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)

To elucidate the action of vitamin C on pathogenic human retroviruses, we investigated and compared the effects of noncytoxic concentrations of ascorbic acid (AA), its calcium salt (Ca-ascorbate), and two thiol-based reducing agents [glutathione (GSH) and N-acetyl-L-cysteine (NAC)] against human immunodeficiency virus (HIV)-1 replication in chronically infected T lymphocytes. Ca-ascorbate reduced extracellular HIV reverse transcriptase (RT) activity by about the same magnitude as the equivalent dose of AA. Long-term experiments showed that continuous presence of ascorbate was necessary for HIV suppression. NAC (10 mmol/L) caused less than twofold inhibition of HIV RT and conferred a synergistic effect (approximately eightfold inhibition) when tested simultaneously with AA (0.426 mmol/L). In contrast, nonesterified GSH (less than or equal to 1.838 mmol/L) had no effect on RT concentrations and did not potentiate the anti-HIV effect of AA. These results further support the potent antiviral activity of ascorbate and suggest its therapeutic value in controlling HIV infection in combination with thiols.
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PMID:Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. 172 May 98

The human immunodeficiency virus type 1 (HIV) Rev protein is thought to be involved in the export of unspliced or singly spliced viral mRNAs from the nucleus to the cytoplasm. This function is mediated by a sequence-specific interaction with a cis-acting RNA element, the Rev response element (RRE), present in these intron-containing RNAs. To identify possible host proteins involved in Rev function, we fractionated nuclear cell extracts with a Rev affinity column. A single, tightly associated Rev-binding protein was identified; this protein is the mammalian nucleolar protein B23. The interaction between HIV Rev and B23 is very specific, as it was observed in complex cell extracts. The complex is also very stable toward dissociation by high salt concentrations. Despite the stability of the Rev-B23 protein complex, the addition of RRE, but not control RNA, led to the displacement of B23 and the formation of a specific Rev-RRE complex. The mammalian nucleolar protein B23 or its amphibian counterpart No38 is believed to function as a shuttle receptor for the nuclear import of ribosomal proteins. B23 may also serve as a shuttle for the import of HIV Rev from the cytoplasm into the nucleus or nucleolus to allow further rounds of export of RRE-containing viral RNAs.
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PMID:Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. 201 66

The 99 residue human immunodeficiency virus type 1 proteinase has been expressed in Escherichia coli as part of an autocleaving fusion protein. Expression of the fusion protein is toxic to the host cells, however yields of the released proteinase have been improved by optimising induction nad harvest times to increase culture biomass, and decrease degradation of the proteinase. Soluble proteinase was extracted from these cells by a simple and highly efficient three step process. N-terminal sequence analysis confirms that the enzyme preparation is highly pure and correctly autoprocessed. The proteinase cleaves peptide substrate IGCTLNFPISPIETV between F and P at pH 6.0 with a Km of 310 microM and a Kcat of 14s-1. The enzyme is sensitive to its ionic environment, showing stimulation of activity at high salt concentrations, and shows a pH optimising 5.5.
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PMID:Expression of an autoprocessing CAT-HIV-1 proteinase fusion protein: purification to homogeneity of the release 99 residue proteinase. 202 53

We have expressed the human immunodeficiency virus type 1 (HIV-1) gag polyprotein (Pr55gag) in bacteria under the control of the T7 phage gene 10 promoter. When the gene encoding the viral protease is included in cis, in the -1 reading frame, the expected proteolytic cleavage products MA and CA are produced. Disruption of the protease-coding sequence prevents proteolytic processing, and full-length polyprotein is produced. Pr55gag, separated from bacterial proteins by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) and immobilized on nitrocellulose membranes, binds RNA containing sequences from the 5' end of the HIV-1 genome. This binding is tolerant of a wide range of pH and temperature but has distinct salt preferences. Conditions were identified which prevented nonspecific binding of RNA to bacterial proteins but still allowed binding to Pr55gag. Under these conditions, irrelevant RNA probes lacking HIV-1 sequences bound Pr55gag less efficiently. Quantitation of binding to Pr55gag by HIV-1 RNA probes with deletions mutations demonstrated that there are two regions lying within the HIV-1 gag gene which independently promote binding of RNA to Pr55gag.
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PMID:Binding of human immunodeficiency virus type 1 (HIV-1) RNA to recombinant HIV-1 gag polyprotein. 203 71

Pepstatin A, a pentapeptide aspartyl protease inhibitor, can spontaneously polymerize into filaments having a helical substructure and, after negative staining, characteristic diameters ranging from 6 to 12 nm. Optical diffraction analysis demonstrated that these filaments consist of a 6-nm-wide strand helically wound with a periodic pitch of 25 nm. Selected images suggest that these filaments may actually be composed of two, intertwined 6-nm-wide strands, an hypothesis not at variance with the diffraction data. These filaments may extend over several micrometers. At low ionic strength and neutral pH, the critical concentration for pepstatin A filament assembly is 0.1 mM. At higher pepstatin A concentrations or in physiological salt solutions, a variety of higher order structures were observed, including ribbons, sheets, and cylinders with both regular and twisted or irregular geometries. Pepstatin A polymerized into these higher order structures loses its ability to inhibit the aspartyl protease of the human immunodeficiency virus type 1. These results have implications not only for model studies on the polymerization of small peptides into higher order structures, but also for the practical development of soluble protease inhibitors.
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PMID:Polymerizing properties of pepstatin A. 210 Jan 51

