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)

The long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV-1) contains sequences required for the initiation of gene transcription. Among the substances known to activate the HIV-1 LTR is hydrogen peroxide (H2O2). We report here that H2O2-induced activation of the LTR in the macrophage cell line THP-1 and the lymphocyte cell line, Jurkat, is greatly increased by vanadate. Activation of the LTR by phorbol myristate acetate, tumor necrosis factor alpha, lipopolysaccharide, or Staphylococcus epidermidis extract was not increased by vanadate, indicating some selectivity for H2O2. H2O2 and vanadate also acted synergistically to increase the production of HIV-1 virions by the latently infected macrophage cell line U-1 as determined by p24 antigen release and the detection of intact virions by electron microscopy. Effects were observed at H2O2 and vanadate concentrations down to 3 x 10(-6) M, with high concentrations leading to cell toxicity. Catalase was strongly inhibitory when added prior to the interaction of H2O2 and vanadate, but was considerably less inhibitory when the H2O2 and vanadate were allowed to preincubate prior to the catalase addition. H2O2 reacts with vanadate to form peroxides of vanadate that have potent biological effects. Our findings suggest that among these is the activation of the HIV-1 LTR.
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PMID:Activation of the HIV long terminal repeat and viral production by H2O2-vanadate. 872 29

Bio-normalizer, a natural Japanese health food prepared by the fermentation of Carica papaya, exhibits therapeutic properties against various pathologies including tumors and immunodeficiency. To understand the mechanism of bio-normalizer's therapeutic effects, we studied its action on the production of active oxygen species in cell-free systems (the Fenton reaction, the xanthine-xanthine oxidase system, and the hydrogen peroxide-hypochloride or hydrogen peroxide-horseradish peroxidase systems) and by human blood neutrophils and erythrocytes and rat peritoneal macrophages. Bio-normalizer efficiently inhibited the formation of oxygen radicals in cell-free systems and partly decreased spontaneous and menadione-stimulated superoxide production by erythrocytes, but manifested both stimulatory and inhibitory effects on oxygen radical release by dormant and activated phagocytes (neutrophils and macrophages). We suggest that bio-normalizer is able to enhance the intracellular production of innocuous superoxide ion and, at the same time, to diminish the formation of reactive hydroxyl radicals, perhaps by the inactivation of ferrous ions, the catalysts of the superoxide-driven Fenton reaction. We also propose that the normalization of an organism's superoxide level is one of the molecular mechanisms of bio-normalizer activity.
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PMID:Effects of bio-normalizer (a food supplementation) on free radical production by human blood neutrophils, erythrocytes, and rat peritoneal macrophages. 874 24

The human immunodeficiency (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. The HIV protease can recognize Phe-Pro and Tyr-Pro sequences as the virus-specific cleavage site. These features provided a basis for the rational design of selective HIV protease-targeted drugs for the treatment of acquired immunodeficiency syndrome (AIDS). HIV protease is formed from two identical 99 amino acid peptides. We replaced the two Cys residues by L-Ala to synthesize [Ala67,95]-HIV-1 protease by the solid phase method and then prepared [Tyr6,42, Nle36,46, (NHCH2COSCH2CO)51-52, Ala67,95] HIV-1 protease (NY-5 isolate) using the thioester chemical ligation method. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) with a hydroxymethylcarbonyl (HMC) isostere. Among them, the conformationally constrained tripeptide kynostatin (KNI)-272 (iQoa-Mta-Apns-Thz-NHBut) was a highly selective and superpotent HIV protease inhibitor (Ki = 0.0055 nM). KNI-272 exhibited potent antiviral activities against both AZT-sensitive and -insensitive clinical HIV-1 isolates as well as HIV-2 with low cytotoxicity. After i.d. administration, bioavailability of KNI-272 was 42.3% in rats. Also, KNI-272 exhibited in vivo anti-HIV activities in human PBMC-SCID mice. The x-ray crystallography and molecular modeling studies showed that the HMC group in KNI-272 interacted excellently with the aspartic acid carboxyl groups of HIV protease active site in the essentially same hydrogen-bonding mode as the transition state. This result implies that the HMC isostere is an ideal transition-state mimic and contributes to the high activity of KNI-272.
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PMID:Design and synthesis of substrate-based peptidomimetic human immunodeficiency virus protease inhibitors containing the hydroxymethylcarbonyl isostere. 878 65

