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)

We investigated the effect of glutathione on the replication of human immunodeficiency virus (HIV) in chronically infected macrophages, a known reservoir of the virus in the body. We found that exogenous GSH strongly suppresses the production of p24gag protein as well as the virus infectivity. This is related to a dramatic decrease in both budding and release of virus particles from chronically infected cells (either macrophages or lymphocytes), together with a selective decrease in the expression of gp120, the major envelope glycoprotein, rich in intrachain disulfide bonds and thus potentially sensitive to the effect of a reducing agent such as GSH. Overall data suggest that GSH can interfere with late stages of virus replication. This would be in agreement with data obtained in cells exposed to herpesvirus type 1 (a DNA virus) or to Sendai (an RNA virus), showing that the suppression of virus replication by GSH is related to the selective inhibition of envelope glycoproteins. These results suggest a potential role of GSH in combination with other antivirals in the treatment of virus-related diseases.
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PMID:Glutathione inhibits HIV replication by acting at late stages of the virus life cycle. 891 79

Glutathione is an important antioxidant tripeptide that is found in high concentrations in the epithelial lining fluid (ELF) of the lung. Previous investigators demonstrated a deficiency of glutathione (GSH) in the epithelial lining fluid of human immunodeficiency virus (HIV)-seropositive patients. The current investigation performed bronchoalveolar lavage (BAL) on 59 asymptomatic HIV-seropositive subjects (mean CD4: 365.9 +/- 31.2 cells/mm3) and 12 normal control subjects. The volume of ELF and the concentration of glutathione and oxidized glutathione were determined. The concentration of total GSH in ELF was not significantly different in HIV-seropositive individuals compared with normal subjects (628.1 +/- 63.9 microM versus 499.9 +/- 86.0 microM, p = 0.38). However, there was a significantly higher concentration of ELF GSH in HIV-seropositive cigarette smokers (n = 30) compared with nonsmokers (n = 29) (800.3 +/- 107.7 microM versus 443.6 +/- 45.3 microM, p = 0.004). The percentage of total GSH in the oxidized form (GSSG) was similar in both the HIV-seropositive and the normal subject groups (3.4 +/- 0.3% versus 3.0 +/- 0.4%, p = 0.559). There were no significant correlations between ELF GSH or GSSG concentrations and age, CD4 count, or pulmonary function. There was, however, a significant negative correlation between BAL lymphocyte percentage and GSH. The current study suggests that for those patients whose HIV infection is at a relatively early phase, the levels of GSH in the lung ELF are normal.
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PMID:Alveolar fluid glutathione is not reduced in asymptomatic HIV-seropositive subjects. 900 39

The genomes of both bacteria and eukaryotic organisms are known to encode selenoproteins, using the UGA codon for seleno-cysteine (SeC), and a complex cotranslational mechanism for SeC incorporation into polypeptide chains, involving RNA stem-loop structures. These common features and similar codon usage strongly suggest that this is an ancient evolutionary development. However, the possibility that some viruses might also encode selenoproteins remained unexplored until recently. Based on an analysis of the genomic structure of the human immunodeficiency virus HIV-1, we demonstrated that several regions overlapping known HIV genes have the potential to encode selenoproteins (Taylor et al. [31], J. Med. Chem. 37, 2637-2654 [1994]). This is provocative in the light of overwhelming evidence of a role for oxidative stress in AIDS pathogenesis, and the fact that a number of viral diseases have been linked to selenium (Se) deficiency, either in humans or by in vitro and animal studies. These include HIV-AIDS, hepatitis B linked to liver disease and cancer, Coxsackie virus B3, Keshan disease, and the mouse mammary tumor virus (MMTV), against which Se is a potent chemoprotective agent. There are also established biochemical mechanisms whereby extreme Se deficiency can induce a proclotting or hemorrhagic effect, suggesting that hemorrhagic fever viruses should also be examined for potential virally encoded selenoproteins. In addition to the RNA stem-loop structures required for SeC insertion at UGA codons, genomic structural features that may be required for selenoprotein synthesis can also include ribosomal frameshift sites and RNA pseudoknots if the potential selenoprotein module overlaps with another gene, which may prove to be the rule rather than the exception in viruses. One such pseudoknot that we predicted in HIV-1 has now been verified experimentally; a similar structure can be demonstrated in precisely the same location in the reverse transcriptase coding region of hepatitis B virus. Significant new findings reported here include the existence of highly distinctive glutathione peroxidase (GSH-Px)-related sequences in Coxsackie B viruses, new theoretical data related to a previously proposed potential selenoprotein gene overlapping the HIV protease coding region, and further evidence in support of a novel frameshift site in the HIV nef gene associated with a well-conserved UGA codon in the 1-reading frame.
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PMID:Genomic structures of viral agents in relation to the biosynthesis of selenoproteins. 915 12

