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)

These last years, numerous molecules have been developed to face HIV-1 infection. All viral replication steps are potential targets for new molecules. The most potent inhibitors of virus-cell adsorption are represented by the different sulfated, sulfonated and carboxylated polymers among which aurintricarboxylic acid (ATA). The soluble CD4 are also potent inhibitors of viral adsorption in vitro. Many compounds are active at the level of the reverse transcriptase (RT), particularly the 2',3'-dideoxynucleosides, represented by the three currently most used drugs in the clinic, AZT, ddC and ddI. The acyclic nucleoside phosphonates (PMEA, PMEDAP) have shown a broad spectrum activity against many human and animal retroviruses, and also unique pharmacological properties allowing infrequent administration. Finally, most recently, highly potent activity, without toxicity, has been demonstrated by TIBO, HEPT and other HIV-1 RT-specific inhibitors.
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PMID:[Current acquisitions in antiviral drugs (anti-HIV)]. 138 88

A myriad of chemical derivatives has been shown to inhibit in vitro replication of the AIDS virus at concentrations that are nontoxic to the host cells. The majority of these agents acts by either (i) inhibiting enzymes such as reverse transcriptase (RT), protease, or glucosidase, (ii) arresting expression of genes or gene products, or (iii) inhibiting viral processes such as giant cell (syncytia) formation or viral binding to the target cell. The nucleoside RT inhibitors are the most widely studied agents at both the preclinical and the clinical levels. Their inability to cure AIDS has stimulated the discovery of several novel nonnucleoside RT inhibitors, possessing varied structures and demonstrating activity at nanomolar concentrations. These agents demonstrate a unique mode of binding to RT and show a high specificity for HIV-1. Protease inhibitors, soluble CD4 derivatives, oligonucleotides, and many anionic derivatives also demonstrate potent anti-HIV-1 activities. These derivatives possess mechanisms of action different to the nucleosides and exhibit selectivity as exemplified by their high in vitro therapeutic indices. This article discusses the structural parameters that govern activity in these agents, the pros and cons regarding the development of these compounds as putative anti-AIDS agents, and the future promise of searching for newer agents directed at novel targets to inhibit the AIDS virus.
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PMID:Anti-AIDS drug development: challenges and strategies. 138 26

During T cell development in the mammalian thymus, immature T cells are observed that lack the cell surface markers CD4, CD8, and CD3. A subtracted cDNA library was constructed to isolate cDNAs that are specific for these immature T cells. Tissue-specific expression of 97 individual cDNAs were examined using different cell types by Northern blot analysis, and six cDNAs were analyzed by reverse transcriptase (RT) polymerase chain reaction (PCR) detection of RNA. Approximately 50% of the clones could not be detected on Northern blots, and 40% of the clones were expressed by at least one other cell-type including monocytes, mature T cells, and B cells. Eight cDNA clones appear to be specific for the CD4-, CD8-, CD3- T cell line, used to construct the library, as determined by Northern blot analysis. In addition, 330 cDNA clones were subjected to partial automated DNA sequence determination. Database searches, with both nucleotide and protein translations, revealed cDNAs that exhibit interesting similarities to human cell-cycle gene 1, platelet-derived growth factor receptor, c-fms oncogene (CSF-1) receptor, and members of the immunoglobulin gene superfamily. This approach of employing subtraction coupled with large scale partial cDNA sequence determination can be useful to identify genes that may be involved in early T cell growth, cellular recognition or differentiation.
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PMID:A new approach to understanding T cell development: the isolation and characterization of immature CD4-, CD8-, CD3- T cell cDNAs by subtraction cloning. 138 65