The crystal structures of the proteases (PRs) encoded by the Rous sarcoma virus (RSV) and the human immunodeficiency virus (HIV) have been compared. The crystallographic monomer of HIV PR superimposes on the two crystallographically independent subunits of the RSV PR dimer with root mean square deviations of 1.45 and 1.55 A for 86 and 88 common C alpha atoms, respectively. There is a conserved structural core consisting of seven beta-strands forming two perpendicular layers, a helix, and the amino- and carboxyl-terminal beta-strands. PRs from related retroviruses fold into similar structures with surface turns of variable length between the beta-strands. Both HIV and RSV PR dimers have significant subunit-subunit interactions in three regions: the "firemen's grip" at the active site; the salt bridges involving Arg8, Asp29, and Arg87 of HIV PR; and the termini of the two subunits, which form a four-stranded antiparallel beta-sheet. The specific interactions of the termini differ in the two PRs. The carboxyl termini, residues 96-99 of HIV PR and residues 119-124 of RSV PR, contribute approximately 50% of the intersubunit ionic and hydrogen bond interactions and approximately 45% of the buried surface area involved in dimer formation. This information may be useful in the design of site-directed mutations or inhibitors of dimer formation.
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PMID:Comparison of the crystal structures and intersubunit interactions of human immunodeficiency and Rous sarcoma virus proteases. 216 50

1) The aspartic proteinase of the human immunodeficiency virus type 1 (HIV-1) was purified from cultures of recombinant E. coli. The enzyme preparation is homogeneous as judged by SDS-polyacrylamide gel electrophoresis and isoelectric focusing. 2) A rapid assay procedure for the proteinase was established which makes use of the cleavage of a radiolabeled decapeptide and the separation of substrate and labeled product by ion-exchange resin. 3) Activity of the enzyme is optimal at an ionic strength of 2.5-3.5M; also, the inhibitor pepstatin is a more potent inhibitor at higher ionic strength. This can be attributed to a tighter binding of both substrate and inhibitor in high-salt buffer. 4) The Km value of the decapeptide substrate is independent of the pH in the range of 3.5-7.5, while kcat shows a bell-shaped curve with a maximum at pH 5.2. The shape of the curve can be attributed to pKa values of 4.2 and 6.2 of groups on the enzyme. Pepstatin inhibition is optimal below pH 5.5, but becomes weak above pH 6.
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PMID:Purification, assay and kinetic features of HIV-1 proteinase. 218 85

The water-soluble ammonium salt of 3'-azido-5'-(O-ethoxycarbonylphosphinyl)-3'-deoxythymidine (ECP-AZT), the prototype of a novel class of compounds incorporating two active antiretroviral agents, in this case 3'-azido-3'-deoxythymidine (AZT) and phosphonoformic acid (PFA), within the same structure, was synthesized and tested as an inhibitor of the replication of human immunodeficiency virus type 1 (HIV-1) in Jurkat cells, a CD4+ human T-lymphocyte cell line. The corresponding 5'-(O-methoxycarbonylphosphinyl) derivative (MCP-AZT) was also prepared. The rationale for the synthesis of ECP-AZT and MCP-AZT was that they may be cleaved intracellularly to AZT and PFA via hydrolysis of the phosphate ester bond or to AZT 5'-monophosphate by oxidative cleavage of the carbon-phosphorus bond. ECP-AZT was found to block viral replication at a 50% inhibitory concentration (IC50) of ca. 10(-6) M as measured by reverse transcriptase (RT) activity in supernatants from cultures of infected cells. Little or no inhibition of cell growth was observed at this concentration, and there was less than 20% inhibition of cell growth at 10(-4) M. AZT itself was a more potent inhibitor of HIV-1 replication than ECP-AZT, but was also more cytotoxic. The antiviral selectivity of ECP-AZT, defined as the ratio IC50 (virus inhibition)/IC50(cell growth inhibition), was in the range considered to be therapeutic for anti-AIDS nucleosides.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate esters of 3'-azido-3'-deoxythymidine. 222 76

Blood samples to be tested for the presence of parasite DNA by using specific DNA probes are routinely stored in our laboratory as high-salt lysates (HSL). To safeguard against the risk of accidental infection with etiological agents such as the human immunodeficiency virus type 1 (HIV-1) while manipulating large numbers of blood samples in preparation for DNA probing, we determined the residual infectivity of HIV-1 after exposure to HSL components. Both high-titer virus stocks or provirus-carrying cells, suspended either in tissue culture medium or freshly drawn blood, were completely inactivated upon contact with the HSL components. This was verified by the absence of any detectable HIV-1-specific antigen in the supernatants of long-term cultures and the absence of virus-specific DNA fragments after amplification by polymerase chain reaction with DNA from such cultures as target DNA. These results support the conclusion that the virus is in fact completely inactivated by contact with the HSL components, rendering blood specimens stored as HSL noninfectious in regard to HIV-1.
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PMID:Inactivation of human immunodeficiency virus type 1 in blood samples stored as high-salt lysates. 227 31

Inosine-pranobex (methisoprinol, isoprinosine; INPX) is the p-acetamidobenzoic salt of N,N-dimethylamino-2-propanol and inosine in a 3:1 molar ratio. In early studies, INPX was found to partially inhibit human immunodeficiency virus (HIV) and to increase the immunocompetence of HIV-infected subjects in vitro. We report the results of a randomised, multicentric clinical trial carried out on 553 HIV+ patients. 261 individuals were treated with INPX (two 500 mg tablets every 6 h for 3 months) and the remaining 292 constituted the untreated control group. INPX treatment was associated with a slightly improved clinical condition or with a trend in that direction, as compared to the untreated group. A preservation of the CD4/CD8 cell ratio values, a decrease in the CD8+ cells and an increase in the Leu 2-7+ cell number better than in the untreated individuals was also observed in the patients taking INPX. No serious or adverse effects of INPX have been observed.
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PMID:Clinical and immunological assessment in HIV+ subjects receiving inosine-pranobex. A randomised, multicentric study. 247 Oct 25


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