A combination of antiretroviral drugs acting at different points in the virus replication cycle was evaluated in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS). Intramuscular administration of high doses of reduced glutathione (GSH, 100 mg/mouse/day) and AZT (0.25 mg/ml in drinking water) was found to reduce lymphoadenopathy (92%), splenomegaly (80%), and hypergammaglobulinemia (90%) significantly more than AZT alone. Combined treatment resulted in a reduction in proviral DNA content of 69, 66, and 60%, respectively, in lymph nodes, spleen, and bone marrow. Furthermore, the stimulation index of B cells was also significantly higher in animals receiving GSH and AZT whereas additional responses were not observed in the T cell stimulation index and blood lymphocyte phenotype analyses. In conclusion, the administration of high doses of GSH and AZT, a new combination of antiviral drugs, seems to provide additional advantages compared to single-agent therapy.
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PMID:Antiretroviral effect of combined zidovudine and reduced glutathione therapy in murine AIDS. 928 14

The aim of the present study was to assess the toxic potential of drugs of abuse and other neuropharmacological agents in the pathogenesis of AIDS dementia complex (ADC), the neurological complication of AIDS. Neuroblastoma and glioblastoma cell lines expressing the dopamine transporter, as well as primary macrophages exposed to human immunodeficiency virus-1 (HIV-1), were used to investigate the possibility of any synergistic effect between the mode of toxicity of such substances and virus exposure. The drugs of abuse used in our experiments were cocaine and morphine, which exert their action, among others, on the dopaminergic system. Effects were compared to treatment with dopamine itself and a typical dopaminergic drug used pharmaceutically, selegiline. In macrophage cultures, glutathione (GSH) was upregulated strongly after treatment with dopamine, morphine or selegiline, and this effect was enhanced when cells were pre-exposed to virus. This upregulation is discussed as a compensatory reaction to an oxidative signal. When hydrogen peroxide plus iron sulfate was used as a strong oxidant in macrophages, GSH concentrations decreased as a result of cell injury. Cell numbers remained constant in all treatment groups. In contrast, in both neuroblastoma and glioblastoma cell lines, the modulation of GSH concentrations by neurotropic substances was accompanied by significant cell loss, which was exacerbated by HIV-1 pretreatment. Selegiline did not change cell numbers when incubated alone. However, when incubated following treatment with HIV-1 cell death was highly significant. Ascorbic acid (AA), included as antioxidant, totally restored cell loss in cultures treated with dopamine. However, no effect was observed in combined treatment of AA and morphine or selegiline. The results demonstrate a synergistic role in cellular toxicity due to neurotropic substances and HIV-1, and suggest that neuropharmacological agents may contribute to the pathogenesis of ADC.
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PMID:Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro. 937 55

