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)

Glutathione (GSH) is known to play an important role in various lymphocyte functions. We now report that different T cell subsets express different requirements for intracellular GSH. Depletion of intracellular GSH by buthionine sulfoximine (BSO), a specific inhibitor of GSH biosynthesis, decreases the proportion of CD8+ cells (i.e., increases the CD4+/CD8+ ratio), and inhibits particularly the generation of large blast-like CD8+ cells and cytotoxic T lymphocyte (CTL) activity. CTL activity is restored by administration of exogenous GSH. Differential effects of GSH depletion were also seen at the level of individual T cell clones. The CD4+ helper T cell clone D10.G4.1.HD was found to express a high rate of interleukin 2 (IL-2) dependent DNA synthesis even after severe depletion of intracellular GSH, whereas other T cell clones including the clone 29 were severely inhibited by BSO. The results of these studies suggest that the decreased intracellular GSH levels of HIV-1 seropositive persons are probably not (directly) responsible for the selective depletion of the CD4+ T cell subset but may be responsible for a cellular dysfunction of the CD8+ subset and for the ultimate failure of the CTL to control the viral infection in these patients.
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PMID:Differential effects of glutathione depletion on T cell subsets. 191 38

Mitogenically stimulated human peripheral blood lymphocytes and T cell clones were found to have weak membrane transport activity for the disulfide cystine but strong membrane transport activity for the thiol amino acid cysteine. Cysteine, however, is represented at the lowest concentration among all protein-forming amino acids in the blood plasma. Complementary laboratory experiments have shown that the cysteine supply is indeed limiting for important lymphocyte functions. Proliferative responses of mitogenically stimulated lymphocytes and T-cell clones and the activation of cytotoxic T cells in allogeneic mixed lymphocyte cultures are strongly influenced by small variations in the extracellular cysteine concentration even in the presence of relatively high and approximately physiologic concentrations of cystine. Cysteine can be substituted by N-acetylcysteine but not by cystine. The more detailed analysis revealed that the extracellular supply of cysteine influences strongly the intracellular level of glutathione (GSH) and also the activity of the transcription factor NF kappa B that regulates the expression of several immunologically relevant genes. In vitro experiments including double-chamber experiments with macrophages and lymphocytes revealed, moreover, that cysteine plays an important role as a regulatory mediator between these cell types. The cysteine supply is impaired directly or indirectly in several pathologic conditions that are associated with immunodeficiencies, including the acquired immune deficiency syndrome (AIDS). Cysteine or cysteine derivatives may therefore be considered for the treatment of patients with HIV-1 infection.
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PMID:Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. 192 6

Plasma levels of vitamin E (Vit E), polyunsaturated fatty acids of phospholipids (PUFA-PL), lipoperoxides as well as erythrocytes glutathione peroxidase activity (GSH-Px), were evaluated in 200 migrants coming from developing countries, some of which at high risk for serious infective diseases. HIV-1 and syphilis infections were also investigated. 114 subjects (57%) had blood levels of Vit E, PUFA-PL and GSH-Px significantly lower (p less than 0.001, p less than 0.01) than those of normal healthy individuals (n = 30), while lipoperoxides values were unchanged. 8 from this group were found to be HIV-1 positive, and 5 TPHA positive. In contrast, the remaining 86 migrants did not show any signs of infections and their blood parameters were normal enough. These results show that factors such as widespread poverty, inadequate housing, malnutrition, insufficient access to medical care, psychological stress are strictly correlated to the reduction of blood parameters which are critical for the normal cell function of mammalian cells. PUFA-PL deficiency may cause lesions likely due to faulty cellular membranes. The lack of Vit E and GSH-Px, which are considered major protective molecules against lipoperoxidation damage in vivo, has been involved in several human diseases. We suggest that low blood levels of Vit E, GSH-Px and particularly PUFA-PL may play a pathogenetic role in the onset and development of AIDS and other infections. In this connection, we have found that a deficiency of these blood parameters occurs in patients with AIDS (n = 50) and in 32% of HIV seronegative intravenous drug abusers (n = 100).
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PMID:[Blood levels of vitamin E, polyunsaturated fatty acids of phospholipids, lipoperoxides, glutathione peroxidase activity and serological screening for syphilis and HIV in immigrants from developing countries]. 208

