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)

The third reading frame of the envelope gene from HIV-1 codes for a protein homologous to the human selenoprotein glutathione peroxidase (GPX). Cells stably or transiently transfected with a HIV-1 GPX construct are protected against the loss of the mitochondrial transmembrane potential and subsequent cell death induced by exogenous reactive oxygen species (ROS) as well as mitochondrion-generated ROS. However, HIV-1 GPX does not confer a general apoptosis resistance, because HIV-1 GPX-transfected cells were not protected against cell death induced by staurosporine or oligomycin. The inhibition of cell death induced by the ROS donor tert-butylhydroperoxide was also observed in cells depleted from endogenous glutathione (GSH), suggesting that GSH is not the sole electron acceptor for HIV-1 GPX. Clinical HIV-1 isolates from long-term non-progressors (untreated patients with diagnosed HIV-1 infection for > 10 years, with CD4 T cell count of > 500 cells/mm3) mostly possess an intact GPX gene (with only 18% of loss-of-function mutations), while HIV-1 isolates from patients developing AIDS contain non-functional GPX mutants in 9 out of 17 cases (53%). Altogether, these data suggest that HIV-1 GPX possesses a cytoprotective, pathophysiologically relevant function.
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PMID:Anti-apoptotic activity of the glutathione peroxidase homologue encoded by HIV-1. 1500 15

We synthesized a series of N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (10) analogues bearing various acyl groups on thiol cysteine or cysteamine residues, to investigate the structure-activity relationship for pro-GSH and anti-HIV properties in human macrophages. The S-substituents were ranked in the following order of efficacy: H > or = acetyl > isobutyryl > pivaloyl > benzoyl. We found that none of these derivatives had pro-GSH or antiviral activities in vitro higher than that of 10, but several displayed similar levels of anti-HIV activity, making them possible candidates for use as adjuvant therapies in conjunction with HAART, for treating neurological aspects of HIV infection.
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PMID:Synthesis and biological evaluation in human monocyte-derived macrophages of N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine analogues with potent antioxidant and anti-HIV activities. 1502 71

Treatment of HIV with AZT (zidovudine) may have toxic side effects as a result of multiple mechanisms. It is known that patients with AIDS may suffer from magnesium deficiency (MgD). We studied selected biochemical and histopathologic consequences of AZT administration (0.7 mg/mL in drinking water) with concurrent Mg-deficient (20% of normal) diet in male C57Bl/6N mice for 3 wk. Significant decreases in red blood cell glutathione (GSH) were evident in the Mg-deficient mice with or without AZT treatment, suggesting compromised antioxidant capacity in the blood. Although MgD alone led to a 1.9-fold increase in plasma thromboxane B(2) (TXB(2), derived from the highly vasoconstrictive TXA(2)), AZT + MgD increased the TXB(2) level 3.5-fold. AZT (+/-MgD) provoked prominent hepatic damage expressed by distortion of lobular architecture, nuclear and cellular swelling, and inflammatory lesions and loss of hepatocytes. AZT alone caused mild cardiac lesions, resulting in partial cardiac fibrosis, especially in the atrium. AZT + MgD caused only scattered small-size cardiac lesions consisting of microscopic foci of inflammatory infiltrates in the ventricles but led to more prominent lesions, fibrosis, and scars in the atrium. MgD or AZT alone caused varying degrees of skeletal muscle degeneration; in combination, more intense degeneration and regeneration of muscle cells were evident. In conclusion, it is suggested that both the decreased blood GSH and elevated plasma TXA(2) might contribute, at least in part, to the aggravated pathological damages observed in the atrium and skeletal muscle of the AZT-treated Mg-deficient mice.
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PMID:Cardiac pathologic effects of azidothymidine (AZT) in Mg-deficient mice. 1537 32