Flow cytometry represents an interesting methodologic approach to human neutrophil biology and pathology. Several aspects of neutrophil activation can be evaluated by flow cytometry: phagocytosis, respiratory burst (superoxide anion generation, intracellular hydrogen peroxide production), intracellular pH, actin polymerization, membrane potential, aggregation, cytotoxicity, degranulation, and surface marker expression. In several instances whole blood methods have been developed and have been shown to be very specific and sensitive. Neutrophils can easily be distinguished from other circulating cells, including eosinophils, and methods for the evaluation of neutrophil phagocytosis and hydrogen peroxide production are currently used. In addition whole blood procedures for the determination of the expression of neutrophil function-associated surface antigens have been recommended in order to avoid the artifactual changes resulting from isolation methods. Purified neutrophil have to be used to study other parameters such as actin polymerization and cytotoxicity. Flow cytometry permits a multiparametric evaluation of neutrophil functions, and advances in software technology facilitate a wide variety of choices for the handling, storage, and evaluation of data. The applications of flow cytometry in human neutrophil diseases include the diagnosis of chronic granulomatous disease and leukocyte adhesion syndrome types 1 and 2, and the evaluation of granulocyte biology in several clinical conditions such as immunodeficiency conditions, recurrent infections, hematologic diseases, and noninfectious diseases caused by uncontrolled neutrophil activation.
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PMID:Applications of flow cytometry in the study of human neutrophil biology and pathology. 879 47

Strain is eliminated as a factor in hydrolysis of the scissile peptide bond by human immunodeficiency virus (HIV)-1 and simian immunodeficiency virus (SIV), based on the first eight complexes of products of hydrolysis with the enzymes. The carboxyl group generated at the scissile bond interacts with both catalytic aspartic acids. The structures directly suggest the interactions of the gemdiol intermediate with the active site. Based on the structures, the nucleophilic water is displaced stereospecifically by substrate binding toward one catalytic aspartic acid, while the scissile carbonyl becomes hydrogen bonded to the other catalytic aspartic acid in position for hydrolysis. Crystal structures for two N-terminal (P) products and two C-terminal (Q) products provide unambiguous density for the ligands at 2.2-2.6 A resolution and 17-21% R factors. The N-terminal product, Ac-S-L-N-F/, overlaps closely with the N-terminal sequences of peptidomimetic inhibitors bound to the protease. Comparison of the two C-terminal products, /F-L-E-K and /F(NO2)-E-A-Nle-S, indicates that the P2' residue is highly constrained, while the positioning of the P1' and P3' residues are sequence dependent.
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PMID:Three-dimensional structures of HIV-1 and SIV protease product complexes. 884 Nov 39

Human immunodeficiency virus (HIV) infection is associated with increased concentrations of neopterin derivatives, released in large quantities by human macrophages on stimulation with interferon-gamma (INF-gamma). Neopterin concentrations thus inversely correlate with absolute CD4+ T-cell numbers and strongly predict progression of disease from latency to AIDS. Investigations of hydrogen peroxide-induced chemiluminescence indicated a potential role of neopterin and 7,8-dihydroneopterin in oxygen free radical-mediated processes. Indeed, 7,8-dihydroneopterin is able to enhance tumor necrosis factor alpha (TNF-alpha)-induced apoptosis, accompanied by an increased production of reactive oxygen intermediates (ROIs). In line with this finding, the same combination appears to contribute to the upregulation of HIV replication due to activation of nuclear factor-kappa B (NF-kappa B), a central enhancer element of the HIV LTR promoter. Thus, besides the role of neopterin as sensitive indicator of disease activity in HIV infection, neopterin derivatives apparently are associated with the cascade of events that regulate the HIV production in infected individuals.
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PMID:Role of neopterin and 7,8-dihydroneopterin in human immunodeficiency virus infection: marker for disease progression and pathogenic link. 886 84

This article demonstrates that human immunodeficiency virus type 1 (HIV-1) gp120 amplifies the activity of tumor necrosis factor alpha (TNF-alpha), a cytokine that stimulates HIV-1 replication through activation of NF-kappa B. In CD4-positive Jurkat cells, gp120 potentiates TNF-induced NF-kappa B activation. TNF-mediated activation of NF-kappa B is known to involve the intracellular formation of reactive oxygen intermediates (ROIs). Accordingly, we examined the influence of gp120 on the cellular redox state. We found that gp 120-modulated TNF-induced NK-kappa B activation was inhibited by the antioxidant butylated hydroxyanisole, indicating the involvement of redox-dependent mechanisms. In addition, we showed that gp120 induces intracellular formation of hydrogen peroxide, which is accompanied by a decrease in the ratio of glutathione to glutathione disulfide. In contrast, in the p56lck-deficient J.CaM1.6 T cell line, a derivative of the Jurkat cell line, gp120 was unable to stimulate hydrogen peroxide, to decrease the ratio of GSH to GSSG, and has no effect on TNF-induced NF-kappa B activation. This demonstrated that p56lck protein tyrosine kinase plays an active role in transmitting a signal that increases the oxidative state of the cell and as a consequence amplifies TNF-mediated NF-kappa B DNA binding. We have demonstrated that Tat protein decreased both the Mn-dependent superoxide dismutase (MnSOD) and the cellular glutathione content (GSH). Here we show that, in contrast to Tat, gp120 is unable to inhibit activity and expression of MnSOD and to decrease GSH content. Taken together, our data suggest that gp120 potentiates TNF-induced NF-kappa B activation by stimulating a signal pathway that involves p56lck and the increased formation of reactive oxygen intermediates such as H2O2. These findings may be relevant for the regulation of HIV-1 replication in T cells.
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PMID:HIV type 1 glycoprotein 120 amplifies tumor necrosis factor-induced NF-kappa B activation in Jurkat cells. 887 Aug 42

