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)

Oxidative stress activates the NF-kappaB/Rel transcription factors which are involved in the activation of numerous immunoregulatory genes and the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). In the present study, we examined the effects of established and novel compounds including antioxidants, ribonucleotide reductase inhibitors, and iron chelators on NF-kappaB activation and HIV LTR-mediated gene expression induced by TNF-alpha. N-Acetylcysteine (NAC), pyrrolidinedithiocarbamate (PDTC), and Trimidox (TD) at various concentrations inhibited TNF-alpha-induced NF-kappaB binding in Jurkat cells. Pretreatment of cells with these compounds prior to stimulation prevented I kappaB alpha degradation. Phosphorylation of I kappaB alpha, a prerequisite for its signal-induced degradation, was abrogated in these cells, indicating that oxidative stress is an essential step in the NF-kappaB activation pathway. On the other hand, iron chelators desferrioxamine, pyridoxal isonicotinoyl hydrazone (PIH), and salicylaldehyde isonicotinoyl hydrazone (SIH) showed no inhibition of TNF-alpha-induced NF-kappaB DNA-binding activity. Synergistic induction of HIV-1 LTR-mediated gene expression by TNF-alpha and the HIV-1 transactivator Tat in Jurkat cells was significantly suppressed in the presence of NAC and TD, but not PDTC. The inhibition of NAC and TD on LTR-directed gene expression was diminished when NF-kappaB-binding sites in the LTR were deleted, indicating that these compounds affected the NF-kappaB component of the synergism. Iron chelators PIH and SIH also showed some inhibitory effect on LTR-mediated gene activation, presumably through an NF-kappaB-independent mechanism. These experiments demonstrate that TD, at concentration 50 times lower than the effective concentration of NAC, potently inhibits NF-kappaB activity and suppresses HIV LTR expression.
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PMID:Selective inhibition of l kappaB alpha phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds. 926 59

Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy.
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PMID:Immune function in patients with beta thalassaemia receiving the orally active iron-chelating agent deferiprone. 933 13

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

Brain iron deposition was assessed at 1.5 T in the caudate nucleus, globus pallidus and frontal and parieto-occipital white matter in 28 human immunodeficiency virus (HIV)-infected patients and 15 control subjects with a new Partially Refocussed Interleaved Multi-Echo sequence by measuring 1/T2, 1/T2* and 1/T2' (i.e., R2, R2* and R2'). There were significant differences in the R2 and R2* of the caudate nucleus (p < 0.0001 and p < 0.05) and the R2, R2* and R2' of the globus pallidus (p < 0.01, p < 0.005 and p < 0.05) in HIV-infected patients compared to control subjects. There was a trend for higher values of R2, R2* and R2' in the globus pallidus and caudate nucleus in HIV-infected patients with later stage HIV disease. These results suggest that there is greater iron deposition in the basal ganglia of HIV-infected patients compared with control subjects, with a predilection for the globus pallidus. The relationship between iron deposition in the brain and various parameters of severity of HIV infection remains uncertain.
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PMID:The measurement of R2, R2* and R2' in HIV-infected patients using the prime sequence as a measure of brain iron deposition. 940 32

The anaemia that is a common complication of human immunodeficiency virus (HIV) infection bears many similarities to the anaemia of chronic disease. These similarities include an impaired erythropoietin (EPO) response to anaemia, reduced concentrations of marrow progenitors giving rise to erythroid colonies, abnormalities of reticuloendothelial iron metabolism, and correction of anaemia with recombinant human EPO. A model has been developed in which the pathophysiologic processes producing the anaemia of chronic disease may be attributed to actions of the cytokines that mediate the immune response, such as interleukin-1, tumor necrosis factor and the interferons. These cytokines are also implicated in HIV-related anaemia. In this review, the applicability of this cytokine-mediated anaemia model to the anaemia of HIV infection is explored.
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PMID:Cytokines and anaemia in human immunodeficiency virus infection. 942 76

Anemia occurs frequently among patients seropositive for human immunodeficiency virus (HIV), but its multifactorial origin complicates its differential diagnosis and adequate treatment. In addition, the etiology of anemia in HIV infection often remains unclear. In recent years several attempts have been undertaken to elucidate the mechanisms leading to HIV-associated anemia. Direct infection of erythroid progenitors has been discussed, but could not be proven. Furthermore, soluble factors like HIV proteins and cytokines have been suggested to inhibit growth of hematopietic cells in the bone marrow of HIV-infected patients. However, so far no statements can be made whether these factors are directly involved in myelosuppression or mediate their effect by inhibiting growth-factor synthesis. Opportunistic complications represent the underlying cause for anemia in a large number of HIV-infected patients. Next to this rather obvious reason for anemia, iatrogenic anemia induced by myelosuppressive drugs is also very common. It is of note, however, that modern dosages of < 600 mg zidovudine (ZDV) daily rarely cause anemia. Instead, other drugs that can induce anemia itself or by enhancing ZDV plasma concentrations must be considered important contributing factors. Deficiency of vitamin B12, folate and iron are frequently reported in HIV patients. However, specific investigations revealed appropriate storage amounts of these micronutrients. Supplementation may be beneficial in some patients, but often fails to reverse anemia in this population. In anemic HIV patients reticulocytopenia is a consistent finding. Additionally, inadequately low endogenous erythropoietin concentrations have been repeatedly reported. Thus, it is speculated that a blunted erythropoietin feedback mechanism contributes substantially to the pathogenesis of anemia in HIV patients.
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PMID:Pathogenesis and pathophysiology of anemia in HIV infection. 943 73

