Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT). A different structure-antiviral activity relationship was found, depending on the nature of the mutated amino acid in the HIV-1 RT. The results show that 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)uracil, and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)-2-thiouracil remain active against the majority of viruses containing single mutations which confer resistance to nonnucleoside RT inhibitors.
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PMID:Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains. 754 Mar 84

Cotransfection of NIH 3T3 cells with a mammalian expression vector containing a v-Ha-ras gene, together with a plasmid carrying the human immunodeficiency virus (HIV) long terminal repeat (LTR) linked to the chloramphenicol acetyl transferase (CAT) reporter gene, significantly stimulated CAT activity. High HIV LTR activation was also observed in cell lines carrying stably transfected ras oncogenes, activated by point mutation or amplification. By contrast an inactivated form of ras (Ha-ras Asn-17) did not stimulate the HIV-LTR but strongly inhibited its basal activity. Activation of the p21ras protein may thus be one of the signals that regulate LTR driven transcription during HIV infection.
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PMID:Modulation of HIV-LTR activity by ras oncogenes. 760 37

The intrinsic fluorescence of tyrosine increases by a factor of approximately two when the carboxy group is liberated from a peptide bond by hydrolysis. The increase in fluorescence provides a novel way to monitor the hydrolysis of native tyrosine peptides that contain only proteinogenic amino acids. Thus, for example, the hydrolysis by HIV-1 proteinase of a heptapeptide viral protein fragment gag129-135, Ser-Gln-Asn-Tyr-Pro-Ile-Val, was followed continuously at excitation and emission wavelengths 275 and 305 nm. The fluorescence increase is magnified by at least a factor of a thousand when a resonance energy quencher, such as paranitrophenylalanine, is in the vicinity. For example, the peptide Lys-Ala-Arg-Val-Tyr-Phe(p-NO2)-Glu-Ala-Nle-NH2 [Richards et al. (1990) J. Biol. Chem. 265, 7733], widely used for spectrophotometric assays of the HIV-1 proteinase, yields a substrate:product fluorescence ratio greater than 1:1000. Tyrosine-containing substrates of pepsin and trypsin showed similar behavior. The detection limit of the present method is at least one order of magnitude lower than absorbance assays of p-nitrophenylalanine peptides.
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PMID:Increase in fluorescence upon the hydrolysis of tyrosine peptides: application to proteinase assays. 766 86

HIV-1 strains were isolated from three patients treated with AZT and from three patients not treated with AZT. Progenomes of HIV-1 RT gene were amplified by PCR and cloned to M13mp18 vecter. Four amino acid mutations in RT gene (Asp67, Lys70, Thr215, Lys219) associated with resistance to AZT were analysed. All of the 14 clones obtained from the three patients with AZT therapy had mutations at codon 215 (Thr-->Tyr or Phe). Some of the 14 clones also had other mutations at codon 67 (Asp-->Asn or Ser), codon 70 (Lys-->Arg) and codon 219 (Lys-->Glu). All of 18 clones obtained from the patients not treated with AZT have no mutation at any codon mentioned above.
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PMID:[Mutations of HIV-1 RT gene isolated from patients treated with AZT]. 768 6

Serial passage of HIV-1 in CEM or MT-4 cell cultures in the presence of different HIV-1-specific reverse transcriptase (RT) inhibitors yielded mutant viruses which were resistant (i.e., 200- to 1000-fold less sensitive) to the homologous compounds. The RT of these mutant HIV-1 strains showed different amino acid substitutions depending on the class of the HIV-1-specific RT inhibitors. The following amino acid substitutions were found: 138 Glu-->Lys (TSAO-T), 181 Tyr-->Cys (nevirapine), 181 Tyr-->Cys (pyridinone), and 100 Leu-->Ile (TIBO R82150). Four TIBO (R82913)-resistant HIV-1 strains contained different amino acid substitutions: 103 Lys-->Asn (strain 2), 100 Leu-->Ile and 138 Glu-->Lys (strain B02), 100 Leu-->Ile and 181 Tyr-->Cys (strain 1), 100 Leu-->Ile and 188 Tyr-->His (strain B22). The level of cross-resistance (or sensitivity) highly depends on the nature of the amino acid substitutions. As a rule, the TSAO-resistant HIV-1 strains (138 Glu-->Lys) and TIBO (R82150 or R82913)-resistant HIV-1 strains (Leu 100-->Ile or 103 Lys-->Asn) are sensitive to the other HIV-1-specific RT inhibitors, whereas the amino acid change 181 Tyr-->Cys results in a significant reduction of sensitivity to all classes of the HIV-1-specific RT inhibitors.
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PMID:HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase. 768 64