LP-BM5 Murine leukemia virus (MuLV) infection of C57BL/6 mice develop a disease that has many features in common with human acquired immunodeficiency syndrome (AIDS), in particular abnormal lymphoproliferation and severe immunodeficiency. Thus, this MAIDS model may be useful for evaluation of potent antirival agents in vivo. Deficiency in antioxidant micronutrients such as selenium, zinc, and glutathione have been observed in AIDs and AIDS-related complex (ARC) patients. In the present study, the MAIDS model was used to evaluate immunological and oxidative effect of Se as sodium selenite. Results indicated that Se treatment 0.1 mg/kg/d (p.o.) inhibited splenomegaly and sera IgG elevation effectively. In addition to abnormal immunity, oxidative imbalance possibly existed in MAIDS model, as lipid peroxide increased significantly in spleen and whole blood glutathione peroxidase (GSH-Px) activity decreased markedly. Se supplementation had good protective effect.
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PMID:Effect of selenium supplementation on mice infected with LP-BM5 MuLV, a murine AIDS model. 952 61

The carcinogen ethylene dibromide (EDB) has been shown to cause glutathione (GSH)-dependent base-substitution mutations, especially GC to AT transitions, in a variety of bacterial and eukaryotic systems. The known DNA adducts S-[2-(N7-guanyl)ethyl]GSH, S-[2-(N2-guanyl)ethyl]GSH, and S-[2-(O6-guanyl)ethyl]GSH were individually placed at a site in a single oligonucleotide. Polymerase extension studies were carried out using Escherichia coli polymerase I exo- (Klenow fragment, Kf-) and polymerase II exo- (pol II-), bacteriophage T7 polymerase exo-, and human immunodeficiency virus-1 reverse transcriptase in order to characterize misincorporation events. Even though extension was not as efficient as with the nonadducted template, some fully extended primers were observed with the template containing S-[2-(N7-guanyl)ethyl]GSH using all of these polymerases. dCTP was the most preferred nucleotide incorporated opposite S-[2-(N7-guanyl)ethyl]GSH by most of polymerases examined; however, dTTP incorporation was observed opposite S-[2-(N7-guanyl)ethyl]GSH with pol II-. Both S-[2-(N2-guanyl)ethyl]GSH and S-[2-(O6-guanyl)ethyl]GSH strongly blocked replication by all polymerases. Only dATP and dGTP were incorporated opposite S-[2-(N2-guanyl)ethyl]GSH by both Kf- and pol II-. S-[2-(O6-Guanyl)ethyl]GSH was shown to strongly code for dATP incorporation by Kf-. With pol II-, dTTP was incorporated opposite S-[2-(O6-guanyl)ethyl]GSH. In conclusion, all three GSH-guanyl adducts derived from the carcinogen EDB blocked the polymerases and were capable of miscoding.
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PMID:Polymerase blockage and misincorporation of dNTPs opposite the ethylene dibromide-derived DNA adducts S-[2-(N7-guanyl)ethyl]glutathione, S-[2-(N2-guanyl)ethyl]glutathione, and S-[2-(O6-guanyl)ethyl]glutathione. 954 1

Dysregulated apoptosis may underlie the etiology of T cell depletion by human immunodeficiency virus type 1 (HIV-1). We show that HIV-induced apoptosis is preceded by an exponential increase in reactive oxygen intermediates (ROIs) produced in mitochondria. This leads to caspase-3 activation, phosphatidylserine (PS) externalization, and GSH depletion. Since mitochondrial ROI levels are regulated by the supply of NADPH from the pentose phosphate pathway (PPP), the effect of transaldolase (TAL), a key enzyme of PPP, was investigated. Jurkat and H9 human CD4+ T cells were transfected with TAL expression vectors oriented in the sense or antisense direction. TAL overexpression down-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. Alternatively, decreased TAL expression up-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. HIV-induced 1) mitochondrial ROI production, 2) caspase-3 activation, 3) proteolysis of poly(ADP-ribose) polymerase, and 4) PS externalization were accelerated in cells overexpressing TAL. In contrast, suppression of TAL abrogated these four activities. Thus, susceptibility to HIV-induced apoptosis can be regulated by TAL through controlling the balance between mitochondrial ROI production and the metabolic supply of reducing equivalents by the PPP. The dominant effect of TAL expression on oxidative stress, caspase activation, PS externalization, and cell death suggests that this balance plays a pivotal role in HIV-induced apoptosis.
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PMID:Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. 956 23

