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)

HIV-1 gp120 and truncated forms were expressed in HeLa T4 cells by vaccinia recombinant viruses. The truncated gp120 molecules consisted of N-terminal overlapping envelope proteins of 204, 287 and 393 amino acids respectively. Immunoprecipitation with specific monoclonal antibodies and SDS-PAGE analyses of HIV-1 gp120 revealed bands corresponding to low amounts of secreted and cell-bound stable dimers. In contrast, the truncated forms of gp120 expressed larger amounts of SDS-stable putative dimers and the amounts observed were inversely proportional to their size. The shortest gp120 mutant (204 aa) was found to be secreted almost exclusively as a dimer. The processing of gp120 and its truncated forms was further investigated in the presence of inhibitors of N-glycosylation. Monomers and dimers migrated on gels with the same relative changes, confirming that the protein with the higher molecular weight is a multimer of the smaller one. The putative dimeric form of the truncated gp120s could be stabilized by chemical cross-linking. Finally, the possible existence of an association domain in the N-terminal 204 amino acids (aa) of gp120 is discussed.
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PMID:Self-association of truncated forms of HIV-1 gp120. 921 91

The HIV-1 capsid protein (CA) makes an essential interaction with the human peptidyl prolyl isomerase, cyclophilin A (CypA), that results in packaging of CypA into the virion at a CA to CypA stoichiometry of approximately 10:1. The 231 amino acid residue capsid protein is composed of an amino-terminal CypA binding domain (1 to approximately 151; CA151) and a carboxyl-terminal dimerization domain (approximately 151 to 231). We find that CypA binds dimeric CA and monomeric CA151 with identical intrinsic affinities (K[d] = 16(+/-4) microM). This result demonstrates that capsid dimerization and cyclophilin A binding are not thermodynamically coupled and suggests that the substoichiometric ratio of CypA in the HIV-1 virion results from the intrinsic stability of the CA/CypA complex. In the known co-crystal structure of the CA151/CypA complex, CypA binding is mediated exclusively by an exposed capsid loop that spans residues Pro85 to Pro93. The energetic contributions to CypA binding were quantified for each residue in this loop, and the results demonstrate that the Gly89-Pro90 dipeptide is the primary cyclophilin A recognition motif, with Pro85, Val86, His87, Ala88, and Pro93 also making energetically favorable contacts. These studies reveal that the active site of CypA, which can catalyze the isomerization of proline residues in vitro, also functions as a sequence-specific, protein-binding motif in HIV-1 replication.
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PMID:Molecular recognition in the HIV-1 capsid/cyclophilin A complex. 922 41

The solution structure of the N-terminal zinc binding domain (residues 1-55; IN1-55) of HIV-1 integrase has been solved by NMR spectroscopy. IN1-55 is dimeric, and each monomer comprises four helices with the zinc tetrahedrally coordinated to His 12, His 16, Cys 40 and Cys 43. IN1-55 exists in two interconverting conformational states that differ with regard to the coordination of the two histidine side chains to zinc. The different histidine arrangements are associated with large conformational differences in the polypeptide backbone (residues 9-18) around the coordinating histidines. The dimer interface is predominantly hydrophobic and is formed by the packing of the N-terminal end of helix 1, and helices 3 and 4. The monomer fold is remarkably similar to that of a number of helical DNA binding proteins containing a helix-turn-helix (HTH) motif with helices 2 and 3 of IN1-55 corresponding to the HTH motif. In contrast to the DNA binding proteins where the second helix of the HTH motif is employed for DNA recognition, IN1-55 uses this helix for dimerization.
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PMID:Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. 922 50

The aggregation and structural properties of the synthetic C-terminal half [Ala330, Ala350(270-373; 104-mer)] polypeptide from HIV-1 p24gag were studied. In concentrated solutions the synthetic polypeptide aggregated to tetramers which, upon dilution, gave a mixture of monomeric and dimeric and dimeric species. These results correlated well with the in vitro aggregation properties of recombinant p24. The tetrameric form of the synthetic polypeptide had a pI which differed by about four units from that of the mixture of monomeric and dimeric species. CD studies indicated that the latter contained, in aqueous solutions, a compact molecule lacking, however, a defined tertiary structure. Addition of MeOH to aqueous solutions of both tetramer and monomer/dimer mixture induced a more defined structure, which was assigned to that of an alpha + beta protein in agreement with secondary structure predictions. A model of the dimeric form of the 104-mer, which takes into account the results presented here and those from a study on the specificity of a set of anti-104-mer MoAbs, is presented. Finally, the results indicated that the structure of the 104-mer in its dimeric form is similar to that adopted by the same sequence when part of full-length p24.
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PMID:The structural and aggregation properties of the synthetic C-terminal half (104-mer) polypeptide from HIV p24gag resemble those of full-length protein. 923 Apr 82

New monomeric (korupensamine E, 6) and dimeric (michellamines D-F, 7-9) naphthylisoquinoline alkaloids have been isolated from exracts of the tropical liana Ancistrocladus korupensis. Structures were determined by spectroanalytical methods, and stereochemistry was defined through NOE correlations, chemical degradation, and CD spectroscopy. Michellamines D-F exhibited in vitro HIV-inhibitory activity comparable to michellamine B, and korupensamine E exhibited in vitro antimalarial activity comparable to korupensamines A-D.
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PMID:Michellamines D-F, new HIV-inhibitory dimeric naphthylisoquinoline alkaloids, and korupensamine E, a new antimalarial monomer, from Ancistrocladus korupensis. 924 70

