UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-infected injection drug users (IDUs) often suffer from serious nutritional deficiencies. This is a concern because plasma levels of micronutrients such as vitamin B12, zinc, and selenium have been correlated with mortality risk in HIV-positive populations. Injection drug use also increases lipid peroxidation and other indicators of oxidative stress, which, combined with antioxidant deficiencies, can stimulate HIV-1 replication through activation of NF-kappaB transcription factors, while weakening immune defenses. As detailed herein, these prooxidant stimuli can also increase the pathogenic effects of HIV-1 by another mechanism, involving viral selenoproteins. Overlapping the envelope coding region, HIV-1 encodes a truncated glutathione peroxidase (GPx) gene (see #6 in reference list). Sequence analysis and molecular modeling show that this viral GPx (vGPx) module has highly significant structural similarity to known mammalian GPx, with conservation of the catalytic triad of selenocysteine (Sec), glutamine, and tryptophan. In addition to other functions, HIV-1 vGPx may serve as a negative regulator of proviral transcription, by acting as an NF-kappaB inhibitor (a known property of cellular GPx). Another potential selenoprotein coding function of HIV-1 is associated with the 3' end of the nef gene, which terminates in a conserved UGA (potential Sec) codon in the context of a sequence (Cys-Sec) identical to the C-terminal redox center of thioredoxin reductase, another cellular regulator of NF-kappaB. Thus, in combination with known cellular mechanisms involving Se, viral selenoproteins may represent a unique mechanism by which HIV-1 monitors and exploits an essential micronutrient to optimize its replication relative to the host.
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PMID:Nutrition, HIV, and drug abuse: the molecular basis of a unique role for selenium. 1112 28

Several chemokine receptors (CKRs) act as coreceptors of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and simian immunodeficiency virus (SIV). These CKRs interact with the V3 domain of the envelope (env) protein of HIV/SIV. In this study, we found that the amino acid sequences of two chemokines (SDF-1beta and RANTES), whose receptors (CXCR4 and CCR5) act as major coreceptors for HIV-1, HIV-2 or SIV, showed statistically significant similarity to those of the region containing the third variable (V3) and the third conserved (C3) domains (the V3--C3 domain) of the env protein of HIV-1 and HIV-2. We made a multiple alignment of amino acid sequences for 24 chemokines and the region encompassing the second conserved (C2), V3 and C3 domains (the C2--V3--C3 region) of 10 strains of HIV/SIV. Surprisingly, the hydropathic profile and several important amino acids for protein conformation, such as cysteine and tryptophan, are remarkably conserved between chemokines and the V3--C3 region of HIV/SIV. Moreover, hydrophobic amino acids, such as leucine, isoleucine and valine, are found to be clustered both in the amino-terminal region of chemokines and the C2 domain of HIV/SIV. Thus, chemokines have significantly similar profiles of amino acid properties to those of the C2--V3--C3 region of the env protein of HIV/SIV. These findings raise a hypothesis that chemokines and the C2--V3--C3 region have a common origin. Namely, the HIV/SIV ancestor incorporated a chemokine gene into its env gene. The captured chemokine gene has rapidly diverged by frequent mutations specific to the retroviral genome, and thereby obtained the ability to interact with various CKRs in a short period of time. This paper proposes that the capture of a ligand gene of the host cells into the viral genome may be one of the important mechanisms of viral evolution to expand its host range and generate new viral species.
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PMID:How can human and simian immunodeficiency viruses utilize chemokine receptors as their coreceptors? 1116 77