Plasma levels of vitamin E (vit E) and polyunsatured fatty acids of phospholipids (PUFA-PL) as well as erythrocyte glutathione peroxidase (GSH-Px) activity are significantly lower (p less than 0.001) in patients HIV sero-positive (AIDS and ARC cases) both affected and not affected with seborrheic dermatitis and in 32% of HIV sero-negative intravenous drug abusers (IVDA, A subgroup) than in controls. The deficiency of PUFA-PL (mainly C20:3 n-6, C20:4 n-6 and C22:6 n-3) which is associated with a significant increase (p less than 0.001) of saturated palmitic and stearic acids and monounsaturated oleic acid, cannot be correlated to an active lipoperoxidative process. In fact the levels of thiobarbituric acid-reactive materials (TBA-RM) are not increased in the plasma of HIV sero-positive patients and A subgroup of IVDA. It is likely that the reduction of PUFA-PL is due to an inhibition of hepatic microsomal desaturase enzymes (delta 6 desaturase, delta 5 desaturase, delta 4 desaturase) which are involved in both n-6 and n-3 pathways. Since IVDA represent, and not only in Italy, a major risk category for HIV infection, we suggest that reduced blood levels of vit E, GSH-Px and particularly PUFA-PL may be added to the list of risk factors favouring the onset and the development of AIDS.
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PMID:[Blood deficiency values of polyunsaturated fatty acids of phospholipids, vitamin E and glutathione peroxidase as possible risk factors in the onset and development of acquired immunodeficiency syndrome]. 222 37

The antileukemic and anti-HTLV-III (anti-HIV) agent avarol, a sesquiterpenoid hydroquinone, was determined to be converted into its corresponding quinone derivative avarone via the semiquinone free radical. Its g-value was 2.0047; after hyperfine splitting the energy levels revealed 16 isotropic Hfs. The redox reaction products were identified at the pH values 4.0, 7.0 and 12.0 and the overall reaction pathways were formulated. In vivo experiments with L5178y mouse lymphoma cells in the ascites of mice revealed that the cytostatic potencies of avarol and avarone cannot be augmented by lowering the pH value. Incubation studies with L5178y cells in vitro showed that the intracellular levels of superoxide dismutases (SODases) and of glutathione (GSH) peroxidase activities significantly change after avarol administration. While both the Mn-SODase and the Cu/Zn-SODase activities dropped significantly, the GSH peroxidase activity increased inversely. From these experiments we assume that the anti-tumour and the antiviral effects of avarol/avarone may be due to an increase, induced by the drug, of the intracellular concentrations of superoxide radicals.
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PMID:Action of the antileukemic and anti-HTLV-III (anti-HIV) agent avarol on the levels of superoxide dismutases and glutathione peroxidase activities in L5178y mouse lymphoma cells. 283 45

Similar to HIV-1-induced suppression of thymus-derived lymphocytes (T cells), oxidatively stressed T cells show inhibited DNA synthesis and proliferation. The influence of oxidative stress on nucleotide pools was explored using 3H-uridine addition to OKT3-stimulated peripheral blood lymphocytes. The cells were preincubated and stimulated in the presence of 1 mM buthionine sulfoximine to inhibit GSH synthesis. This treatment gave rise to a significant reduction in dUDP and TTP biosynthesis following 18-32 hours stimulation, indicating possible impairment of ribonucleotide reductase activity.
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PMID:Nucleotide changes in oxidatively stressed lymphocytes. 747 4

