UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In studies presented here, we demonstrate that antioxidants regulate NF-kappa B activation and signal transduction pathways leading to HIV expression. We show (1) that N-acetyl-L-cysteine (NAC), an antioxidant and an efficient glutathione (GSH) precursor, inhibits NF-kappa B activation and HIV expression under conditions in which GSH is depleted and NAC cannot be converted to GSH, (2) that the D-stereoisomer of NAC and a wide variety of chemically unrelated antioxidants also inhibit NF-kappa B activation and/or transcription directed by the HIV LTR, and (3) that depletion of GSH, the principal intracellular antioxidant, augments HIV production in an acute infection model. Taken together, these findings suggest direct antioxidant action as the mechanism for inhibition of HIV transcription by NAC. They also confirm that GSH, acting in its capacity as an antioxidant, regulates HIV expression and that exogenous antioxidants can potentiate this regulation.
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PMID:Antioxidants inhibit stimulation of HIV transcription. 851 45

Glutathione (GSH) levels are markedly depleted in patients infected with human immunodeficiency virus type 1 (HIV-1) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiols prevents HIV-1 replication in cultured cells. We were intrigued whether chemopreventive enzyme inducers might represent a more pharmacologically feasible method to inhibit HIV-1 replication since these compounds elevate intracellular concentrations of GSH at nontoxic doses in vivo. After establishing that all inducers surveyed were able to elevate GSH levels in human T-cell and monocytoid cell lines, we were surprised to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM). Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhibit acute HIV-1 replication by inactivating reverse transcriptase (RT). However, among DTTs that inhibit HIV-1 replication in acutely infected cells, only oltipraz was able to inhibit HIV-1 replication in a chronic infection model. Thus, in addition to inactivating RT, oltipraz appears to have an additional antiviral mechanism distal to viral integration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-1 replication in chronically infected cells; we are also attempting to determine the bioorganic mechanism for the inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectively, our studies should be relevant to understanding the diverse medicinal properties of DTTs. Oltipraz, an antischistosomal drug undergoing clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to consider oltipraz as a therapeutic agent not only for its antiretroviral activity, but also for the prevention of HIV-1 associated neoplasms.
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PMID:Oltipraz, a novel inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. 853 88

Despite its recognition as the most prevalent HIV associated cancer, speculation still abounds regarding the pathogenesis of AIDS-related Kaposi's sarcoma (AIDS-KS). However, it has been established that both cytokines, e.g. IL-6, and HIV-associated products, e.g., Tat, are integral in AIDS-KS cellular proliferation. Further, both experimental and clinical evidence is accumulating to link reactive oxygen intermediates (ROI) with both cytokine induction (primarily via nuclear factor-kappa B[NF-kappa B] dependent routes) as well as the subsequent cytokine, tumor necrosis factor alpha (TNF alpha) stimulation of HIV replication. Features of AIDS-KS patients, such as retention of phagocytes, presence of sustained immunostimulation, and a frequent history of KS lesions arising at traumatized sites, make oxidant stress a viable clinical factor in AIDS-KS development. Time course nucleotide profile analyses show that AIDS-KS cells have an inherent, statistically significant, biochemical deficit, even prior to oxidant stress, due to 1) a more glycolytic bioenergetic profile, resulting in lower levels of high energy phosphates (impairing capacity for glutathione [GSH] synthesis and DNA repair); 2) lower levels of NADPH (compromising the activities of GSSG reductase and peroxidase function of catalase); and 3) reduced levels of GSH (impeding both GSH peroxidase and GSH-S-transferases). Following exposure to physiologically relevant levels of H2O2, only the human microvascular endothelial cells (a putative AIDS-KS progenitor cell) responded with bioenergetic adaptations that reflected co-ordination of energy generating and cytoprotective pathways, e.g., retention of the cellular energy charge, increased NAD+, and an accentuation of the ATP, NADPH, and total adenine nucleotide differences relative to AIDS-KS cells. Also, some of the AIDS-KS strains retained intracellular GSSG subsequent to oxidant challenge, inviting the formation of deleterious protein mixed disulfides. While the results of our study address some AIDS-KS issues, they also raise an etiological question, i.e., Does the inability to tolerate oxidant stress arise in conjunction with AIDS-KS neoplastic development, or is it pre-existing in the population at risk? Regardless, use of antioxidant therapy (low risk/ potentially high benefit) in both the "at risk" population as well as in those individuals with active disease may prove a useful preventative and/or treatment modality.
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PMID:Cultured AIDS-related Kaposi's sarcoma (AIDS-KS) cells demonstrate impaired bioenergetic adaptation to oxidant challenge: implication for oxidant stress in AIDS-KS pathogenesis. 856 50

Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. In order to gain more insight into the mechanisms responsible for the deranged sulphydryl homeostasis in HIV infection, the release of GSH into the circulation, an estimate of the systemic production of GSH, was determined using a pharmacokinetic approach. The basal plasma concentrations of free GSH (3.3 +/- 1.3 vs. 5.3 +/- 1.9 mumol L(-1)) and cysteine (7.7 +/- 2.6 vs. 13.4 +/- 4.9 mumol L(-1)) were significantly lower in eight HIV-infected patients than in eight controls. Upon infusion of GSH at a constant rate of 1 mumol min-1 kg-1, GSH in plasma reached a new plateau. The increment in plasma GSH was significantly larger in the HIV-infected patients than in the controls. The input of GSH into the circulation (12.9 +/- 5.7 vs. 30.1 +/- 11.7 mumol min-1; P < 0.01) and the clearance of GSH (25 +/- 7 vs. 35 +/- 7 mL min-1 kg-1) were significantly lower in patients with HIV-infection. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.
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PMID:Decreased release of glutathione into the systemic circulation of patients with HIV infection. 868 53

Epidemiological and experimental studies suggest that dietary milk products may exert an inhibitory effect on the development of several types of tumors. Some recent experiments in rodents indicate that the antitumor activity of the dairy product is in the protein fraction and more specifically in the whey protein component of milk. It has been demonstrated that whey protein diets result in increased glutathione (GSH) concentration in a number of tissues, and that some of the beneficial effects of whey protein intake are abrogated by inhibition of GSH synthesis. Whey protein is particularly rich in substrates for GSH synthesis. It has been suggested that whey protein may be exerting its effect on carcinogenesis and VIH infection by enhancing GSH concentration. Lactoferrin, one of the proteins contained in whey has aise been studied in this way. It has been suggested that lactoferrin binding may play an important role in maintaining, optimal mononuclear phagocyte function, thus protecting adjacent tissue against phagocyte derived radicals. Moreover it has been demonstrated by one of us that the level of plasma lactoferrin were decreased in HIV-1 infected patients in relation to the progression of the disease. The aim of the present study is to evaluate in rat the reactive oxygen species, scavenger activities (ROSSA) of red blood cells (RBCs) with a multifermented whey (SK 344), by repeated doses during 16 days. This study has permitted to demonstrate in vivo that the SK 344 has an excellent ROSSA corresponding to a limitation of the lipoperoxidation of RBCs membranes by singlet oxygen and nitric oxide. We can conclude that whey protein, lactoferrin and multifermented whey are good candidates as dietary inhibitors of the oxidative stress and should be considered as potential medicinal foods in various pathologies as HIV infection and cancer.
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PMID:[Evaluation of the antiradical protector effect of multifermented milk serum with reiterated dosage in rats]. 876 41

Considerable progress has been made in the last few years in the molecular identification and characterization of hepatic GSH transporter-associated polypeptides. We are now poised to determine their precise mechanisms of action and regulation at the transcriptional and post-translational level. It is also anticipated that molecular characterization of the mitochondrial GSH transporter and sodium GSH co-transporters will be accomplished in the near future. With this information, a more complete understanding of GSH/cysteine homeostasis can be achieved which can be applied to furthering the prevention and treatment of the diseases of oxidative stress, such as aging, HIV, cataract, atherosclerosis, cancer and alcoholic liver disease.
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PMID:GSH transporters: molecular characterization and role in GSH homeostasis. 882 17