A series of phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT) bearing aliphatic amino acid methyl esters (3a, 3c, 4a, 4c, 5-7) and methyl amides (3b, 3d, 4b, 4d) was prepared and evaluated for anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs). These compounds, which showed no cytotoxicity at concentrations of 100 microM, were effective at inhibiting HIV-1 replication at concentrations of 0.08-30 microM. Since the D-phenylalanine and D-tryptophan derivatives exhibited equivalent or enhanced antiviral activity compared to their L-counterparts, there appears to be no specific stereochemical requirement for the amino acid side chain. In addition, except for the D-phenylalanine derivatives, the methyl amides had greater antiviral activity than the corresponding methyl esters. On the basis of the observed antiviral activity of AZT phosphoramidate monoesters 3a and 4a in PBMCs and CEM cells, the mechanism of action of these two compounds was investigated. AZT-MP and substantial amounts of either phosphoramidate were detected in PBMCs and CEM cells treated with either 3a or 4a. Biological mechanistic studies demonstrated that 3a and 4a affect viral replication at a stage after virus entry and preceding viral DNA integration. Quantitation of the intracellular levels of AZT-TP in PBMCs and CEM cells treated with 3a and 4a in the presence and absence of exogenous thymidine correlated the intracellular levels of AZT-TP to the antiviral activity and suggested that AZT-TP was responsible for the activity observed. In addition, the reduced toxicity of 3a and 4a toward CEM cells relative to AZT correlated with reduced levels of total phosphorylated AZT and not AZT-TP. Stable carbamate analogues of 3a and 4a were prepared and shown to inhibit the production of AZT-MP from cell-free extracts of CEM cells, further suggesting that a phosphoramidate hydrolase may be responsible for intracellular P-N bond cleavage. Taken together, these results suggest that the biological activity and intracellular metabolism of nucleoside phosphoramidate monoesters are distinct from that of phosphoramidate diesters.
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PMID:Amino acid phosphoramidate monoesters of 3'-azido-3'-deoxythymidine: relationship between antiviral potency and intracellular metabolism. 1117 Jun 32

Quinolinate (pyridine-2,3-dicarboxylic acid, Quin) is a neurotoxic tryptophan metabolite produced mainly by immune-activated macrophages. It is implicated in the pathogenesis of several brain disorders including HIV-associated dementia. Previous evidence suggests that Quin may exert its neurotoxic effects not only as an agonist on the NMDA subtype of glutamate receptor, but also by a receptor-independent mechanism. In this study we address ability of ferrous quinolinate chelates to generate reactive oxygen species. Autoxidation of Quin-Fe(II) complexes, followed in Hepes buffer at pH 7.4 using ferrozine as the Fe(II) detector, was found to be markedly slower in comparison with iron unchelated or complexed to citrate or ADP. The rate of Quin-Fe(II) autoxidation depends on pH (squared hydroxide anion concentration), is catalyzed by inorganic phosphate, and in both Hepes and phosphate buffers inversely depends on Quin concentration. These observations can be explained in terms of anion catalysis of hexaaquairon(II) autoxidation, acting mainly on the unchelated or partially chelated pool of iron. In order to follow hydroxyl radical generation in the Fenton chemistry, electron paramagnetic resonance (EPR) spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was employed. In the mixture consisting of 100 mM DMPO, 0.1 mM Fe(II), and 8.8 mM hydrogen peroxide in phosphate buffer pH 7.4, 0.5 mM Quin approximately doubled the yield of DMPO-OH adduct, and higher Quin concentration increased the spin adduct signal even more. When DMPO-OH was pre-formed using Ti3+ /hydrogen peroxide followed by peroxide removal with catalase, only addition of Quin-Fe(II), but not Fe(II), Fe(III), or Quin-Fe(III), significantly promoted decomposition of pre-formed DMPO-OH. Furthermore, reaction of Quin-Fe(II) with hydrogen peroxide leads to initial iron oxidation followed by appearance of iron redox cycling, detected as slow accumulation of ferrous ferrozine complex. This phenomenon cannot be abolished by subsequent addition of catalase. Thus, we propose that redox cycling of iron by a Quin derivative, formed by initial attack of hydroxyl radicals on Quin, rather than effects of iron complexes on DMPO-OH stability or redox cycling by hydrogen peroxide, is responsible for enhanced DMPO-OH signal in the presence of Quin. The present observations suggest that Quin-Fe(II) complexes display significant pro-oxidant characteristics that could have implications for Quin neurotoxicity.
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PMID:Quinolinic acid-iron(ii) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction. 1137 28