Among a series of unmodified phosphodiester (PO)-oligodeoxynucleotides (PO-ODNs) complementary to some of the human immunodeficiency virus type 1 (HIV-1) regulatory genes, several PO-ODN sequences complementary to the vpr gene (PO-ODNs-a-vpr, where a-vpr is the antisense vpr sequence) emerged as potent inhibitors (at concentrations of 0.8 to 3.3 microM) of HIV-1 multiplication in de novo infected MT-4 cells, while they showed no cytotoxicity for uninfected cells at concentrations up to 100 microM. Unlike phosphorothioate counterparts, PO-ODN-a-vpr sequences were not inhibitory to HIV-2 multiplication in de novo infected C8166 cells and neither prevented the fusion between chronically infected and bystander CD4+ cells nor inhibited the activity of the HIV-1 reverse transcriptase in enzyme assays. Moreover, they were not inhibitory to HIV-1 multiplication in chronically infected cells. Delayed addition experiments showed that PO-ODNs-a-vpr inhibit an event in the HIV-1 replication cycle following adsorption to the host cell, but preceding reverse transcription. Structure-activity relationship studies indicated that the antiviral activity of the test PO-ODN-a-vpr sequences is not related to an antisense mechanism but to the presence, within the active sequences, of contiguous guanine residues. Physical characterization of the test PO-ODNs suggested that the active structure is a tetramer stabilized by G quartets (i.e., four G residues connected by eight hydrogen bonds).
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PMID:Native oligodeoxynucleotides specifically active against human immunodeficiency virus type 1 in vitro: a G-quartet-driven effect? 887 76

The purpose of our study was to determine whether proton magnetic resonance spectroscopy (MRS) could detect early brain involvement by human immunodeficiency virus (HIV). We recruited 19 asymptomatic HIV-infected patients, 9 with and 10 without a history of intravenous drug use (IDU), as well as 10 control subjects. All subjects had to have normal MR imaging to be enrolled. We identified the following peaks on proton MRS: n-acetyl aspartate, creatine, choline, and a conglomerate amino acid peak between 2.1 and 2.6 parts per million that we call the marker peaks. Proton MRS was able to demonstrate a statistically significant difference between HIV-infected subjects and controls. The marker/Cr was the best ratio to separate patients from controls, with controls having a mean ratio of 0.50 +/- 0.51 and patients having a mean ratio of 1.8 +/- 0.85 (p = 0.001). There was no difference between HIV-infected subjects with and without a history of IDU. No significant relationship was found between either neuropsychological test scores or CD4 count and metabolite ratios. In brief, MRS seems more sensitive than magnetic resonance imaging (MRI), being able to detect abnormalities in HIV-infected patients when imaging is normal.
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PMID:Proton spectroscopy in asymptomatic HIV-infected adults: initial results in a prospective cohort study. 889 69

Infection of sheep by visna-maedi virus causes an interstitial pneumonitis similar to that associated with human immunodeficiency virus type-1 (HIV-1). Visna-maedi virus infection of alveolar macrophages leads to their activation. In this study we determined whether an imbalance in oxidant-antioxidant activity may be involved in the pathogenesis of the disease. We investigated the spontaneous and phorbol myristate acetate (PMA)-induced release of hydrogen peroxide (H2O2), and the activities of superoxide dismutase and glutathione peroxidase in alveolar macrophages from lambs experimentally-infected with visna-maedi virus, and in ovine alveolar macrophages infected in vitro. Alveolar macrophages from lambs experimentally-infected in vivo exhibited normal spontaneous H2O2 release and had superoxide dismutase and glutathione peroxidase activities similar to those from control animals. In contrast, after in vitro stimulation with PMA the H2O2 production by macrophages from experimentally-infected lambs was significantly increased. Similarly, spontaneous and PMA-induced H2O2 production by in vitro infected macrophages was significantly increased as compared to controls. In conclusion, the increased capacity of alveolar macrophages infected with the human immunodeficiency virus type-1-related visna-maedi virus to release hydrogen peroxide on stimulation suggests an oxidant-antioxidant imbalance, which may contribute to the pathogenesis of the observed chronic interstitial pneumonitis.
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PMID:Oxidant-antioxidant imbalance in the experimental interstitial lung disease induced in sheep by visna-maedi virus. 890 54


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