UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A synthetic RNA oligonucleotide (15-mer) corresponding to the 3' end of the lysine tRNA primer was hybridized to single-stranded DNA containing the human immunodeficiency virus type 1 (HIV-1) primer-binding site and extended with a DNA polymerase. The resulting structures were used to study primer removal by the RNase H activity of HIV-1 reverse transcriptase. The initial cleavage event removes the RNA primer as a 14-mer and leaves a single ribonucleotide A residue bound to the 5' end of the DNA strand. This result explains the observation by several groups that HIV-1 circle junctions contain 4 bp that are not present in the integrated provirus instead of the predicted 3 bp. Subsequent cleavage events occur at other sites internal to the RNA molecule, and the ribonucleotide A residue on the end of the DNA strand is ultimately removed. Therefore, the biologically relevant cleavage that produces the 14-mer reflects the kinetics of the reaction as well as a specificity for nucleic acid sequence. When the RNA oligonucleotide alone was hybridized to the primer-binding site and tested as a substrate for HIV-1 RNase H, the cleavage pattern near the 3' end of the RNA was altered.
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PMID:Incomplete removal of the RNA primer for minus-strand DNA synthesis by human immunodeficiency virus type 1 reverse transcriptase. 137 87

Contact of human immunodeficiency virus (HIV)-infected MOLT-4 lymphocytes with epithelial cells derived from small intestine (I407; Intestine 407) resulted in a rapid polar budding of viral particles into an enclosed space formed by interdigitating microvilli of the contacting cells. Electron microscopy showed that released HIV was taken up into the mucosal cell via three independent mechanisms: (1) phagocytosis, (2) coated pits, and (3) direct fusion. Morphological evidence suggests that internalized HIV may escape into the cytoplasm of the target cell by uncoating at the endosomal membrane. Based on CD4 antibody binding and CD4 antibody blocking experiments, HIV entry does not appear to be mediated by a viral CD4 receptor. Productivity of I407 infection was confirmed by virus isolation from cocultured MT-4 lymphocytic cells, reverse transcriptase assay, p24 antigen ELISA, in situ HIV mRNA hybridization, and Southern dot blot analysis. Contrary to infection with free virus, the cell-to-cell infection was not blocked by anti-gp120 or antiviral serum from HIV-positive individuals. It appears that HIV transmission within the confined space between contacting cells enables HIV to evade immune protection provided by neutralizing antibodies. Our results reveal a mechanism of HIV infection of epithelial cells which is triggered by cell-cell contact. Furthermore, these observations offer an insight into the cellular sequence of events which may take place during sexual transmission of HIV across an intact epithelial barrier.
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PMID:Mechanism of HIV spread from lymphocytes to epithelia. 137 Jan 28

The bisheteroarylpiperazines (BHAPs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and specifically block HIV-1 replication (Romero, D. L., Busso, M., Tan, C.-K., Reusser, F., Palmer, J. R., Poppe, S. M., Aristoff, P. A., Downey, K. M., So, A. G., Resnick, L., and Tarpley, W. G. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 8806-8810). Here we show that the radiolabeled BHAP [3H]U-88204 binds specifically to HIV-1 RT with high affinity (KD of 50 nM) and a stoichiometry of 1 mol of U-88204 per 1 mol of p66/p51 RT heterodimer. Binding of [3H]U-88204 to RT is unaffected by the presence of saturating poly(rC).oligo (dG)12-18 template-primer. Direct measurement of competition between [3H]U-88204 and other RT inhibitors for binding to RT reveals mutually exclusive competition between [3H]U-88204 and the non-nucleoside RT inhibitor BI-RG-587 (Kopp, E. B., Miglietta, J. J., Shrutkowski, A. G., Shih, C.-K., Grob, P. M. and Skoog, M.T. (1991) Nucleic Acids Res. 19, 3035-3039), indicating that both share the same binding site. Phosphonoformate in concentrations up to 50 microM shows no competition with [3H]U-88204 for binding to RT either alone or in the presence of template-primer. Dideoxynucleotide RT inhibitors affect the binding of [3H]U-88204 to RT when complementary template-primer is present. [3H]U-88204 and the dideoxynucleotide ddGTP can bind RT simultaneously, but the presence of one ligand decreases the affinity of RT for the second. Inasmuch as ddGTP approximates the nucleotide substrate of RT, the direct demonstration of an RT-dideoxynucleotide-[3H]U-88204 complex validates the use of indirect kinetic methods to assess the strength of BHAP interaction with RT and suggests that RT inhibition by U-88204 is achieved via effects on nucleotide substrate binding.
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PMID:The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase. 137 Apr 45