Two molecular dynamics simulations have been carried out on the HIV-1 integrase catalytic core starting from fully determined crystal structures. During the first one, performed in the absence of divalent cation (6-ns long), the catalytic core took on two main conformations. The conformational transition occurs at approximately 3.4 ns. In contrast, during the second one, in the presence of Mg(2+) (4-ns long), there were no such changes. The molecular dynamics simulations were used to compute the fluorescence intensity decays emitted by the four tryptophan residues considered as the only chromophores. The decay was computed by following, frame by frame, the amount of chromophores that remained excited at a certain time after light absorption. The simulation took into account the quenching through electron transfer to the peptide bond and the fluorescence resonance energy transfer between the chromophores. The fit to the experimental intensity decays obtained at 5 degrees C and at 30 degrees C is very good. The fluorescence anisotropy decays were also simulated. Interestingly, the fit to the experimental anisotropy decay was excellent at 5 degrees C and rather poor at 30 degrees C. Various hypotheses such as dimerization and abnormal increase of uncorrelated internal motions are discussed.
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PMID:HIV-1 integrase catalytic core: molecular dynamics and simulated fluorescence decays. 1142 30

From the screening of a microbial extract library, isocomplestatin (1), a new axial-chiral isomer of complestatin (2) which is a known rigid bicyclic hexapeptide, was identified as a potent natural product inhibitor of HIV-1 integrase, a unique enzyme responsible for viral replication. Isocomplestatin showed inhibitory activities (IC(50)) in coupled 3'-end processing/strand transfer (200 nM), strand transfer (4 microM), and HIV-1 replication (200 nM) in virus-infected cells. Attempted large-scale isolation of 1 by the literature method, used for the isolation of complestatin, led to lower yield and limited availability. We have developed several new, two-step, high-yielding absorption/elution methods of isolation based on reverse-phase chromatography at pH 8 that are applicable to scales from one gram to potential industrial quantities. We have also discovered and determined the structure of two new congeners of 1, namely, complestatins A (4) and B (5), with almost equal HIV-1 integrase activity. They differ from 1 at C2' and C3' of the tryptophan moiety (residue F). Selective acid hydrolysis of chloropeptin I (3), itself a known acid-catalyzed rearranged isomer of 1 and 2 (8'- vs 7'-substitution in tryptophan residue F, respectively), an isomer of complestatin, and isocomplestatin resulted in a number of fragments (6-10) with retention of most of the HIV-1 integrase activity. The structure-activity relationship as revealed by these compounds could possibly lead to the design of better inhibitors or understanding of the HIV-1 integrase target.
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PMID:The complestatins as HIV-1 integrase inhibitors. Efficient isolation, structure elucidation, and inhibitory activities of isocomplestatin, chloropeptin I, new complestatins, A and B, and acid-hydrolysis products of chloropeptin I. 1147 15

Self-assembly of HIV-1 integrase (IN) in solution has been studied previously by time-resolved fluorescence, using tryptophan anisotropy decay. This approach provides information on the size of macromolecules via the determination of rotational correlation times (theta). We have shown that, at submicromolar concentration, IN is characterized by a long rotational correlation time (theta(20 degrees C) = 90-100 ns) corresponding to a high-order oligomeric form, likely a tetramer. In the present work, we investigated the self-assembly properties of the DNA-bound IN by using three independent fluorophores. Under enzymatic assay conditions (10(-7) M IN, 2 x 10(-8) M DNA), using either fluorescein-labeled or fluorescent guanosine analog-containing oligonucleotides that mimic a viral end long terminal repeat sequence, we found that the DNA-IN complex was characterized by shorter theta(20 degrees C) values of 15.5-19.5 and 23-27 ns, calculated from experiments performed at 25 degrees C and 37 degrees C, respectively. These results were confirmed by monitoring the Trp anisotropy decay as a function of the DNA substrate concentration: the theta of IN shifted from 90-100 ns to lower values (<30 ns) upon increasing the DNA concentration. Again, the normalized theta(20 degrees C) values were significantly higher when monitored at 37 degrees C as compared with 25 degrees C. These results indicate that upon binding the viral DNA end, the multimeric enzyme undergoes a dissociation, most likely into a homogeneous monomeric form at 25 degrees C and into a monomer-dimer equilibrium at 37 degrees C.
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PMID:DNA binding induces dissociation of the multimeric form of HIV-1 integrase: a time-resolved fluorescence anisotropy study. 1150 11