The anti-human immunodeficiency virus type I (anti-HIV-1) effects of gamma-glutamylcysteine ethyl ester (gamma-GCE; TEI-2306) were examined in vitro. In initial studies using a vigorously HIV-1-producing human T-lymphocytic cell line, gamma-GCE displayed a novel biphasic repressive effect on chronic HIV-1 infection that was unlike that of other glutathione prodrugs or other reported antioxidants. In high doses, up to a concentration of 2.5 mM, at which neither glutathione (GSH) nor another GSH precursor has shown inhibitory effects, gamma-GCE potently inhibited the production of HIV-1 by a selective cytopathic effect against infected cells, while the viability and growth of uninfected cells were unaffected at the same gamma-GCE concentrations. At lower concentrations (200 to 400 microM), gamma-GCE significantly repressed the virus production from chronically HIV-1-expressing cells without affecting their viability. The discrepancy of the thresholds of the toxic doses between infected and uninfected cells was found to be more than 10-fold. Relatively high doses of gamma-GCE, utilized in acute HIV-1 infection of T-lymphocytic cells, entirely blocked the propagation of HIV-1 and rescued the cells from HIV-1-induced cell death. Furthermore, gamma-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within 4 h. Repressive effects of gamma-GCE on acute HIV-1 infection in human primary human peripheral blood mononuclear cells were also demonstrated. Here, the anti-HIV-1 strategy utilizing gamma-GCE is removal of both HIV-1-producing cells and free infectious HIV-1 in vitro, in place of specific immunoclearance in vivo, which might lead to an arrest or slowing of viral propagation in HIV-1-infected individuals.
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PMID:Novel inhibitory effects of gamma-glutamylcysteine ethyl ester against human immunodeficiency virus type 1 production and propagation. 959 50

The redox chemistry of two synthetic model peptides for the 603-609 disulfide loop found in envelope glycoprotein gp41 of the human immunodeficiency virus type 1 (HIV-1) are reported. The two peptides: N-Ac-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys-Thr-Thr-NH2 (I) and N-Ac-Trp-Gly-Cys-Ser-Gly-Arg-His-Ile-Cys-Thr-Thr-NH2 (II) were synthesized by the solid phase method. Peptide I corresponds to amino acids 601-611 of gp41 of the North American/European strain of HIV-1. Peptide II incorporates amino acid replacements frequent in African HIV-1 isolates. The redox chemistry of the disulfide bonds in the two peptides was characterized in aqueous and aqueous/urea solution by studying their thiol-disulfide exchange reactions with the tripeptide glutathione (GSH). GSH reacts with the disulfide bonds to form mixed disulfides, which in turn react with another molecule of GSH to give the dithiol form of the peptide and GSSG. Equilibrium constants were determined for each step and for the overall reduction reactions. Redox potentials of -0.246V and -0.241V were calculated from the equilibrium constants for the disulfide bonds in peptides I and II in aqueous solution at 25 degrees C and pH 7.0. The overall equilibrium constants are less in 8 M urea solution, which indicates a stabilization of the reduced, dithiol form of both peptides by secondary structure which can be denatured by urea. This conclusion is supported by nuclear Overhauser enhancement data obtained from 2D-ROESY NMR spectra which provide evidence of elements of secondary structure for the reduced forms of both peptides. The results are discussed in terms of a protein disulfide isomerase catalyzed reduction of the disulfide bond in gp41.
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PMID:Characterization of the thiol/disulfide chemistry of peptides corresponding to the 603-609 disulfide loop of the human immunodeficiency virus (HIV) envelope glycoprotein gp41. 965 Jul 18


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