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)

In inflammatory lung disorders, oxidants and proteases complement each other in their potential to destroy lung parenchyma. It is therefore rational to combine therapeutic strategies aimed at augmenting the antiproteolytic defenses of the lung in diseases such as emphysema with antioxidant strategies. In the healthy lung, the oxidant burden is balanced by the local antioxidant defenses. However, both an increased oxidant burden and/or decreased antioxidant defenses may reverse the physiologic oxidant-antioxidant balance in favor of oxidants, leading to lung injury. This concept points to an obvious therapeutic strategy: augmentation of the antioxidant screen of the lung to prevent oxidant-mediated tissue damage. Studies using reduced glutathione (GSH), the major pulmonary antioxidant, as a model therapeutic agent demonstrated that GSH can be administered directly to the respiratory epithelial surface by aerosol and is fully functional as an antioxidant both in vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary fibrosis or following HIV infection, GSH aerosol therapy not only normalized deficient pretherapy GSH levels in the lung, but was capable of favorably influencing cellular events such as oxidant release by pulmonary inflammatory cells. The same was true for oral antioxidant therapy with N-acetylcysteine, a glutathione precursor. These results suggest that it is possible to use antioxidants to reverse the imbalance between oxidants and antioxidants at the site of oxidant injury to prevent the progressive tissue damage in lung disorders characterized by high oxidant states. Antioxidants, alone and in combination with antiproteases, merit further long-term studies for clinical therapy.
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PMID:Oxidant-protease interaction in the lung. Prospects for antioxidant therapy. 898 63

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

Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
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PMID:Glutathione deficiency is associated with impaired survival in HIV disease. 905 Aug 88

TNF-alpha stimulates HIV-1 replication via activation of the transcription factor NF-kappa B. TNF-mediated activation of NF-kappa B is known to involve the intracellular formation of reactive oxygen intermediates (ROIs). We recently demonstrated that HIV-1 Tat protein potentiates TNF-induced NF-kappa B activation by downregulation of manganese-dependent superoxide dismutase (MnSOD), shifting the cellular redox state towards pro-oxidative conditions. This study shows that treatment of Jurkat cells with iron chelator deferoxamine (DFO) strongly decreases HIV-1 Tat-potentiated TNF-induced NF-kappa B activation but does not modify NF-kappa B activation by TNF-alpha. The ability of iron chelators to reduce Tat-potentiated TNF-induced NF-kappa B binding activity suggests that iron and intracellular hydroxyl radicals (OH.) are required for Tat effect. Moreover, we have shown that exogenously generated OH. markedly enhanced TNF-induced NF-kappa B activation in a dose-dependent manner while was not sufficient to trigger activation of NF-kappa B by itself. In addition, iron chelators had no effect either on MnSOD activity or on the decrease of this activity by Tat. Iron chelators had also no effect on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), but could elevate the GSH:GSSG ratio decreased by Tat protein. These observations suggest that the formation of intracellular OH. in the presence of iron ions play a major role in HIV-1 Tat enhancement of TNF-induced NF-kappa B activation and that iron chelation may protect Jurkat T cells, at least in part, against oxidative stress induced by Tat.
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PMID:Iron chelation decreases human immunodeficiency virus-1 Tat potentiated tumor necrosis factor-induced NF-kappa B activation in Jurkat cells. 911 Jan 46

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

In vitro HIV-1 infection induced a significant decrease in intracellular reduced glutathione (GSH) in human macrophages. Such a decrease was observed at the time of infection corresponding to maximum release of virus from infected cells and was not related to cell cytotoxicity. GSH los was not related to its oxidation or leakage through the cell membrane. Inhibition of intracellular GSH synthesis by buthionine sulfoximine (BSO) did not further decrease GSH levels with respect to the decrease caused by HIV alone. However, treatment of macrophages with BSO significantly increased the HIV yield in the supernatant. Exogenous GSH strongly suppressed the production of p24 gag protein as well as the virus infectivity. Previous observations with other RNA and DNA viruses consistently showed that GSH antiviral effect occurred at late stages of virus replication and was related to the selective decrease of specific glycoproteins, such as gp120, which are particularly rich in disulfide bonds.
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PMID:Intracellular GSH content and HIV replication in human macrophages. 922 93

HIV-gp120 sensitizes Th1 clones from seronegative donors to apoptosis, which occurs through two distinct events: expression of CD95L followed by its interaction with CD95 to trigger cell death. gp120-apoptosis of the Th1 clone 103 was inhibited by Cyclosporin A, the PTK inhibitors Genistein and PNU152518, as well as the anti-oxidants Ascorbic Acid and Glutathione. Cyclosporin A interfered with CD95L expression, Ascorbic Acid and Glutathione inhibited cell death triggered by CD95/CD95L interaction; Genistein and PNU152518 acted on both steps. The occurrence of oxidative stress during CD95-dependent apoptosis was supported by the direct evidence of ROI production.
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PMID:Apoptosis induced by HIV-gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering. 924 48

Loss of skeletal muscle tissue (cachexia) is one of the hallmarks of HIV infection. It has been found (1) that creatine kinase, i.e., an enzyme of pivotal importance in muscular mitochondrial energy metabolism, is inhibited by oxidative glutathiolation, and (2) that reduced glutathione (GSH) is decreased in skeletal muscle of SIV-infected rhesus monkeys. We, therefore, have studied the phosphocreatine (P-Cr) levels. Muscle tissue from SIV-infected macaques showed significantly decreased P-Cr but normal creatine (Cr), ATP, and ADP when compared with uninfected macaques. Individual P-Cr levels were significantly correlated with GSH. Our findings may explain the dysregulation of energy metabolism in cachexia.
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PMID:Decrease in phosphocreatine level in skeletal muscle of SIV-infected rhesus macaques correlates with decrease in intracellular glutathione. 928 13

Previous studies have suggested that the two conserved cysteines of the HIV-1 protease may be involved in regulating protease activity. Here, we examined diglutathionylated wild type protease (Cys-67-SSG, Cys-95-SSG) and the monoglutathionylated protease mutants (C67A, Cys-95-SSG and C95A, Cys-67-SSG) as potential substrates for thioltransferase (glutaredoxin). Time-dependent changes in the extent of deglutathionylation of each protein were assayed by reverse phase-high performance liquid chromatography. Glutathione alone was not an effective reductant, whereas thioltransferase displayed differential catalysis toward the Cys-95-SSG and Cys-67-SSG sites. At low thioltransferase concentrations (5 nM), deglutathionylation occurred almost exclusively at Cys-95-SSG. With substantially more thioltransferase (100 nM) Cys-67-SSG was partially deglutathionylated but only at 20% of the rate of Cys-95-SSG reduction. Treatment of the diglutathionylated protease with thioltransferase not only restored protease activity but generated an enzyme preparation that had a 3- to 5-fold greater specific activity relative to the fully reduced form. Immunoblot analysis of HIV-1MN virus with an antibody to thioltransferase detected a band co-migrating with recombinant thioltransferase that persisted following subtilisin treatment, indicating the presence of thioltransferase within HIV-1. Our results implicate thioltransferase in the regulation and/or maintenance of protease activity in HIV-1 infected cells.
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PMID:Thioltransferase (glutaredoxin) is detected within HIV-1 and can regulate the activity of glutathionylated HIV-1 protease in vitro. 932 27

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


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