Human immunodeficiency virus type 1 (HIV-1)-infected CEM cells were treated by the HIV-1-specific inhibitors bis-heteroarylpiperazine (BHAP), 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)-on e (TIBO) R82913, nevirapine, and the N3-methylthymine derivative of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO-m3T), as single agents or in combination, at escalating concentrations. When used individually, the compounds led to the emergence of drug-resistant virus strains within two to five subcultivations. The resulting strains were designated HIV-1/BHAP, HIV-1/TIBO, HIV-1/Nev, and HIV-1/TSAO-m3T, respectively. The mutant viruses showed the following amino acid substitutions in their reverse transcriptase (RT): Leu-100-->Ile for HIV-1/BHAP; Lys-103-->Asn for HIV-1/TIBO; Val-106-->Ala for HIV-1/Nev; and Glu-138-->Lys for HIV-1/TSAO-m3T. Both the Tyr-181-->Cys and Val-106-->Ala mutations were found in another mutant emerging following treatment with nevirapine at escalating concentrations. The BHAP-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and TSAO-m3T, whereas the TSAO-m3T-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and BHAP. When different pairs of nonnucleoside RT inhibitors (i.e., BHAP plus TSAO-m3T, nevirapine plus TSAO-m3T, TIBO plus TSAO-m3T, nevirapine plus TIBO, and BHAP plus nevirapine) were used, resistant virus emerged as fast as with single-drug therapy. In all cases the Tyr-181-->Cys mutation appeared; the virus showed markedly reduced sensitivity to all HIV-1-specific inhibitors but retained sensitivity to 2',3'-dideoxynucleoside analogs such as zidovudine, ddC, and ddI. Our findings argue against simultaneous combination of two different nonnucleoside RT inhibitors that are unable to inhibit HIV-1 mutant strains containing the Tyr-181-->Cys mutation when administered as single drugs.
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PMID:Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. 768 22

Certain human immunodeficiency virus type 1 (HIV-1) isolates are able to productively infect nondividing cells of the monocyte/macrophage lineage. We have used a molecular genetic approach to construct two different HIV-1 integrase mutants that were studied in the context of an infectious, macrophage-tropic HIV-1 molecular clone. One mutant, HIV-1 delta D(35)E, containing a 37-residue deletion within the central, catalytic domain of integrase, was noninfectious in both peripheral blood mononuclear cells and monocyte-derived macrophages. The HIV-1 delta D(35)E mutant, however, exhibited defects in the assembly and/or release of progeny virions in transient transfection assays, as well as defects in entry and/or viral DNA synthesis during the early stages of monocyte-derived macrophage infection. The second mutant, HIV-1D116N/8, containing a single Asp-to-Asn substitution at the invariant Asp-116 residue of integrase, was also noninfectious in both peripheral blood mononuclear cells and monocyte-derived macrophages but, in contrast to HIV-1 delta D(35)E, was indistinguishable from wild-type virus in reverse transcriptase production. PCR analysis indicated that HIV-1D116N/8 entered monocyte-derived macrophages efficiently and reverse transcribed its RNA but was unable to complete its replication cycle because of a presumed block to integration. These data are consistent with the hypothesis that integration is an obligate step in productive HIV-1 infection of activated peripheral blood mononuclear cells and primary human macrophage cultures.
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PMID:Integration is required for productive infection of monocyte-derived macrophages by human immunodeficiency virus type 1. 770 54