The p2gag peptide (AEAMSQVTNTATIM) processed from HIV-1 Pr55gag by HIV-1 protease was identified as a suicide inhibitor of the enzyme (Ki = 30 microM and IC50 = 10 microM for the synthetic peptide substrate, succinyl-SQNYPIVQ), and potently inhibited the proteolytic cleavage of the viral precursor protein (Pr55gag) into functional structural units (p17gag and p24gag) in vitro. The nonapeptide (AEAMSQVTN) derived from N-terminus of the p2gag peptide exhibits a potent inhibitory action on HIV-1 protease, but the other peptides (AEAMSQ, AEAMSQV, AEAMSQVT, VTN and VTNTATIM) do not. It was determined by exclusion gel chromatography that HIV-1 protease after treatment of the synthetic p2gag peptide dissociated from the active dimeric form to an inactive monomeric form. The p2gag peptide and HIV-1 protease were also detected in HIV-1 viral particles using both matrix-assisted laser desorption/ionization time-of-flight mass spectrometric (MALDI TOF-MS) and western immunoblot analyses. Taken together, these results suggest that the p2gag peptide is the inhibitor of preventing dimerization of HIV-1 protease and that the enzyme activity is completely suicide inhibited with the accumulated p2gag peptide producing by the processing of Pr55gag during viral maturation.
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PMID:The p2gag peptide, AEAMSQVTNTATIM, processed from HIV-1 Pr55gag was found to be a suicide inhibitor of HIV-1 protease. 942 62

In vitro experiments indicate that components of the host present in body fluids may prevent the attachment of human immunodeficiency virus type 1 (HIV-1) to target cells. Fibronectin (Fn), a dimeric 440-kDa extracellular matrix adhesion protein, is secreted by mesenchymal cells and assembled into insoluble matrices. Fn exerts important effects on cell growth and differentiation through a number of discrete functional domains. Several microorganisms are known to bind Fn. We show that, under physiological conditions, HIV-1 gp120 and gp160 are capable of binding plasma and cellular Fn as well as laminin and vitronectin. Experiments were set up to analyze in detail the binding of HIV gp120 and gp160 to Fn. The gp120 and gp160 specifically recognize the C-terminal heparin-binding domain of Fn (Fn-CTHBD) with a calculated KD of 2.8 x 10(-7) M for gp160. Binding of gp160 to Fn-CTHBD is a saturable and specific process that is blocked by antibodies to Fn-CTHBD and by heparin and is inhibited to a minor extent by heparan sulfate and dextran sulfate. These observations suggest that gp120/160 specifically recognize the III15 repeat within Fn-CTHBD. Intact Fn and Fn-CTHBD strongly inhibit the interaction of gp120/160 with soluble CD4 and, under low serum conditions, are capable of neutralizing the infectivity of HIV-1 for CD4-positive T cells. Thus, Fn that is present in plasma and mucinous secretions may well affect HIV infectivity and virus distribution in vivo.
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PMID:Heparin-binding domain of human fibronectin binds HIV-1 gp120/160 and reduces virus infectivity. 944 8

The fixed-point algebraic method [Storer and Cornish-Bowden (1976) Biochem. J. 159, 1-5] for computing the concentrations at equilibrium of complex biochemical mixtures fails for many binding stoichiometries, especially those that include molecular self-association. A typical example is the monomer-dimer-tetramer equilibrium. This paper reports two main results. First, the above algorithm is analysed theoretically to predict for which binding stoichiometries it succeeds and for which it will fail. Secondly, an alternative algorithm is described for self-associating biochemical systems. Illustrative examples are based on the dimeric proteinase from HIV.
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PMID:Fixed-point methods for computing the equilibrium composition of complex biochemical mixtures. 953 99

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a dimeric enzyme consisting of p66 and p51 subunits. The functional role of the p51 subunit remains elusive since all the catalytic functions appear to be executed through the p66 subunit. We report here that the p51 subunit, in addition to providing structural support to the p66 subunit, may be involved in facilitating the loading of the p66 subunit on to the template-primer (TP). This possibility is supported by following observations: (i) Upon binding to the TP, the p51 subunit can be dissociated by acetonitrile treatment and the template-primer-bound p66 monomer alone is capable of catalyzing DNA synthesis. (ii) Photo-cross-linking of template-primer to HIV-1 RT is abolished by dissociation of the p51 subunit prior to the TP binding but remains unaffected after the TP binding step. (iii) The p66-TP covalent complex selectively generated by UV irradiation and separated by gel electrophoresis can incorporate a single nucleotide in situ upon its renaturation in the gel. (iv) Treatment of HIV-1 RT with (tert-butyldimethylsilyl)spiroaminooxathioledioside (TSAO), an inhibitor that specifically binds to the beta7 beta8 loop of p51, destabilizes the heterodimeric enzyme, resulting in the subsequent loss of DNA binding.
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PMID:The p51 subunit of human immunodeficiency virus type 1 reverse transcriptase is essential in loading the p66 subunit on the template primer. 955 23

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


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