Reducing agents such as glutathione (GSH), glutathione ester (GSE), and N-acetylcysteine (NAC) have been shown to suppress the induction of HIV expression in chronically infected cells stimulated by cytokines. We present data which show the effects of the organic thiophosphate WR-151327 on the expression of latent HIV in U1 cells. The chronically infected promonocytic cell line U1 constitutively expresses low levels of HIV that can be increased by 13-phorbol 12-myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), and granulocyte/monocyte colony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-dependent fashion, the reverse transcriptase (RT) activity induced by TNF-alpha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, and 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot analysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in transfected human rhabdomyosarcoma cells (RD). Suppression of HIV expression by WR-151327 was observed in the absence of a cytotoxic or cytostatic effect. Incubation of WR-151327 with human recombinant TNF-alpha for 6 hr at 37 degrees C did not alter the capacity of TNF-alpha to induce the expression of HIV. Our observations further support the hypothesis that reducing agents are important in the control of HIV replication and that the clinical evaluation of WR-151327 may be indicated.
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PMID:Organic thiophosphate WR-151327 suppresses expression of HIV in chronically infected cells. 752 Nov 93

Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients.
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PMID:The role of oxidative stress in HIV disease. 759 Apr 4

The methylation and transsulfuration pathways are intimately linked and have been implicated in the progression of neurologic damage and immune cell depletion caused by human immunodeficiency virus (HIV) infection. We studied the following metabolites related to these pathways: S-adenosylmethionine (SAMe), homocysteine, cysteine, cysteinyl-glycine, and glutathione (GSH) in blood and CSF of 16 HIV-infected patients with neurologic complications and 20 HIV-negative control patients undergoing lumbar punctures for other medical reasons. We confirmed recent studies of decreased CSF SAMe concentrations in HIV infection and demonstrated that diastereomers of SAMe are present in CSF but not in plasma or erythrocytes from both HIV-infected and HIV-negative patients. In HIV-infected patients, CSF GSH and cysteinyl-glycine, but not homocysteine or cysteine, were significantly reduced. This is the first report of decreased CSF GSH induced by HIV infection. GSH has a regulatory effect on the synthesis of SAMe in hepatic tissue, and the same mechanism may also apply in the CNS. Administration of SAMe-butanedisulphonate, 800 mg/d intravenously for 14 days, was associated with significant increases in CSF SAMe and GSH. These findings have potentially important therapeutic implications for the use of SAMe in protecting against SAMe and GSH deficiency in the CNS of HIV-infected patients.
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PMID:Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: effect of parenteral treatment with SAMe. 767 26

We investigated the effects of glutathione (GSH), the major naturally occurring thiol, and a pharmacologic thiol precursor of GSH, N-acetyl cysteine (NAC), on the expression of human immunodeficiency type 1 (HIV-1) in primary cord blood and adult donor monocyte-derived macrophages (MDM). HIV-1 infection of cord blood and adult MDM was accomplished after incubating 10-15-d-old cultures for 4 h with a monocyte-tropic strain of HIV-1 (Bal). After 1 wk in culture cell supernatants were tested for reverse transcriptase (RT) activity. MDM were exposed to 5, 10 and 20 mM concentrations of both GSH and NAC before infection, during infection, and after infection was established. GSH and NAC suppressed the replication of HIV-1 in both primary cord blood and adult donor MDM in a concentration dependent fashion. These suppressive effects were more pronounced in cord-derived cells than in adult-derived cells. In cells treated with GSH or NAC before infection, there was no significant rise in RT activity as compared with controls. Similarly, when cells were treated with GSH and NAC and simultaneously infected, there was also no significant rise in RT activity after 1 wk in culture. In cells treated after infection was established, RT values were suppressed 80-90% that of untreated controls. This effect persisted for 1-2 wk after exposure to GSH and NAC. Untreated controls demonstrated syncytium formation and lost characteristics of spreading and elongation 2 wk after HIV-1 infection, whereas most of the treated cells remained free of syncytium and retained cytoplasmic spreading, adherence, and elongation. These data are consistent with other studies of thiol suppression of HIV-1 replication and demonstrate a similar observation for primary cultured cord MDM. These results may offer new approaches toward cellular protection after infection with HIV-1.
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PMID:Thiol suppression of human immunodeficiency virus type 1 replication in primary cord blood monocyte-derived macrophages in vitro. 767 9


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