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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Glu-89-->Gly alteration in the human immunodeficiency virus type 1 reverse transcriptase (RT) was previously shown to result in resistance to several dideoxynucleoside analogs and to phosphonoformic acid (PFA; foscarnet). This residue was altered to Ala, Val, Ser, Thr, Gln, Asp, Asn, or Lys, and the ddGTP and PFA sensitivities of the mutant RTs were measured. Replacements with Ala, Gly, Val, and Thr led to resistance to inhibition by ddGTP, while mutants with amino acid Ser, Gln, Asn, Asp, or Lys displayed only moderate or no resistance. A similar result was obtained with inhibition by PFA, except that the Asp-89 mutant also displayed resistance. Furthermore, the introduction of Glu-89-->Gly alteration into the RT of human immunodeficiency virus type 2 likewise rendered it resistant to both ddGTP and PFA.
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PMID:Mutagenesis of the Glu-89 residue in human immunodeficiency virus type 1 (HIV-1) and HIV-2 reverse transcriptases: effects on nucleoside analog resistance. 127 7

Human immunodeficiency virus (HIV-1) isolates from 8 Ethiopian and 8 Swedish AIDS patients, none of them treated with antiviral drugs, were compared for sensitivity to azido-deoxy-thymidine (AZT), dideoxy-inosine (ddI) and interferon-alpha. HIV was isolated from peripheral blood mononuclear class, identified by Western blot and nucleotide sequencing, and passaged 1-3 times. Sensitivity to the 3 drugs, expressed as ED50s relative to positive controls, was determined by culturing HIV in the presence of drugs in a range of concentrations and assaying the supernatant for p24 antigen and the virus pellet for reverse transcriptase (RT). Dose-dependent anti-HIV activity for AZT was seen in the 8 Ethiopian isolates, and ED50s for p24 antigen and RT activity were correlated. 1 Ethiopian HIV isolate was sensitive to ddI, and another, to interferon-alpha. 1 Swedish HIV was resistant to AZT, and on analysis had a mutation from threonine to tyrosine at position 215. There were no significant differences between ED50s for interferon in the Swedish and Ethiopian HIVs. Combined data for each drug showed correlation between the p24 antigen and RT activities of the Ethiopian and Swedish HIVs. Since there was no resistance observed in the Ethiopian HIV to AZT or ddI, low-dose treatment would probably slow progression of HIV infection in Ethiopians, if these drugs could be made available for clinical trials.
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PMID:Response of Ethiopian human immunodeficiency virus type 1 isolates to antiviral compounds. 128 93

Two antibodies, affinity-purified from human immunodeficiency virus-positive human plasma with synthetic peptides in the region gp41(566-596), were found to recognize oligomeric gp41 more strongly than the monomeric form in an immunoblot assay. In contrast, a murine anti-gp160 monoclonal antibody, which maps within this sequence to gp41(581-596), recognized only monomeric gp41 after disruption of the oligomer with sodium dodecyl sulfate. This monoclonal anti-gp160 antibody did not recognize chemically crosslinked oligomeric gp41 that had been treated with similar conditions used to disrupt the gp41 oligomer. These results indicate that this epitope is inaccessible to binding by this antibody when gp41 is oligomeric. Cyanogen bromide cleavage of gp41 resulted in a 17-kD fragment Thr-541-Met-631. A significant proportion of this fragment was oligomeric when derived from chemically crosslinked gp41. The region Ala-566-Gln-596, within the cyanogen bromide fragment, contains the oligomerization-sensitive epitopes as well as two lysine residues available for crosslinkage. This region is relatively conserved and has the propensity to form an amphipathic alpha-helix.
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PMID:Antibody epitopes sensitive to the state of human immunodeficiency virus type 1 gp41 oligomerization map to a putative alpha-helical region. 128 26

