SMM3. Lymphomagenesis in the SIV-infected monkeys was not related directly to the SIV-infectious dose given. All SIV-infected animals developed severe immunodeficiency. No significant difference in immunodeficiency was observed between tumor-bearing and non-tumor-bearing animals. In contrast, no lymphomas were observed in a comparable group of HIV-2-infected monkeys, which did not develop immunodeficiency; nor did the noninfected control monkeys. All 9 SIV-related tumors were high-grade B-cell lymphoblastic or pleomorphic lymphomas with extranodal, disseminated growth. Most tumors showed marked infiltration by monocytes and CD8+ T lymphocytes. Occasional tumor infiltrating cells showed immunohistochemical reaction for SIV. The cells of two tumors were established in vitro and shown to be of B-cell phenotype. The tumor cell cultures showed no reverse transcriptase activity and no evidence of virus infection by electron microscopy. Our observations indicate that SIV-induced immunodeficiency in cynomolgus monkeys also mimics HIV infection and AIDS in humans with regard to increased lymphomagenesis and type of lymphomas.
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PMID:Malignant lymphomas in cynomolgus monkeys infected with simian immunodeficiency virus. 170 62


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