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

To study the interaction between the primate lentiviruses simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) and the CD4 receptor we have cloned and sequenced the CD4 molecule from six non-human primate species: African green monkeys (three subspecies: sabeus, pytherethrus, aethiops), sooty mangabeys, patas monkeys, chimpanzees, rhesus macaques, and pig-tail macaques. Molecular cDNA clones representing CD4 mRNA were generated from total RNA from peripheral blood mononuclear cells (PBMC) by polymerase chain reaction (PCR) amplification including reverse transcriptase in initial reactions followed by two rounds of nested amplifications. Primer sequences were selected from regions conserved among human and rodent CD4 genes. Alignments of deduced amino acid sequences revealed interesting findings. First, all of the primate CD4 molecules were about 90% identical to the human CD4 sequence except the chimpanzee (98%). Second, two macaques or two African green monkey subspecies were as distanly related as the human versus chimpanzee sequences. Third, relatedness of CD4 sequences could not be predicted on the basis of geographic origin (Asian vs. African). Finally, upon sequencing several clones from individual monkeys, a low degree of sequence variation (nucleotide substitutions, deletions, and insertions) was found within the same animal, and in case of sooty mangabeys two distict populations of CD4 molecules were present within three of four individuals. The distinguishing features involved eight amino acid changes, including a single lysine deletion relative to a primate consensus sequence in the first complementary-determing region of V1J1. These two CD4 populations were present also at the genomic DNA level and may arrive from the two chromosomal alleles, suggesting the existence of distinct sooty mangabey subspecies. Overall, the V1J1 and to a lesser extent V2J2 were the most variable regions among the sequences examined. By construction and expression in mammalian cell lines of CD4 chimeras in which these regions of the human CD4 were replaced by those of the African green monkey and pig-tail macaques, a higher molecular mass of the CD4 chimeras were obtained in sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the additional N-linked glycosylation sites present in these monkey CD4 are also used.
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PMID:Cloning and sequences of primate CD4 molecules: diversity of the cellular receptor for simian immunodeficiency virus/human immunodeficiency virus. 142 21

We have isolated a lymphoid cell line, MDS, from the pleural exudate of a patient with chronic myelomonocytic leukemia. The cells are biphenotypic, containing various T-cell and myeloid markers, and are surface negative for CD4 and CD8 but have low CD4 mRNA. The cells grow in suspension with a doubling time of 15 hr, have been karyotyped as trisomy 21, are negative for human immunodeficiency virus type 1 (HIV-1), and are tumorigenic in the nude mouse. We have isolated two stable HIV-1-producing cell lines, MDS-T, by transfecting MDS cells with pHXBc2, and MDS-I, by infecting MDS cells with HIV-1IIIB. In 24 hr, 1 x 10(5) MDS-T or MDS-I cells produce 46 ng of p24 per ml and reverse transcriptase that is capable of incorporating 0.2 pmol of [32P]TTP into oligo(dT).poly(A). Ultrastructural studies showed numerous mature viral particles in MDS-T and MDS-I cells that are capable of infecting T cells. HIV-1 infection could be inhibited by 25% in the MDS cells with the anti-CD4 antibody Leu 3a. For over a year MDS-T and MDS-I cells have been producing high concentrations of HIV-1 in culture. A subclone derived from the MDS cells behaves like the parent cells when transfected or infected with HIV-1. In contrast to other T-cell lines, neither phorbol 12-myristate 13-acetate nor tumor necrosis factor alpha stimulated the replication of HIV-1, whereas bromoadenosine 3',5'-cyclic monophosphate or interferon alpha caused 50% and 80% inhibition of reverse transcriptase production, respectively. These chronically infected T-cell lines are a useful model system to study the effect of anti-HIV agents and cellular factors required for HIV-1 replication.
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PMID:Productive nonlytic human immunodeficiency virus type 1 replication in a newly established human leukemia cell line. 143 50

The study presents a new in vitro method to investigate the interaction between the glycoprotein (gp)120 of human immunodeficiency virus (HIV) and its receptor, CD4. The method is based on the binding of soluble recombinant CD4 to a human T cell line, 8E5, which constitutively expresses gp120 at its surface as a result of infection with HIV (LAV) and lacks reverse transcriptase activity. The binding of CD4 to gp120 on the cell surface is revealed by immunofluorescence using a murine monoclonal antibody to CD4. Binding can be inhibited by different substances like dextran sulfate, heparin, pentosan polysulfate, but not Leu3a. The reasons for this discrepancy are discussed. We propose this assay as a simple, reproducible, and rapid new method to screen new, pharmacological inhibitors of the gp120/CD4 interaction.
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PMID:A method to analyze the interaction between gp120 of human immunodeficiency virus and CD4. 147 79