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

The imbalance of the redox state in cells and body fluids in HIV-1-infected patients may result in progression of the disease as well as in immunologic disfuctions. In this report, we have evaluated whether the direct administration of high doses of reduced glutathione (GSH) exerts any antiviral activity and/or improves immune functions in a murine immunodeficiency animal model. Intramuscular administration of 50 or 100 mg GSH/mouse for five consecutive days weekly to LP-BM5-infected mice did not show local or systemic signs of acute toxicity. During the first 3 weeks from infection, a period in which clinical signs of disease were not yet detectable, GSH significantly reduced the viral load in lymph nodes and spleen as evaluated by a PCR semiquantitative assay of the proviral DNA content. At 10 weeks a GSH concentration-dependent reduction of splenomegaly, lymphadenopathy and hypergammaglobulinemia was evident in all treated mice. Evaluation of proviral DNA content showed that GSH was effective in inhibiting LP-BM5 infectivity in lymph nodes, spleen, and bone marrow at 100 mg/day, while it was less effective when administered at 50 mg/day. At 10 weeks some animals receiving the highest GSH dose died, thus only the mice receiving 50 mg GSH were followed up to 15 weeks without signs of toxicity. In this case, almost not significant differences among infected untreated or treated animals were observed. Thus, GSH is effective in reducing the proviral DNA load in the first period of infection. These data and the failure of sulfhydril supplementation to further counteract the progression of disease after 10 weeks of infection suggest that combinations of GSH and other antiviral agents may be useful for improving current antiviral therapies.
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PMID:Inhibition of murine AIDS by reduced glutathione. 889 Nov 17

The oxidative stress in human erythrocytes was studied in asymptomatic and symptomatic patients infected by the human immunodeficiency virus (HIV), and patients with the acquired immunodeficiency syndrome (AIDS). tert-Butyl hydroperoxide initiated chemiluminescence, superoxide dismutase and catalase activities, and total glutathione were evaluated in the erythrocytes and the total antioxidant capacity in the plasma of control, patients infected with HIV that have not yet developed acquired immunodeficiency syndrome, and patients in the later stage of AIDS. tert-Butyl hydroperoxide initiated chemiluminescence was increased by 33% in asymptomatic (stage A1) and symptomatic patients (stage B2) infected with HIV and 82% for patients with AIDS (stage B3) (P < 0.05). While catalase activity did not show any difference between patients and controls, other indices showed differences that, in some cases, reached statistical significance. Superoxide dismutase activity was increased by 24% in stages A1 and B2 of HIV infection and 65% in patients in stage B3 (P < 0.05). Glutathione was decreased by 20% in stages A1 and B2, and by 32% in stage B3 patients (P < 0.05). Total plasma antioxidant capacity was increased in 30 and 57% for the asymptomatic and AIDS patients groups, respectively (P < 0.05). The data indicate that erythrocyte's oxidative stress is associated with the progressive development of HIV disease. Parameters indicating oxidative stress could be an interesting form to screen the evolution of these patients and their response to anti-oxidant therapies.
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PMID:Oxidative stress in blood of HIV infected patients. 893 54

In AIDS patients, chronic inflammation and elevated levels of cytokines seem to be associated with reduced levels of glutathione (GSH). GSH has been proposed to inhibit the activation of NF-kB, which results in the inhibition of HIV-1 replication. Here, we show the evidence that GSH and N-acetylcysteine, but not L-cysteine or dithiothreitol, could inhibit the reverse transcriptase (RT) process of HIV-1. Such inhibition was not observed with the RT of murine leukemia virus.
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PMID:Intracellular glutathione as a possible direct blocker of HIV type 1 reverse transcription. 894 99

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