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 AIDS dementia complex (ADC) is a consequence of excessive immune activation driven at least in part by systemic HIV infection and probably brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cytokines or infection with HIV-1. Consequently it has been implicated in ADC pathogenesis. However, macrophages infected with HIV-1 synthesize numerous neurotoxic substances. Therefore we conducted experiments using human fetal brain tissue to determine the relative importance of QUIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-D-tryptophan, an inhibitor of QUIN biosynthesis, was added to half the macrophage cultures to block formation of QUIN. Supernatants containing QUIN (SQpos) or in which QUIN biosynthesis had been inhibited (SQneg) were then added to human fetal brain aggregate cultures. Toxicity was evaluated using lactate dehydrogenase efflux, trypan blue exclusion, immunohistochemistry, image analysis, and electron microscopy. Each technique showed a reduction of toxicity in SQneg-treated cultures. These studies confirm the significance of QUIN as a neurotoxin in ADC and suggest that neuroprotective strategies may have a place in the treatment of this disease.
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PMID:Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages. 940 65

Mixtures of a good hydrogen bond donor, 2,2,2-trifluoroethanol (TFE) or 1,1,1,3,3,3-hexafluroisopropanol, and an acceptor, dimethylformamide (DMF) (1:1, v/v), containing 4% buffer have been described as adequate solvent systems for trypsin-catalyzed peptide fragment condensations [Mihara et al. (1993) Int. J. Pept. Protein Res. 41, 405]. Thus, we decided to study the behaviour of trypsin in such solvent systems. We investigated whether this protease would efficiently catalyze condensations between fragments derived from an analogue of the gp-41 capsid protein of HIV virus or from cholecystokinin-22. None of the reactions carried out yielded the desired condensation products. However, when Fmoc-NLQNLDPSHR-OH and cholecystokinin-12 (H-ISDRDYMGWMDF-NH2) were used as substrates, the last had its R-D peptide bond hydrolyzed producing cholecystokinin-8. The proteolytic activity of this enzyme measured against a fluorogenic peptide derivative was 50 times lower in DMF/TFE containing 5% of aqueous phase than in buffer. Steady-state fluorescence studies in DMF/TFE buffer were performed to examine the structure of this protease in these media. Steady-state spectra obtained with increasing proportions of these two organic solvents in buffer showed that the emission intensities built up. Quenching studies with iodide revealed that the Io/I ratio (where Io and I are the fluorescence emission intensities in the absence and presence of quencher, respectively) changed from 1.2 in aqueous media to 2.2 in DMF/TFE (1:1, v/v) containing 11% 0.2 M Tris-HCl buffer, pH 8.0, for 0.5 M iodide. The complete data indicated a higher exposure of tryptophan residues to the quencher in organic media, probably because of the partial unfolding of the enzyme.
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PMID:Mixtures of trifluoroethanol or hexafluoroisopropanol and dimethylformamide are not of general applicability for peptide condensations catalyzed by trypsin. 949 88

The external envelope glycoprotein (gp125) of human immunodeficiency virus type 2 (HIV-2) contains 22 cysteine residues. The positions of the 11 disulfide bridges in HIV-2 gp125 were determined by analogy with the experimental position of the disulfide bonds found in the gp120 of HIV-1. Peptides expected to mimic all 11 disulfide-bonded domains containing from 13 to 47 amino acids were synthesized by the solid-phase method according to 9-fluorenylmethoxycarbonyl strategy, except for peptide 5, which was assembled according to t-butoxycarbonyl (Boc) strategy. Analysis of all the crude peptides showed that the expected peptides were obtained with good yields, between 75% and 85%. Peptides were purified further by high-performance liquid chromatography (HPLC) on an Aquapore RPC30 C8 column. Peptide homogeneity was more than 90%. For each peptide, linear peptides (L) were SH-iodoacetamidated, whereas cyclization of peptides (C) was performed by air oxidation. Oxidation kinetics was followed with the Ellman test and HPLC. Cyclic peptides were purified by HPLC and characterized by fast atom bombardment mass spectrometry. This analysis showed that a small quantity (<10%) of dimeric peptides (2 and 8) and cyclic peptides containing oxidized methionine or tryptophan residues (4, 9 and 10) were formed. To assess the relevance of conformation for the antigenicity of disulfide-bonded loops of HIV-2 gp125, the antigenicity of linear and cyclic peptides was tested against a set of 76 HIV-2 positive human sera by enzyme-linked immunosorbent assay. Peptides 2, 4 and 9, mimicking the V1, V2 and V3 regions of the external envelope glycoprotein (gp 125) of HIV-2, were the most highly reactive with HIV-2 positive human sera tested at the dilution of 1:50. Cyclic peptides generally were recognized more than linear peptides, as shown by their greater inhibition (2 to 10 times more) of antigen-antibody complexes. Structure-antigenicity of peptide V3, the most reactive peptide (75% of the HIV-2 positive sera tested), was analyzed further. Cyclic peptide 9C had a higher affinity for anti-gp125 antibodies than linear peptide 9L. In addition, circular dichroism showed that linear and cyclic peptides 9 had a similar structure, but when analyzed in aqueous solution or in trifluoroethanol (TFE), the structural difference shown with antibodies was not confirmed. No significant difference was observed between the antigenicity of linear and cyclic peptides 1, 8 and 11, mimicking the C1, C2 and C4 regions of HIV-1 gp125. These peptides were weakly reactive with HIV-2 positive sera. This result agrees with the low immunogenicity of conserved regions.
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PMID:Antigenicity of linear and cyclic peptides mimicking the disulfide loops in HIV-2 envelope glycoprotein: synthesis, reoxidation and purification. 960 17