It has been suggested that oxidative stress participates in the pathogenesis of hepatitis C virus infection. It also has been made clear that redox status in T cell and macrophage relates to the activity of virus infectious disease such as HIV infection. With such background we evaluated the relationship between the intracellular redox status of T cell and macrophage and the activity of HCV positive chronic liver disease. Intracellular GSH and GSSG levels of T cell and macrophage were determined in twenty-five HCV positive asymptomatic carriers (C-ASC), sixty-three chronic hepatitis patients (C-CH), ten HCV positive liver cirrhosis patients (C-LC) and twenty-nine healthy controls. The intracellular GSH levels of T cell (T-GSH) significantly decreased in both C-CH and C-LC compared with healthy controls. No significant differences in the T-GSH levels were found between healthy controls and C-ASC. T-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. The intracellular GSH levels of macrophage (CD14-GSH) of C-LC were significantly decreased compared with healthy controls. The CD14-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. There was no correlation between intracellular GSH, GSSG levels and the serum levels of iron-related markers, fibrogenesis markers and other clinical parameters. These results suggest that the intracellular redox status of T cell and macrophage relates to the progression of HCV related chronic liver disease.
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PMID:[The relationship between the intracellular redox status of immune cells and progression of hepatitis C virus related chronic liver disease]. 1555 20

Oxidative stress decreases immune defences and is also suggested to participate in the activation of HIV virus replication. That is why we decided to explore some biomarkers of oxidative stress (reduced glutathione, lipoperoxides, true malondialdehyde and vitamin C) in 20 HIV positive patients whose HIV replication was determined by measurement of RNA viral load. Reduced glutathione is decreased in HIV positive patients, without correlation with the viral load. The patients mean content of lipoperoxides is twice that of controls but with such a large range that there is no statistical difference.
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PMID:[Redox status in HIV+ patients under HAART]. 1556 32

There is an overwhelming interest in the study of the redox status of the cell surface affecting redox signaling in the cells and also predicting the total redox status of the cells. Measuring the total surface thiols (cell surface molecule thiols, csm-SH) we have shown that the overall level of surface thiols is tightly controlled. In vitro, the total concentration of intracellular glutathione (iGSH) seems to play a regulatory role in determination of the amounts of reduced proteins on cells. In addition, short term exposure of the cell surface to glutathione disulfide (GSSG, oxidized GSH) seems to reduce the overall levels of csm-SH suggesting that the function of some cysteine containing proteins on the cell surface may be regulated by the amount of GSSG secreted from the cells or the GSSG available in the extracellular environment. Examination of peripheral blood mononuclear cells (PBMCs) from healthy or HIV-infected subjects failed to reveal a similar correlation between the intra- and extracellular thiol status of cells. Although there is a relatively wide variation between individuals in both csm-SH and iGSH there is no correlation between the iGSH and csm-SH levels measured for healthy and HIV-infected individuals. There are many reports suggesting different redox active proteins on the cell surface to be the key players in the total cell surface redox regulation. However, we suggest that the redox status of the cells is regulated through a complex and tightly regulated mechanism that needs further investigation. In the mean time, overall surface thiol measurements together with case specific protein determinations may offer the most informative approach. In this review, we discuss our own results as well as results from other laboratories to argue that the overall levels of surface thiols on the exofacial membrane are regulated primarily by redox status of the cell surface microenvironment.
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PMID:The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIV-infected subjects. 1562 5

The blood-brain barrier (BBB) has an important role in the development of AIDS dementia. The HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 are neurotoxic and cytotoxic and have been implicated in the development of HIV dementia. They are known to cause oxidative stress and are associated with disruption of the BBB. Here, we used an immortalized endothelial cell line from rat brain capillaries, RBE4, to determine whether gp120 and Tat can induce oxidative stress in an in vitro model of the BBB. RBE4 cells were exposed to gp120 or Tat and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG), catalase (CAT) activity, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity, and malondialdehyde (MDA) used as measures of oxidative stress. Both gp120 and Tat significantly decreased the levels of intracellular GSH, GPx, and GR and increased the levels of MDA in RBE4 cells, showing that the cells were oxidatively challenged. The ratio of GSH/GSSG, a widely accepted indicator of oxidative stress, was also significantly decreased. These studies show that both of these viral proteins can induce oxidative stress in immortalized BBB endothelial cells.
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PMID:HIV-1 viral proteins gp120 and Tat induce oxidative stress in brain endothelial cells. 1591 Jul 62

