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)

The N-terminal domain of human immunodeficiency virus (HIV-1) integrase (IN) contains the sequence motif His-Xaa3-His-Xaa23-Cys-Xaa2-Cys, which is strongly conserved in all retroviral and retrotransposon IN proteins. This structural motif constitutes a putative zinc finger in which a metal ion may be coordinately bound by the His and Cys residues. A recombinant peptide, IN(1-55), composed of the N-terminal 55 amino acids of HIV-1 IN was expressed in Escherichia coli and purified. Utilizing a combination of techniques including UV-visible absorption, circular dichroism, Fourier transform infrared, and fluorescence spectroscopies, we have demonstrated that metal ions (Zn2+, Co2+, and Cd2+) are bound with equimolar stoichiometry by IN(1-55). The liganded peptide assumes a highly ordered structure with increased alpha-helical content and exhibits remarkable thermal stability. UV-visible difference spectra of the peptide-Co2+ complexes directly implicate thiols in metal coordination, and Co2+ d-d transitions in the visible range indicate that Co2+ is tetrahedrally coordinated. Mutant peptides containing conservative substitutions of one of the conserved His or either of the Cys residues displayed no significant Zn(2+)-induced conformational changes as monitored by CD and fluorescence spectra. We conclude that the N terminus of HIV-1 IN contains a metal-binding domain whose structure is stabilized by tetrahedral coordination of metal by histidines 12 and 16 and cysteines 40 and 43. A preliminary structural model for this zinc finger is presented.
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PMID:Structural implications of spectroscopic characterization of a putative zinc finger peptide from HIV-1 integrase. 157 1

A proviral fragment from human immunodeficiency virus type 1 (HIV-1) (LAV-1BRU) containing only protein-coding information, was expressed in COS cells using constitutive promoters in transient and stable transfection experiments. The presence of viruslike particles in cell supernatants was verified by Western blot analysis, density gradient centrifugation, and electron microscopy. Transfection of Vero cells with a similar construct employing the human metallothionein promoter led to the isolation of stable cell lines exhibiting inducible viruslike particle expression in response to cadmium chloride treatment. Induction ratios for viruslike particle expression were in excess of 1000-fold with production levels of p24 core antigen as high as 0.6 mg/L per 24 h. HIV-1 viruslike particles were immunogenic in mice, leading to strong envelope and core-specific humoral responses after two immunizations. The development of stable cell lines expressing significant quantities of HIV-1 viruslike particles offers an alternative to the use of live virus vectors for the production and evaluation of particle-based AIDS vaccines.
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PMID:Production of immunogenic HIV-1 viruslike particles in stably engineered monkey cell lines. 170 39

Diethyldithiocarbamate (Ditiocarb) is a drug with diverse biological activities suggesting that it may have multiple, clinical uses. Thus, it is an inhibitor of such enzymes as cytochrome P450, it is a chelating agent for nickel and cadmium, it is a free-radical scavenger and finally, it is an immunomodulator. As such, it can restore the immune responses of immunosuppressed mice. In the murine retrovirus-induced immunodeficiency disease (LP-BM5 in C57 black 10 mice), it can prevent the development of disease when given from the day of virus inoculation until 2 weeks after virus inoculation. In addition, it can reverse disease manifestations including lymphadenopathy when started as late as 10 weeks after virus inoculation. Associated with these effects is a reduction in mortality from 100 percent to between 0 and 10 percent. When drug is stopped however, disease progression resumes. In man, Ditiocarb has been used in a series of open, non-randomized as well as randomized prospectively-controlled clinical trials in patients with HIV infection. Three randomized placebo-controlled studies have been conducted. In the largest of these, involving 389 patients, Ditiocarb was shown to be safe, non-toxic and effective. Thus, there was a 62 percent reduction in new opportunistic infections (OI) in all of the treated patients, a 50 percent reduction in ARC patients and an 82 percent reduction in AIDS patients. When new and recurrent OI and other events indicating progression were taken together, there were 17 events in 193 treated patients and 42 events in 196 placebo control patients. Statistically significant reductions in these events were seen in ARC patients, AIDS patients and all patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biological activity of diethyldithiocarbamate (Ditiocarb, Imuthiol) in an animal model of retrovirus-induced immunodeficiency disease and in clinical trials in patients with HIV infection. The Ditiocarb Study Group. 217 28