Fluorescence spectroscopy (both steady-state and time-resolved) was used to study the fragment 579-601 of gp41 ectodomain (HIV-1), a highly conserved sequence and major epitope, regarding (1) structural information, (2) interaction with membrane model systems, and (3) location in the phospholipid bilayer. The peptide was characterized both in its monomeric (after reduction of the disulfide bond between cysteine residues) and in the dimeric forms. The change of the fluorescence anisotropy between monomer and dimer was rationalized on the basis of energy migration, and a distance between the two tryptophan (Trp) residues of approximately 6 A was obtained. Using different fluorescence spectroscopy approaches, it was demonstrated that, despite the fact that monomeric gp41 fragment incorporates in the membrane model systems studied, the dimeric form does not interact with these vesicles. A methodology based on the increase of the mean fluorescence lifetime averaged by the preexponentials was derived, to obtain the partition coefficient of the peptide in the different lipid systems. Fluorescence quenching using lipophilic probes and red edge excitation shift (REES) were used to study the location of the gp41 fragment in the membrane. It was concluded that the Trp residue is located in a shallow position, near the interface. The REES results show an uncommonly large wavelength shift (18 nm) for the gp41 fragment incorporated in the membrane. Our results are consistent with a "two steps" model for the gp41 fusion mechanism similar to the one proposed for influenza virus hemagglutinin.
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PMID:Interaction of the major epitope region of HIV protein gp41 with membrane model systems. A fluorescence spectroscopy study. 962 29

This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV-infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.
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PMID:Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. 965 28

Pellagra was diagnosed in a 48-year-old female patient with a bullous skin disease. The skin disease with purple/red sharply demarcated spots on hands and feet had worsened after sun exposure. She was a chronic alcoholic and for the last few months she had had diarrhoea. The treatment included vitamin B3, vitamin B complex and a high-quality protein diet. Within three days her skin disease improved. Pellagra is caused by a deficiency of nicotinamide or of its precursor tryptophan. It may occur in patients with dietary deficiency diseases (e.g. chronic alcoholics), carcinoid syndrome, HIV infections and drugs: fluorouracil, isoniazid, chloramphenicol and mercaptopurine. Pellagra leads to the triad: dermatitis, diarrhoea and dementia, eventually followed by death. The skin changes are characteristic and pathognomonic. Recognition of pellagra is important; the prognosis is good after treatment.
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PMID:[Pellagra (deficiency of vitamin B3 or of the amino acid tryptophan): a disease still extant in the Netherlands]. 985 71

Evolutionary conservation of homologous genes that cause related phenotypes in humans and Drosophila help to unravel genes implicated in polygenic human diseases. Among them are neurodegenerative disorders, such as Huntington, Parkinson, Alzheimer and HIV-induced diseases. They are characterized by a late onset disturbances of memory, changes in volumetric indices of the brain structures involved in memory formation, synaptic and glial pathology, and altered content of the intermediates of the kynurenine pathway, the endogenous modulators of the NMDA receptors. This pathway in conserved in insects, rodents and humans. We, therefore, studied the effects of aberrant tryptophan metabolism on memory, brain plasticity, synaptic and glial immunoreactivity in the Drosophila mutants vermilion (no kynurenines) and cinnabar (excess of neuroprotective kynurenic acid) over the life time. The mutant vermilion demonstrated gradual decline of 3-th memory performance and complete memory failure on the 28th day of life in a paradigm of conditioned courtship suppression. A drastic increase in the volume of the calyces of the mushroom bodies, and a decay in immunochemical staining of this brain structure with antibodies to synaptic protein csp and glia, precede the age-dependent memory defect and develop from the 12th day of adult life.
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PMID:Age-dependent changes in memory and mushroom bodies in the Drosophila mutant vermilion deficient in the kynurenine pathway of tryptophan metabolism. 1038 74