A series of hydrophobic, water soluble and non-toxic amino acid phosphoramidate monoesters of dideoxyadenosine (ddA) and 3'-azido-3'-deoxythymidine were shown to inhibit the replication of HIV-1 in human peripheral blood mononuclear cells (PBMC) from two donors. The tryptophan methyl ester phosphoramidates of AZT and ddA were equally potent (EC50S = 0.3-0.4 microM), while the phenyl methyl ester of ddA was 40- to 100- fold more potent than the AZT derivatives. The alaninyl methyl ester of AZT was found to be 70- fold more potent than the ddA derivative. The methyl amide derivatives were found to be 5-20 fold less active than the methyl esters for the ddA series, while for AZT the derivatives were found to be of similar potency or 60- to 166- fold more potent than the methylesters.
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PMID:Comparison of the antiviral activity of hydrophobic amino acid phosphoramidate monoesters of 2'3'-dideoxyadenosine (DDA) and 3'-azido-3'-deoxythymidine (AZT). 1155 46

The membrane-proximal tryptophan-rich region of the HIV transmembrane glycoprotein, gp41, plays an important role in the membrane fusion reaction. Using NMR spectroscopy, we have studied the tertiary structure of a synthetic 19-residue amidated peptide (NH2-KWASLWNWFNITNWLWYIK-CONH2) corresponding to this region in membrane-mimetic environments. Initial experiments in sodium dodecyl sulfate/H2O micelles and trifluoroethanol gave poor results, because of low solubility. However, in dodecylphosphocholine micelles, we obtained excellent 500 and 800 MHz NMR spectra, suggesting that the peptide has a preference for a zwitterionic membrane-like environment. The final NMR structures demonstrated a well-defined helical peptide with a backbone rmsd of 0.47 +/- 0.18 A. Four of the five tryptophan residues, as well as the tyrosine residue, formed a "collar" of aromatic residues along the axial length of the helix. By analogy to related tryptophan-rich antimicrobial peptides, the structure indicates that the aromatic residues of the HIV peptide are positioned within the membrane-water interface of a phospholipid bilayer. This is confirmed by the observation of direct NOEs between the aromatic residues of the peptide to the headgroup and interfacial protons of prototonated dodecylphosphocholine. The bulk of the polar residues are positioned on one face of this structure, with the hydrophobic phenylalanine side chain on the opposing face, forming an amphipathic structure. This work shows that the Trp-rich membrane-proximal region of HIV and related viruses can bind to the surfaces of zwitterioninc membranes in a "Velcro-like" manner.
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PMID:The membrane-proximal tryptophan-rich region of the HIV glycoprotein, gp41, forms a well-defined helix in dodecylphosphocholine micelles. 1158 56

The interaction of dNTPs with the active site of HIV-1 reverse transcriptase (HIV RT) has been investigated. The kinetic parameters of primer elongation catalyzed by wild-type HIV-1 RT and two of its mutants with substitutions for Tyr115 using dTTP and two of its photoreactive analogs were determined. The substitution for Tyr115 with alanine or tryptophan resulted in an increase in K(m) values of dTTP and its analogs. Wild-type RT and its mutants were photoaffinity modified using photoreactive primer synthesized in situ. The modification was made in two variants: direct photocross-linking under UV irradiation and photosensitized modification using Pyr-dUTP as a sensitizer. The use of the sensitizer decreased the number of modification products and increased selective labeling of the catalytic subunit of both the mutant and wild-type RT.
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PMID:Investigation of the dNTP-binding site of HIV-1 reverse transcriptase using photoreactive analogs of dNTP. 1170 83

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