Recent findings have indicated that megakaryocytes may be susceptible to human immunodeficiency virus (HIV) infection, suggesting a potential role for megakaryocytes as viral reservoirs in HIV-infected patients. We report that the megakaryocytic cell line Dami could be productively infected with the HTLV III-B strain of HIV-1, in 26 different experiments (results of 16 experiments are reported); productive infection lasted up to 30 weeks. Despite a lack of detectable surface expression of the CD4 molecule and very low levels of CD4 mRNA, between 40% and 60% of megakaryocytic cells produced viral proteins after contact with HIV-1. Neither cytopathogenic effects nor syncytial formation was observed. Production of high levels of functional viral particles was indicated by analysis of p24 protein levels, reverse transcriptase activity, ultrastructural studies, and the capacity of supernatants from infected Dami cells to infect the Molt-4 T-lymphocytic cell line. HIV-1 RNA and protein levels in infected Dami cells were enhanced by treatment with tumor necrosis factor-alpha (TNF-alpha), and decreased by treatment with interferon-alpha (IFN-alpha) and IFN-gamma. Transient transfection of the megakaryocytic cells with various constructs of the HIV-1 promoter (LTR) linked to the luciferase reporter gene suggested that the effect of TNF-alpha was related, as in monocytic and T-cell lines, to transactivation of the enhancer region of the HIV-1 LTR. These findings indicate that signals provided by the immune system may modulate HIV-1 expression in cells of the megakaryocytic lineage.
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PMID:Productive human immunodeficiency virus-1 infection of megakaryocytic cells is enhanced by tumor necrosis factor-alpha. 158 16

Two interleukin 2 (IL-2)-independent feline immunodeficiency virus (FIV) producer cell lines (FL-4 and FL-6) were produced by selecting cells from an IL-2-dependent culture of mixed peripheral blood lymphocytes infected with FIV. The new cell lines have been stable for over 1 year and spontaneously produce FIV with an average reverse transcriptase titer of 300,000 cpm/ml and an average sucrose gradient purified viral protein concentration of 1 mg/l. FIV produced from these cultures is highly infectious in vitro and in vivo. The FL-6 cell line was phenotyped as expressing the feline CD8 and Pan-T antigens, while the FL-4 cell line expressed the CD4, CD8, and Pan-T antigens. Both cell lines, however, express high levels of viral core and envelope proteins. Paraformaldehyde-inactivated whole virus and similarly inactivated whole-cell virus preparations induced a strong antibody response to core and envelope antigens in immunized cats. The establishment of FIV-producing feline IL-2-independent peripheral blood lymphocyte lines should be valuable for the development of FIV-diagnostic reagents and vaccines and also as a model for human acquired immunodeficiency syndrome vaccine development.
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PMID:Development of IL-2-independent feline lymphoid cell lines chronically infected with feline immunodeficiency virus: importance for diagnostic reagents and vaccines. 165 26

Eleven (nine CD4+ and two CD8+) protein purified derivative-specific and eight tetanus toxoid-specific T cell clones (TCC), established from the peripheral blood of healthy persons, were cocultured in vitro with irradiated mononuclear cells from patients infected by HIV in the presence of PHA and polybrene. Two weeks post-HIV exposure, all 17 CD4+, but neither of the two CD8+, TCC exhibited integration of HIV in their genoma, as detected by polymerase chain reaction analysis, and released HIV into their supernatants, as detected by measuring both reverse transcriptase activity and p24 Ag. When co-cultured with either autologous or allogeneic B cells, all CD4+ HIV-infected TCC induced the synthesis of extraordinarily high amounts of IgM, IgG, and IgA. In contrast, their noninfected counterparts could provide helper function for Ig synthesis by autologous B cells only in the presence of the specific Ag (or anti-CD3 antibody), and induced allogeneic B cells to synthesize Ig only upon stimulation with anti-CD3 antibody. The supernatants of HIV-infected TCC failed to stimulate Ig synthesis in B cells. More importantly, when HIV-infected clonal T blasts and B cells were cultured in different chambers separated by a millipore membrane, permeable to molecules but not to cells, Ig synthesis did not occur. The Ig synthesis induced by HIV-infected TCC was also markedly inhibited by the addition in culture of either anti-CD4 or anti-LFA-1 antibody. In contrast, HIV-infected TCC maintained their ability to provide helper function for Ig synthesis in the absence of any stimulus, even after fixation with p-formaldehyde. These data demonstrate that in vitro infection with HIV enables human T cells to stimulate Ig synthesis by B cells by an Ag-nonspecific, MHC-unrestricted, contact-dependent mechanism. This may explain, at least in part, the hypergammaglobulinemia and other phenomena related to polyclonal B cell activation frequently seen in HIV-infected persons.
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PMID:In vitro infection with HIV enables human CD4+ T cell clones to induce noncognate contact-dependent polyclonal B cell activation. 167 84


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