The Eps15 homology (EH) domain is a protein-protein interaction module that binds to proteins containing the asparagine-proline-phenylalanine (NPF) or tryptophan/phenylalanine-tryptophan (W/FW) motif. EH domain-containing proteins serve important roles in signaling and processes connected to transport, protein sorting, and organization of subcellular structure. Here, we report the solution structure of the apo form of the EH1 domain of mouse Eps15, as determined by high-resolution multidimensional heteronuclear NMR spectroscopy. The polypeptide folds into six alpha-helices and a short antiparallel beta-sheet. Additionally, it contains a long, structured, topologically unique C-terminal loop. Helices 2-5 form two EF-hand motifs. Structural similarity and Ca(2+) binding properties lead to classification of the EH1 domain as a member of the S100 subclass of EF-hand-containing proteins, albeit with a unique set of interhelical angles. Binding studies using an eight-residue NPF-containing peptide derived from RAB, the cellular cofactor of the HIV Rev protein, show a hydrophobic peptide-binding pocket formed by conserved tryptophan and leucine residues.
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PMID:The EH1 domain of Eps15 is structurally classified as a member of the S100 subclass of EF-hand-containing proteins. 1047 Dec 76

A multi-component vaccine has been defined, which contains six different synthetic 24- to 32-amino acid lipopeptides derived from the sequence of HIV-1 proteins. The physicochemical properties of the lipopeptide components were compatible with multi-dimensional analysis, using RP-HPLC, Edman sequencing, electrospray mass spectrometry, and 2D-NMR. Detailed analysis of the impurity profiles led to the detection and evaluation of the relative proportions of most by-products: several contaminants resulted from the formation of acetylated fragments, transpeptidation reactions with succinimide or piperidide formation, or methionine and/or tryptophan mono-oxidations. The first batch to be produced underwent extensive pharmacotoxicological testings to confirm its safety; this vaccine candidate has now been used in phase I clinical trials. Despite the complexity of such multi-lipopeptide vaccines, our findings suggest the possibility of preparing a clear and precise assignment of by-products to toxicologically qualified impurities in the eventuality of a future production of several successive batches.
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PMID:Characterization of a multi-lipopeptides mixture used as an HIV-1 vaccine candidate. 1050 50

The structure of the 56 amino acid nucleocapsid protein NCp10 of retrovirus MoMuLV, which contains a single CX(2)CX(4)HX(4)C-type zinc finger, has been determined previously by NMR. The important role of NCp10 (or NCp7 for HIV-1) in the retroviral life cycle seems mainly related to their preferential binding to single-stranded nucleic acids. We report here the structure of the complex formed between the biologically active (14-53)NCp10 and the oligonucleotide d(ACGCC) in aqueous solution determined by 2D (1)H NMR based methods. The aromatic residue Trp(35) of NCp10 directs nucleic acid complexation as shown by its complete fluorescence quenching upon addition of d(ACGCC). (1)H and (31)P NMR studies support the insertion of Trp(35) between the G(3) and C(4) bases. A total of 577 NOE distance restraints, of which 40 were intermolecular, were used for the structure determination. The zinc finger provides a well-defined surface for the binding of d(ACGCC) through hydrophobic interactions and tryptophan stacking on the guanine. This latter interaction was also observed in the NMR-derived structures of the complexes between NCp7, which contains two successive zinc fingers, and single-stranded DNA and RNA, supporting the proposal for a major role played by aromatic residues of NCp proteins in nucleic acid recognition. Upon binding to the nucleotide a new loop in NCp10 that participates in the intermolecular interaction is formed. Additional interactions provided by positively charged residues surrounding the zinc finger appear necessary for tight binding. The structure of the complex NCp10-d(ACGCC) gives a structural explanation for the loss of virus infectivity following point mutations in the finger domain.
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PMID:NMR structure of the complex between the zinc finger protein NCp10 of Moloney murine leukemia virus and the single-stranded pentanucleotide d(ACGCC): comparison with HIV-NCp7 complexes. 1052 68


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