An expression system has been established in Escherichia coli to facilitate the preparation of the HIV-1 capsid protein in amounts sufficient for structural analysis. A plasmid vector pTCA5, containing the gene for the recombinant HIV-1 capsid protein rp24 under the control of the lambda-PR-promoter, was constructed which gave an expression product that spanned 234 amino acid residues. It differs at the N-terminus from the authentic sequence in that the residues Pro-Ile- are replaced by Met-Asn-Ser-Ala-Met-. Recombinant p24 was produced, as inclusion bodies in E. coli LE392 containing pTCA5, at a level of approximately 15% of the total cellular protein. After dissolution of the inclusion bodies in the acidic urea system, the protein was easily reconstituted in a soluble state by dialysis. The yield of reconstituted and purified protein was 12 mg per liter in rich medium. Recombinant rp24 consists of about 40% alpha-helix and 10% beta-sheet from circular dichroism measurements and the two cysteine residues, within the rp24 sequence, are bridged by a disulfide bond.
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PMID:A recombinant human immunodeficiency virus type-1 capsid protein (rp24): its expression, purification and physico-chemical characterization. 771 31

Upon in vitro processing of the recombinant HIV-1/gag p24 protein, expressed in Escherichia coli as a fusion protein, by HIV-1 protease, a cleavage site within the staphylococcal protein A fusion partner was found. N-terminal sequencing of the protein A fragments showed that HIV-1 protease cleavage occurred between phenylalanine-235 and tyrosine-236 within the sequence Gln-Asn-Ala-Phe/Tyr-Glu-Ile-Leu (QNAF/YEIL) in the IgG-binding domain C of the protein A encoded by the pRIT2T fusion gene vector (Pharmacia). Results presented here have proven that the protease-sensitive site is viable in vitro on the protein A alone and other chimeric protein, protein A/beta-galactosidase. A possible significance of this phenomenon in biotechnology work is discussed.
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PMID:Staphylococcal protein A is a novel heterologous substrate for the HIV-1 protease. 776 14

Mutations of human immunodeficiency virus type 1 (HIV-1) protease at four positions, Val82, Asp30, Gly48, and Lys45 were analyzed for the resulting effects on kinetics and inhibition. In these mutants, Val82 was substituted separately by Asn, Glu, Ala, Ser, Asp, and Gln; Asp30 was individually substituted by Phe or Trp; Gly48 by His, Asp, and Tyr, respectively; and Lys45 by Glu. By examination of the inhibition of a single inhibitor, the differences in Ki values between the native and mutant enzymes can range from very large to insignificant even for the mutants with substitutions at the same position. By examination of a single mutant enzyme, the same broad range of Ki changes was observed for a group of inhibitors: Thus, how much the inhibition changes from the wild-type enzyme to a mutant is dependent on both the mutation and the inhibitor. The examination of Ki changes of inhibitors with closely related structures binding to Val82 mutants also reveals that the change of inhibition involves subsites in which Val82 is not in direct contact, indicating a considerable flexibility of the conformation of HIV protease. For the catalytic activities of the mutants, the kcat and Km values of many Val82 mutants and a Lys45 mutant are comparable to the native enzyme. Surprisingly, Gly48 mutations produce enzymes with catalytic efficiency superior to that of the wild-type enzyme by as much as 10-fold. Modeling of the structure of the mutants suggests that the high catalytic efficiency of some substrates is related to an increase of rigidity of the flap region of the mutants. The examination of the relative changes of inhibition and catalysis of mutants suggests that some of the Val82 and Gly48 mutants are potential resistance mutants. However, the resistance is specific with respect to individual inhibitors.
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PMID:Effect of point mutations on the kinetics and the inhibition of human immunodeficiency virus type 1 protease: relationship to drug resistance. 782 64


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