Mutations designed by analysis of the Rous sarcoma virus (RSV) and human immunodeficiency virus (HIV)-1 protease (PR) crystal structures were introduced into 1) the substrate binding pocket, 2) the substrate enclosing "flaps," and 3) surface loops of RSV PR. Each mutant PR was expressed in Escherichia coli. Changes in activity were detected by following cleavage of a truncated (NC-PR) precursor polypeptide in E. coli and cleavage of synthetic peptide substrates representing RSV and HIV-1 PR cleavage sites in vitro. Mutations in the substrate binding pocket exchanged amino acid residues located close to the substrate in the HIV-1 PR for structurally equivalent residues in the RSV PR. Changing histidine 65 to glycine (H65G) gave an inactive enzyme, while a double mutant R105P,G106V, as well as the triple mutant, H65G,R105P,G106V, produced enzymes which showed significant activity toward a substrate that represented a HIV-1 cleavage site. Mutating the catalytic aspartate (D37S) or an adjacent conserved alanine to threonine (A40T), produced inactive enzymes. In contrast, the substitution A40S was active, but showed a reduced rate of catalysis. Mutations in the flaps of conserved glycines (G69L, G70L) produced inactive PRs. Two extended RSV PR surface loops were shortened to the size found in HIV-1 PR and resulted in drastically reduced activity. These results have confirmed some of the basic predictions made from structural models but have also revealed unexpected roles and interactions in the protein.
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PMID:Mutations that alter the activity of the Rous sarcoma virus protease. 131 55

To investigate whether human immunodeficiency virus type 1 pol gene mutations are selected during prolonged 2',3'-dideoxycytidine (ddC) therapy, we used the polymerase chain reaction to amplify a portion of the reverse transcriptase segment of the pol gene from the peripheral blood mononuclear cell DNA of a patient with AIDS before and after an 80-week course of ddC therapy. The consensus sequence from the second sample contained a unique double mutation (ACT to GAT) in the codon for reverse transcriptase amino acid 69, causing substitution of aspartic acid (Asp) for the wild-type threonine (Thr). A mutation (ACA to ATA) also occurred in the codon for position 165, causing substitution of isoleucine (Ile) for Thr. The GAT (Asp) codon was introduced into the pol gene of a molecular clone of human immunodeficiency virus via site-directed mutagenesis. Following transfection, mutant and wild-type viruses were tested for susceptibility to ddC by a plaque reduction assay. The mutant virus was fivefold less susceptible to ddC than the wild type; cross-resistance to 3'-azido-3'-deoxythymidine or 2'3'-dideoxyinosine was not found. The Ile-165 mutation did not confer additional ddC resistance. The Asp-69 substitution may have contributed to the generation of resistant virus in this patient.
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PMID:Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. 131 43

Multiple mutations in the reverse transcriptase (RT) gene were observed in a drug-resistant isolate of human immunodeficiency virus type 1 (HIV1) from an individual having prolonged (greater than 2 years) zidovudine (AZT) therapy. The virus replicated in PBMC's in the presence of very high concentrations of AZT (125 microM). Drug-sensitive strains were curtailed by 0.01 microM AZT. Eleven defined mutations were observed as compared with published sequences of RT for eight strains of HIV1. Eight of these mutations were found in the domain involved in nucleotide recognition and enzyme function. Only one of the mutations, giving a Thr--Tyr change at amino acid 215, matched those previously ascribed (67, 70, 215, and 219) to the generation of high-level resistance to AZT. Therefore additional amino acid changes may have significance in the emergence of super-resistant viruses.
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PMID:Sequence analysis of an HIV-1 isolate which displays unusually high-level AZT resistance in vitro. 137 91

Peptide T, from the human immunodeficiency virus (HIV), whose sequence is Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr, has been shown to inhibit attachment of this virus to T cells and neural cells bearing the CD4 receptor. This peptide shares extensive homology with the 19-26 segment of ribonuclease A (RNase A), whose sequence is Ala-Ala-Ser-Ser-Ser-Asn-Tyr-Cys. Based on comparison of the structures of peptides occurring in proteins of known structure that are homologous to peptide T, viz, RNase A and endothiapepsin and on conformational energy calculations, we predicted that peptide T adopts a structure much like that for residues 19-26 in RNase A. A critical feature is a bend involving residues Thr 4-Asn 7 in peptide T corresponding to Ser 22-Tyr 25 in the RNase A peptide. Our proposed structure for peptide T has recently been confirmed by Cotelle et al. (Biochem. Biophys. Res. Commun. 171, 596-602). We now show directly that the RNase A peptide, with Met replacing Cys 26 to prevent disulfide exchange reactions, strongly induces monocyte-chemotaxis that is blocked by anti-CD4 monoclonal antibody. Both peptide T and RNase A fail to induce chemotaxis, however, in neutrophils which do not express surface CD4 receptors. These results suggest that both peptides interact with the CD4 receptor in inducing monocyte chemotaxis. We have also prepared cyclo-RNase A peptide with Met 26. Using molecular dynamics and conformational energy calculations, we find that the cyclic peptide cannot form a bend structure involving Ser 22-Tyr 25 that is superimposable on the RNase A bend.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation of the conformation of a modified ribonuclease octapeptide, homologous to peptide T, with its ability to induce CD4-dependent monocyte chemotaxis. 144 97