Diarrhea and malabsorption are common findings in patients with the acquired immunodeficiency syndrome (AIDS). The pathogenesis and consequences of malabsorption in human immunodeficiency virus (HIV) infection are similar to those found in non-HIV-related conditions, and are related to both direct intestinal damage and alterations in the coordination of the body's response to feeding. The pathogenesis of malabsorption is multifactorial and includes primary enterocyte injury with partial villus atrophy and crypt hyperplasia, ileal dysfunction with bile salt wasting and fat malabsorption, and exudative enteropathy. Clinical studies show that intestinal cryptosporidiosis leads to excess fecal losses of about 20% for protein and fat. The consequences of malabsorption include decreased appetite; "enterogastrone" effects including dry mouth, decreased gastric acid secretion, decreased rate of gastric emptying, and slowed intestinal transit; anemia resulting from iron, folate, or vitamin B12 malabsorption; and metabolic effects including osteomalacia, gallstones, renal stones, and hypocholesterolemia. Few studies of nutritional therapy have been applied specifically to AIDS patients with malabsorption. Total parenteral nutrition promotes weight gain, although the response to this therapy depends on the underlying clinical problem, with body cell mass repletion noted in patients with malabsorption but predominantly fat gain in patients with systemic infections. Nutritional stabilization also was noted in response to oral administration of a semielemental diet.
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PMID:Human immunodeficiency virus-related wasting: malabsorption syndromes. 962 87

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.
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PMID:Tuberculosis and iron overload in Africa: a review. 963 Nov 2

Lactoferrin is a mammalian iron-binding glycoprotein present in many biological secretions, such as milk, tears, semen and plasma and a major component of the specific granules of polymorphonuclear leucocytes. The effect of bovine lactoferrin (BLf) in apo-form or saturated with ferric, manganese or zinc ions, on human immunodeficiency virus type 1 (HIV-1) infection in the C8166 T-cell line was studied. Both HIV-1 replication and syncytium formation were efficiently inhibited, in a dose-dependent manner, by lactoferrins. BLf in apo and saturated forms markedly inhibited HIV-1 replication when added prior to HIV infection or during the virus adsorption step, thus suggesting a mechanism of action on the HIV binding to or entry into C8166 cells. Likewise, the addition of Fe3+BLf prior to HIV infection and during the attachment step resulted in a marked reduction of the HIV-1 DNA in C8166 cells 20 h after infection. The potent antiviral effect and the high selectivity index exhibited by BLf suggest for this protein, in apo or saturated forms, an important role in inhibiting the early HIV-cell interaction, even though a post adsorption effect cannot be ruled out.
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PMID:Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection. 978 69

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the trans -activation responsive region (TAR) RNA, a 59 base stem-loop structure located at the 5'-end of all HIV transcripts. We have used an intramolecular RNA self-cleaving strategy to determine the folding of TAR RNA and its interactions with a Tat peptide. We incor-porated an EDTA analog at position 24 in the HIV-1 Tat binding site of the TAR RNA. After isolation and purification of the EDTA-TAR conjugate, RNA self-cleavage was initiated by the addition of an iron salt, ascorbate and hydrogen peroxide. Hydroxyl radicals generated from the tethered Fe(II) cleaved TAR RNA backbone in two localized regions. Sites of RNA cleavage were mapped by sequencing reactions. A Tat fragment, Tat(38-72), specifically inhibited RNA self-cleavage. To determine the structural changes caused by the Tat peptide, we performed Fe(II)-EDTA footprinting experiments on Tat-TAR complex. Our high-resolution footprinting results suggest that the inhibition of self-cleavage of EDTA-TAR is due to two effects of Tat binding: (i) Tat binds in the bulge and protects residues in the vicinity of the bulge from self-cleavage and (ii) RNA goes through a structural change where EDTA-U24 is rigidly positioned out of the helix and cannot get access to other nucleotides in the loop of TAR RNA, which are not protected by the Tat peptide. Our results demonstrate that Fe(II)-EDTA-mediated RNA self-cleavage can be applied to study RNA tertiary structures and RNA-protein interactions.
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PMID:Visualizing tertiary folding of RNA and RNA-protein interactions by a tethered iron chelate: analysis ofHIV-1 Tat-TAR complex. 992 43


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