The tat protein encoded by the human immunodeficiency virus type 1 is a potent trans-activator of gene expression from the viral long terminal repeat. The domains that are essential for trans-activation, a Pro-Xaa3-Pro triad, a cysteine-rich metal-binding sequence motif, and a cluster of basic residues, are present within the N-terminal 57 residues of tat. To determine the structural requirements for tat function and the role of metal binding at the transcription level alone, tat-(1-86) (full-length tat peptide), tat-(1-57), and tat-(1-47) were chemically synthesized. These peptides as well as the Cd2+ and Zn2+ complexes of tat-(1-86) and tat-(1-57) were evaluated for stimulation of transcription from the human immunodeficiency virus type 1 long terminal repeat by using cell-free in vitro methods. All three peptides produced a 7- to 9-fold increase over the basal level of transcription at a peptide concentration of 0.4 microM. Interestingly, at 4 microM, both tat-(1-57) and tat-(1-86) inhibited even the basal level of transcription. In contrast, tat-(1-47), which lacks the basic domain (residues 49-57), exhibited full stimulatory activity at 4 microM. Our data suggest, therefore, that the basic region may be responsible for the observed inhibitory activity of tat-(1-86) and tat-(1-57). Furthermore, binding to Zn2+ and not to Cd2+ ions only slightly augments (approximately 2-fold) the activity of the tat peptides.
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PMID:Activity of synthetic tat peptides in human immunodeficiency virus type 1 long terminal repeat-promoted transcription in a cell-free system. 220 50

The transactivating protein from human immunodeficiency virus type 1 (HIV-1), Tat, was found to bind to the nuclear matrix from uninfected and HIV-1-infected H9 cells. Addition of the Zn2+, Cd2+ and Cu2+ chelator o-phenanthroline destroyed the matrix fibrils and the binding affinity of Tat to the matrix. A sequential treatment of the matrix, first with o-phenanthroline and then with ZnCl2, partially restored the fibrillar-like matrix structure. Infection of H9 cells with HIV-1 resulted in a displacement of cellular mRNA by viral mRNA from the nuclear matrix. Both the matrix-bound host cell and HIV-1 mRNA were found to dissociate from the matrix in the presence of o-phenanthroline. This could be prevented by coincubation with Zn2+ or Cu2+ (but not Mg2+), which stabilize the mRNA containing nuclear matrix structure.
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PMID:Association of Tat protein and viral mRNA with nuclear matrix from HIV-1-infected H9 cells. 254 27

Following injury or activation in some immune cell lines, elevation of intracellular Ca2+ concentration (Cai2+) is an early and major event that precedes cell death. Agents shown to elevate Cai2+ and to result subsequently in the death of some cells include human immunodeficiency virus (HIV) (in T4+ cells), 25-hydroxy cholesterol, tumor necrosis factor (TNF), cyclosporine, dexamethasone, alpha-interferon, and Ca2+ ionophores. The effects of these agents, both on Cai2+ and on cytotoxicity, are additive. This type of Ca2+-related cytotoxicity may be associated with either accelerated synthesis of triglycerides (TNF), accelerated synthesis of cholesterol ester (25-hydroxy cholesterol), or cholesterol (HIV) and terminally with declining synthesis of structural phospholipid. Agents that can lower Cai2+ (e.g., phorbol esters, diglycerides, lipoproteins [LDL], oleic acid, or serum) under appropriate conditions ameliorate the Ca2+-induced cytotoxicity. Metabolism of other divalent metals, i.e., Zn2+ and Cd2+, also become altered with cell injury, e.g., glucocorticoids elevate Cai2+, but block uptake of Zn2+. These observations support the idea that chronic elevation of Cai2+ by many chemically unrelated agents leads to cell death by creating imbalance both in cell biosynthetic mechanisms--especially in those controlling lipid metabolism--as well as creating imbalances in metabolism of other trace metals, especially Zn2+.
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PMID:Intracellular Ca2+ and cytotoxicity. 257 16

We have synthesized an 18-amino acid peptide that contains the cysteine-rich region of the tat protein from human immunodeficiency virus. Previous experiments in vitro with the intact tat protein have shown that these cysteines serve as metal ligands, causing tat to form metal-linked dimers. Ultraviolet absorption spectra show that the synthetic peptide (tat21-38) binds two Cd2+ or two Zn2+ ions per peptide monomer, and some changes in the circular dichroism spectra are seen as the metals bind. The peptide-metal complexes are completely resistant to proteolytic digestion, and mass spectrometry demonstrates that this peptide forms metal-linked dimers. The peptide can also combine with the intact tat protein to form metal-linked heterodimers. If these heterodimers are unable to trans-activate viral transcription, tat21-38 could be a lead compound for designing drugs to treat acquired immunodeficiency syndrome.
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PMID:Dimerization of the tat protein from human immunodeficiency virus: a cysteine-rich peptide mimics the normal metal-linked dimer interface. 284 63