Two immunologically distinct glycoproteins, fractions C4 and C6, with a molecular weight of 28,000 and 28,500, respectively, estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were isolated from seeds of Luffa cyclindrica using acetone precipitation, gel filtration on Sephadex G-75, and ion exchange chromatography on CM-Sepharose CL-6B. Fractions C4 and C6 correspond to luffin-a and luffin-b, respectively, according to the ion exchange chromatographic behavior and amino acid compositions. Fraction C6 and luffin-b were characterized by a lower content of threonine and a higher content of proline than fraction C4 and luffin-a. The 2 luffins, the protein from Luffa acutangula (luffaculin) and trichosanthin exhibited an overall similarity in amino acid composition. The proteins differed in the content of aspartic acid, threonine, proline, and alanine but were otherwise similar in amino acid composition. The ribosome inactivating proteins from Luffa cylindrica seeds also possessed abortifacient activity: they were capable of inducing mid term abortion in mice, inhibiting protein synthesis in a cell-free system, and suppressing thymidine uptake by human choriocarcinoma cells. The abortifacient activity of these proteins is possibly the result of their inhibitory effects on the biosynthetic activity of implanting embryos and endometrial cells. Trichosanthin inhibits the replication of human immunodeficiency virus (HIV) in acutely and chronically infected cells of lymphocyte and mononuclear phagocyte lineage with a potential in AIDS therapy. However, it is still unknown whether the proteins from Luffa cylindrica seeds also possess anti-HIV activity.
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PMID:Two proteins with ribosome-inactivating, cytotoxic and abortifacient activities from seeds of Luffa cylindrica roem (Cucurbitaceae). 150 59

Rate constants for binding of five inhibitors of human immunodeficiency virus (HIV) protease were determined by stopped-flow spectrofluorometry. The two isomers of quinoline-2-carbonyl-Asn-Phe psi-[CH(OH)CH2N]Pro-O-t-Bu (R diastereomer = 1R; S diastereomer = 1S) quenched the protein fluorescence of HIV protease and thus provided a spectrofluorometric method to determine their binding rate constants. The dissociation rate constants for acetyl-Thr-Ile-Leu psi(CH2NH)Leu-Gln-Arg-NH2 (2), (carbobenzyloxy)-Phe psi[CH(OH)CH2N]Pro-O-t-Bu (3), and pepstatin were determined by trapping free enzyme with 1R as 2, 3, and pepstatin dissociated from the respective enzyme.inhibitor complex. Association rate constants of 1R, 2, and pepstatin were calculated from the time-dependent inhibition of protease-catalyzed hydrolysis of the fluorescent substrate (2-aminobenzoyl)-Thr-Ile-Nle-Phe(NO2)-Gln-Arg-NH2 (4). The kinetic data for binding of 1S to the protease fit a two-step mechanism. Kd values for these inhibitors were calculated from the rate constants for binding and were similar to the respective steady-state Ki values.
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PMID:Two-step binding mechanism for HIV protease inhibitors. 151 Sep 76

Genetic diversity is a hallmark of the human immunodeficiency virus (HIV) genome, but the role of distinct HIV variants in the development of AIDS is unclear. Envelope (env) is the most highly variable gene in HIV as well as in other retroviruses. We have previously demonstrated that variation in simian immunodeficiency virus (SIV) env is primarily localized in two regions (V1 and V4) during progression to simian AIDS. To determine whether there is a common genotype that evolves as AIDS develops, a total of 160 SIV env genes isolated directly from the tissue DNAs of four macaques infected with cloned virus were compared. Common amino acid sequence changes were identified within V1, V4, and, in the late stages of disease, near V3. At several positions, the same amino acid change was seen frequently in the variant genomes from all four animals. As AIDS developed, the majority of viruses evolved an extended sequence in V1 that was rich in serine and threonine residues and shared similarity with proteins modified by O-linked glycosylation. Several of the predominant common sequence changes in V1 and V4 created new sites for N-linked glycosylation. Thus, common features of the SIV variants that evolve during progression to AIDS are motifs that potentially allow for structural and functional changes in the env protein as a result of carbohydrate addition.
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PMID:Alterations in potential sites for glycosylation predominate during evolution of the simian immunodeficiency virus envelope gene in macaques. 152 47


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