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is present in virions and infected cells as an heterodimer (p66/p51). A new class of potent and selective HIV-1 inhibitors, the tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, were found to exert their antiviral activity by interacting with monomeric HIV-1 RT (p66) in a way different from that of previously studied RT inhibitors such as azidothymidine 5'-triphosphate. Upon examination of the kinetic properties of the heterodimeric HIV-1 RT and its inhibition by TIBO compounds, a positive cooperativity between the subunits of the enzyme with regard to the 2'-deoxynucleoside 5'-triphosphates and the template/primer was observed. The cooperativity with respect to the template/primer may result from a progressive dimerization in the presence of increasing concentrations of the template/primer, a process referred to as polysteric linkage. Because the cooperativity of p66/p51 was abolished in the presence of TIBO, these compounds behave as allosteric inhibitors.
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PMID:Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds. 137 Jul 7

The genomic hypervariation of human immunodeficiency virus 1 (HIV-1) could result from misincorporations by the viral reverse transcriptase. We developed an assay for reverse transcriptase fidelity during RNA-dependent as well as DNA-dependent DNA polymerization in vitro. A lacZ alpha RNA fragment transcribed by T3 RNA polymerase was used to mimic first-strand reverse transcription. The corresponding DNA template was used to examine errors by reverse transcriptase during second-strand DNA synthesis. With both templates, the mutations introduced by reverse transcriptase were identified by their mutant phenotypes in an M13 lacZ alpha-complementation assay. We found that the reverse transcriptase from human immunodeficiency virus 1 (HIV-1 RT) was less accurate than the reverse transcriptase from Moloney murine leukemia virus (MLV RT) or the Klenow fragment of Escherichia coli DNA polymerase I (Pol I) on either RNA or DNA templates. The frequency of misincorporation by HIV-1 RT was 1 in 6900 nucleotides polymerized on the RNA template and 1 in 5900 on the DNA template. The error rates of MLV RT and Pol I on the RNA template were less than 1 in 28,000 and 37,000, respectively. The most frequent mutations produced by HIV-1 RT copying the RNA template were C----T transitions and G----T transversions resulting from misincorporation of dAMP.
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PMID:Fidelity of HIV-1 reverse transcriptase copying RNA in vitro. 137 Sep 10

Early events in the retroviral replication cycle include the conversion of viral genomic RNA into linear double-stranded DNA. This process is mediated by the reverse transcriptase (RT), a multifunctional enzyme that possesses RNA-dependent DNA polymerase, DNA-dependent DNA polymerase, and RNase H activities. In the course of studies of a recombinant RT of human immunodeficiency virus type 1 (HIV-1), we observed an additional, unexpected activity of the enzyme. The purified RT catalyzes a specific cleavage in HIV-1 RNA hybridized to tRNALys, the primer for HIV-1 reverse transcription. The cleavage at the primer binding site (PBS) of HIV RNA is dependent on the double-stranded structure of the HIV RNA-tRNALys complex. This RNase activity appears to be distinct from the RNase H activity of HIV-1 RT, as the substrate specificity and the products of the two activities are different. Moreover, Escherichia coli RNase H and avian myeloblastosis virus RT are unable to cleave the HIV RNA-tRNALys complex. We refer to this unusual activity as RNase D. Two lines of evidence indicate that the specific RNase D activity is an integral part of recombinant HIV RT. The specific RNase D activity comigrates with the other RT activities, DNA polymerase, and RNase H upon filtration on a Superose 6 gel column or chromatography on a phosphocellulose column. Moreover, three recombinant HIV-1 RT preparations expressed and purified in different laboratories by various procedures exhibit RNase D activity. Sequence analysis indicated that RNase D activity cleaves the substrate HIV-1 RNA-tRNALys at two distinct sites within the PBS sequence 5'-UGGCGCCCGA decreases ACAG decreases GGAC-3'. The sequence specificity of RNase D activity suggests that it might be involved in two stages during the reverse transcription process: displacement of the PBS to enable copying of tRNALys sequences into plus-strand DNA or to facilitate the second template switch, which was postulated to occur at the PBS sequence.
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PMID:Double-stranded RNA-dependent RNase activity associated with human immunodeficiency virus type 1 reverse transcriptase. 137 Oct 14

The inhibitory potency of 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) against HIV-1 reverse transcriptase (HIV-1 RT) has been further evaluated. The results indicate that the previously reported low Ki values for AZTTP against HIV-1 RT (2.35 nM) are due neither to the to the direct tight binding of AZTTP to HIV-1 RT nor to the interaction of the enzyme with AZTMP moiety terminated primer-templates, but instead they are an artifact of the use of a homotemplate-primer [poly(rA).oligo(dT)]. With a set of RNAs of defined sequence as templates, we demonstrate that the observed Ki value for AZTTP depends on the length of the poly(rA) region following the primer in the RNA template. The more adenosyl residues in the RNA template that are available for processive incorporation of TMP moieties, the lower is the observed Ki value for AZTTP. Since the potencies of new inhibitors of HIV-1 RT are usually compared with that for AZTTP, these results have important consequences for the process of discovery of new HIV inhibitors that are of potential use in AIDS therapy.
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PMID:The observed inhibitory potency of 3'-azido-3'-deoxythymidine 5'-triphosphate for HIV-1 reverse transcriptase depends on the length of the poly(rA) region of the template. 137 Oct 70

Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, NSC 614846) is an anti-retroviral agent that may be useful in the treatment of AIDS. We have examined the ability of (-)-enantiomeric carbovir triphosphate to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (EC 2.7.7.49). A comparison of inhibition kinetics was made with 3'-azido-2',3'-dideoxythymidine triphosphate and phosphonoformate. Inhibition of the reverse transcriptase was evaluated using poly(rA).oligo(dT)12-18, poly(rC).oligo(dG)12-18, or influenza virion RNA template with a specific oligodeoxynucleotide as primer. (-)-Carbovir 5'-triphosphate was shown to be a potent inhibitor of HIV-1 reverse transcriptase with an apparent Ki similar to that of 3'-azido-2',3'-dideoxythymidine triphosphate. Chain elongation studies utilizing an MS2 RNA template showed that (-)-carbovir 5'-triphosphate terminated transcription at positions identical to those where dideoxy-GTP terminated. This indicates that (-)-carbovir 5'-monophosphate is incorporated into the newly synthesized DNA and terminates transcription at that point. We conclude that (-)-carbovir 5'-triphosphate is a potent inhibitor of the HIV-1 reverse transcriptase enzyme and that (-)-carbovir most likely inhibits HIV by activity at the triphosphate level by a combination of direct competition for binding of the natural deoxynucleoside triphosphates to the reverse transcriptase and chain termination.
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PMID:DNA chain termination activity and inhibition of human immunodeficiency virus reverse transcriptase by carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine triphosphate. 137 Dec 85

HIV inhibitors targeted at the virus-associated reverse transcriptase (RT) can be divided into two groups, depending on whether they are targeted at the substrate or nonsubstrate binding site. To the first group belong the 2',3'-dideoxynucleosides (i.e., DDC, DDI), 3'-azido-2',3'-dideoxynucleosides (i.e., AZT), 3'-fluoro-2',3'-dideoxynucleosides (i.e., FLT), 2',3'-didehydro-2',3'-dideoxynucleosides (i.e., D4C, D4T) and carbocyclic derivatives thereof (i.e., carbovir), 2'-fluoro-ara-2',3'-dideoxynucleosides, 1,3-dioxolane derivatives (i.e., 2',3'-dideoxyl-3'-thiacytidine), oxetanocin analogues and carbocyclic derivatives thereof (i.e., cyclobut-G) and the 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) derivatives. These compounds need to be phosphorylated intracellularly to their triphosphate forms before they act as competitive inhibitors or alternate substrates (chain terminators) of HIV RT. The second group includes the tetrahydro-imidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)one (TIBO), 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT), dipyrido[3,2-b:2',3'-e]-[1,4]diazepin-6-one (nevirapine) and pyridin-2(1H)one derivatives, which interact as such, noncompetitively, with a specific allosteric binding site of HIV-1 RT. Compounds belonging to the two different groups may give rise to synergism which combined, and, likewise, viral resistance to the compounds may arise through different mutations, depending on the nature of the compounds and the group to which they belong.
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PMID:HIV inhibitors targeted at the reverse transcriptase. 137 90

Nevirapine, a dipyridodiazepinone, is a highly specific inhibitor of HIV-1 reverse transcriptase (RT) which exhibits an IC50 = 84nM in enzyme assays and IC50 = 40nM against HIV-1 replication in cell culture. This nonnucleoside inhibitor acts noncompetitively with respect to nucleoside triphosphates, template and primer suggesting that nevirapine does not bind to the active site of RT. Studies employing an azido analogue of nevirapine as a photoaffinity probe indicated that one molecule of inhibitor is sufficient to inactivate one molecule of heterodimeric enzyme and demonstrated that only the p66 subunit of p66/p51 heterodimeric RT is covalently labeled by this probe. When subjected to trypic mapping, Tyr 181 and Tyr 188 were labeled with probe and consequently these aromatic residues are apparently near or actually within the RT binding site for nevirapine. The extent to which Tyr 181 and Tyr 188 participate/contribute to nevirapine binding was determined by making amino acid substitutions at these positions using the corresponding residues from HIV-2 RT which is not sensitive to nevirapine. A change at either position dramatically decreased the enzymes' sensitivity to nevirapine, as well as to TIBO derivative and Merck L-693,593, indicating that both Tyr 181 and 188 are crucial for inhibitor-enzyme interaction. Cell culture selection in the continued presence of nevirapine results in the appearance of resistant HIV-1, Tyr 181 to Cys, raising the concern that combination drug therapy will be required in the clinic.
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PMID:Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype drug. 137 91

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