Rat cell lines were established in which the bacterial chloramphenicol acetyltransferase (CAT) gene under control of the human immunodeficiency virus (HIV) long terminal repeat (LTR) was stably integrated. The cell lines showed a repressed phenotype for CAT expression, but could be induced for it by inhibition of protein synthesis, as well as by heat-shock and chemical inducers of the cellular stress response, such as sodium arsenite, 8-hydroxyquinoline and the heavy metals cadmium and copper. A decameric sequence present in the NF-kB binding sites in the HIV LTR (GGGACTTTCC) resembles the cellular heat-shock core sequence and may therefore be involved in the heat-shock response.
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PMID:Heat-shock induction of the human immunodeficiency virus long terminal repeat. 318 32

Stimulation of antigen receptors of lymphocytes triggers a transitory release of Ca2+ from internal stores and the opening of a transmembrane Ca2+ conductive pathway. The latter underlies the sustained increase of intracellular free calcium concentration, and it seems to be a key event in the Ca(2+)-dependent biochemical cascade leading to T cell proliferation. Alternatively, pharmacological depletion of internal stores by itself activates Ca2+ influx. This has led to the hypothesis that antigen-triggered Ca2+ influx is secondary to Ca2+ release from internal stores. However, the precise relationship between antigen and Ca2+ release-activated Ca2+ currents remains unclear, particularly since neither of them has been electrophysiologically recorded in normal lymphocytes. Using the whole-cell and the perforated configurations of the patch clamp technique on peripheral blood lymphocytes, we found that a low amplitude Ca(2+)-selective current was triggered when intracellular stores were depleted by stimuli such as the intracellular perfusion of inositol triphosphate or thapsigargin and the extracellular perfusion of ionomycin. A similar current was elicited by the cross-linking of the T cell receptor-CD3 complex. This current displayed an inward rectification below 0 mV and was completely blocked by the divalent cation Cd2+. It was very selective for Ca2+ over Na+ and insensitive to changes in chloride concentration. The physiological relevance of this conductance was investigated with the analysis of abnormal Ca2+ signaling in lymphocytes from a patient suffering from a primary immunodeficiency associated with a defective T cell proliferation. Using fura-2 video imaging, an absence of Ca2+ influx was established in the patient's lymphocytes, whereas the Ca2+ release from internal stores was normal. This was the case whether cells were stimulated physiologically through their antigen receptors or with store depleting pharmacological agents. Most importantly, no Ca(2+)-selective current was elicited in these cells. Our data strongly suggest that the Ca2+ release-activated current underlies the sustained Ca2+ influx during antigenic stimulation and that it plays a key role in the immune function.
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PMID:The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. 779 33

Heme and a series of synthetic heme analogs were tested for inhibition of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT) activity. Heme and the protoporphyrin complexes of cadmium, magnesium, and tin significantly inhibited HIV-1 RT, whereas other metalloporphyrins had a lesser or no effect on the enzyme. The mechanism of inhibition was examined with respect to heme and tin protoporphyrin (SnPP), as both compounds have been utilized clinically as treatment for noninfectious disorders. Heme and SnPP inhibited HIV-1 RT in a noncompetitive manner with respect to deoxythymidine triphosphate. Inhibition depended in part on the protoporphyrin structure, because the mesoderivatives of the heme analogs essentially were without effect. Heme also markedly enhanced the inhibitory effect of azidothymidine (zidovudine, AZT) on HIV-1 RT, and the combination of the two compounds showed synergy in inhibiting HIV-1 RT. HIV-1 RT was used to reverse transcribe the glyceraldehyde phosphate dehydrogenase (GAPDH) gene from human kidney. Subsequently, GAPDH cDNA was amplified with Taq polymerase, and electrophoresis showed that HIV-1 RT catalyzed the reverse transcription of human mRNA at a rate comparable to that of Moloney murine leukemia virus. Heme and SnPP prevented cDNA synthesis by HIV-1 RT in this RT-polymerase chain reaction assay. We also examined the effects of these compounds on normal human bone marrow function. Heme stimulated both erythroid and myeloid progenitor colony formation, whereas SnPP was essentially without effect. In contrast, ZnPP had a suppressive effect on hematopoiesis. Finally, we show that heme has a sparing effect against the myelotoxicity of AZT. The results of these studies raise the possibility that combination therapy with AZT and heme, or heme plus an inhibitor of heme catabolism, might have therapeutic potential in the acquired immunodeficiency syndrome.
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PMID:Inhibition of human immunodeficiency virus-1 reverse transcriptase by heme and synthetic heme analogs. 883 64


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