HIV infection is associated with subnormal GSH levels. An increase in glutathione levels has been observed in HIV-infected adults under oral whey protein supplementation. We studied the features associated with a whey protein concentrate supplementation in children with rapidly progressive AIDS. A prospective double-blind clinical trial was carried out for 4 months with 18 vertically HIV-infected children (1.98-6.37 years), under antiretroviral therapy, who had received whey protein, maltodextrin (placebo) or none. Erythrocyte glutathione concentration, T lymphocyte counts (CD4+ and CD8+) and occurrence of associated co-infections were evaluated. Wilcoxon's and Fischer's Exact tests were used to assess differences between whey protein-supplemented and control (placebo and non-supplemented) groups. A significant median increase of 16.14 mg/dl (p = 0.018) in erythrocyte glutathione levels was observed in the whey protein-supplemented group; the TCD4/CD8 lymphocyte ratio showed a non significant increase and lower occurrence of associated co-infections was also observed. In conclusion, whey protein concentrate supplementation can stimulate glutathione synthesis and, possibly, decrease the occurrence of associated co-infections.
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PMID:Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection. 1601 59

Sulphonamides, such as sulphamethoxazole (SMX) and the related sulphone dapsone (DDS), show a higher incidence of cutaneous drug reactions (CDRs) in patients with the acquired immunodeficiency syndrome (AIDS) compared with human immunodeficiency virus (HIV) negative patients. During HIV infection, pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are increased. We hypothesized that this increase in pro-inflammatory cytokines may increase the toxicity of the arylhydroxylamine metabolites of SMX (S-NOH) and DDS (D-NOH) in keratinocytes through a reduction in glutathione (GSH) content. We evaluated the effect of TNF-alpha on GSH levels in normal human epidermal keratinocytes (NHEK) and found a significant decrease in GSH after 24h. Pre-treatment with TNF-alpha also resulted in an increase in the recovery of D-NOH, but failed to alter drug-protein covalent adduct formation in NHEK. We also evaluated the effect of TNF-alpha, IL-1 beta, interferon-gamma (IFN-gamma), lipopolysaccharide (LPS) and conditioned media (obtained from monocytes stimulated with LPS) on the cytotoxicity of pre-formed arylhydroxylamine metabolites in NHEK. Priming cells with cytokines did not significantly alter the cytotoxicity of the metabolites. The effect of pre-treatment with TNF-alpha on reactive oxygen species (ROS) generation in NHEK was also determined. While ROS formation in NHEK was increased in the presence of D-NOH, TNF-alpha did not alter the level of ROS generation. Our data suggest that the level of GSH reduction induced by pro-inflammatory cytokines does not predispose NHEK to cellular toxicity from either S-NOH or D-NOH.
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PMID:Effect of pro-inflammatory cytokines on the toxicity of the arylhydroxylamine metabolites of sulphamethoxazole and dapsone in normal human keratinocytes. 1628 51

Pyridine N-oxide derivatives represent a new class of anti-HIV compounds for which some members exclusively inhibit HIV-1 RT, whereas other members act, additionally or alternatively, at a post-integrational event in the replicative cycle of HIV. A prototype pyridine N-oxide derivative, JPL-32, inhibited tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 expression in latently HIV-1-infected OM-10.1 and U1 cells, which could be reversed by the addition of N-acetyl-L-cysteine (NAC). The reversal of the antiviral activity of JPL-32 by NAC suggested the possible role of a redox-sensitive factor as target of inhibition. Indeed, when nuclear extracts of TNF-alpha-stimulated OM-10.1 and U1 cells cultured in the presence of JPL-32 were analyzed by an electrophoretic mobility shift assay (EMSA), a dose-dependent inhibition of DNA binding of nuclear NF-kappaB was observed, which could be reversed by the addition of NAC. JPL-32 did not inhibit the release and subsequent degradation of IkappaBalpha, nor did JPL-32 affect the nuclear translocation of NF-kappaB. EMSA revealed that the inhibition of the NF-kappaB DNA binding activity by JPL-32 could be reversed by the addition of reducing agents such as dithiothreitol or beta-mercaptoethanol. Moreover, JPL-32 was able to directly oxidize the thiol groups on the purified p50 subunit of recombinant NF-kappaB. The oxidative modification of the thiol groups on NF-kappaB by JPL-32 could be ascribed to the intracellular pro-oxidant effect of JPL-32. Consequently, JPL-32 was able to increase the intracellular glutathione (GSH) levels and to induce apoptosis in a dose-dependent way.
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PMID:Pyridine N-oxide derivatives inhibit viral transactivation by interfering with NF-kappaB binding. 1643 40


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