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

Recombinant human immunodeficiency virus (HIV-1) Tat protein added to the culture medium of rat cerebellar neurons promoted aggregation and formation of spoke-like neurites in a dose-dependent manner. Tat proteins containing mutations in the Arg-Gly-Asp (RGD) cell adhesion motif or a deletion of the cysteine-rich domain had no effect on neuronal morphology. In contrast, a Tat protein that contained a deletion of the proline-rich domain promoted neuronal aggregation. Aggregation of neurons was inhibited by the addition of monoclonal antibodies directed against the RGD and basic domains of Tat, but not against the proline-rich domain. The same domains of Tat required to induce aggregation also mediated adhesion of neurons to Tat-coated substrates. The HIV-2 Tat protein, which lacks an RGD sequence but contains cysteine-rich and basic domains similar to HIV-1 Tat, induced aggregation and acted as a substrate for adhesion when added at higher concentrations than HIV-1 Tat. Vitronectin, fibronectin, and RGD-containing peptides did not induce morphological changes in neurons or act as substrates for adhesion. The ability of Tat to induce morphological changes and promote adhesion was independent of the ability of Tat to transactivate HIV gene expression. Our results suggest that extracellular Tat protein most likely alters neuronal morphology and mediates adhesion by acting in a manner similar to an extracellular matrix protein.
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PMID:Extracellular human immunodeficiency virus type 1 Tat protein promotes aggregation and adhesion of cerebellar neurons. 878 30

In view of the high antigenic variability of human immunodeficiency virus type 1 (HIV-1), a vaccine against AIDS must induce an immune response to epitopes as invariable as possible among the various virus strains and clones. Previously the highly conserved six amino acid sequence Glu-Leu-Asp-Lys-Trp-Ala (ELDKWA) from gp41, defining the epitope of the human MAb 2F5, was shown to elicit HIV-1-neutralizing antibodies when presented on haemagglutinin of influenza virus. We investigated the immunogenic potential of the MAb 2F5 epitope and two of its major escape epitopes as internal fusions to the hepatitis B virus (HBV) surface antigen (HBsAg). Recombinant HBsAg-HIV proteins produced in the methylotrophic yeast Pichia pastoris self-assembled into 22 nm lipoprotein particles. Mice immunized with these particles developed an anti-HBsAg immune response in a range that is considered to be protective against HBV infection in humans. More importantly, antisera had extremely high titres of antibodies reactive with a structurally flexible form of the HIV-1 epitope, whereby strong cross-reactivity with the escape variants of the epitope was observed. Although HIV-1 gp 160 and the ectodomain of gp41 containing the epitope were significantly recognized, the antisera failed to neutralize HIV-1 in vitro. These data, together with those on the haemagglutinin-ELDKWAS fusion suggest that the ability of the MAb 2F5 epitope to induce neutralizing antibodies depends on the molecular context in which it is presented. Therefore, further characterization of secondary and tertiary structure requirements of the epitope is indispensable for the full exploitation of its potential as a vaccine component.
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PMID:Immunogenic presentation of a conserved gp41 epitope of human immunodeficiency virus type 1 on recombinant surface antigen of hepatitis B virus. 881 Sep 96

Tyr115 is located in the vicinity of the polymerase catalytic site of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Site-directed mutagenesis was used to generate variant enzymes having Phe, Trp, Ala, Ser, Asp or Lys instead of Tyr115. The substitution of Tyr115 by Phe renders a fully active polymerase, displaying similar kinetic parameters, processivity and misinsertion fidelity of DNA synthesis as the wild-type enzyme. In contrast, the replacement of Tyr by Asp or Lys produced enzymes with a very low polymerase activity. The activity of the variant enzymes having Trp, Ala or Ser instead of Tyr115 was reduced significantly, particularly when poly(rA)484 was used as template. This effect was caused by a dramatic increase in the Km value for dTTP, and was detected using a DNA template mimicking a proviral HIV-1 gag sequence. Misinsertion fidelity assays revealed that mutants Y115W, Y115A and Y115S had a higher misinsertion efficiency than the wild-type reverse transcriptase. The low fidelity of these mutants appears to be related to nucleotide recognition rather than altered DNA-DNA template-primer interactions. The effects observed on the steady state kinetic constants, processivity and fidelity were mediated by the 66 kDa subunit, as demonstrated using chimeric heterodimers with the Y115A substitution in either p66 or p51.
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PMID:Human immunodeficiency virus type 1 reverse transcriptase: role of Tyr115 in deoxynucleotide binding and misinsertion fidelity of DNA synthesis. 886 70

Proline-rich peptides are known to adopt preferentially the extended polyproline II (PPII) helical conformation, which is involved in several protein-protein recognition events. By resorting to molecular modelling techniques, we wished to investigate the extent to which PPII helices could be used for the formation of isochelical peptide-DNA complexes leading to the selective recognition of the major groove of B-DNA. For that purpose, we have grafted to a cationic intercalator, 9-amino-acridine, an oligopeptide having the sequence: Pro- Arg-Pro-Pro-Arg-Pro-Pro-Arg-Pro-Pro-Asp-Pro-Pro. Each residue in the sequence was set in the D configuration, to prevent enzymatic hydrolysis, and each Arg residue was designed to target O6/N7 of a guanine base following the intercalation site. The Asp residue was designed to target a cytosine base, whilst simultaneously forming a bidentate complex with the Arg three residues upstream. Energy-minimization, using the JUMNA procedure, led to the following conclusions : 1) major groove binding is favoured over minor groove or exclusive binding to the phosphates by large energy differences, of over 50 and 90 kcal/mole, respectively: 2) the two best bound sequences are those having three successive guanine bases on the same DNA strand, immediately adjacent to the intercalation site. Sequence d(CGGGC G), encountered in the Primer Binding Site of the HIV retrovirus, thus ranks amongst the best-bound sequences; 3) replacement of an individual guanine amongst the three ones upstream of the intercalation site, by an adenine base, weakens by > 6 kcal/mole the binding energetics; 4) the conformational rigidity of the DNA-bound PPII helix should enable for a modulation of the base sequence selectivity, by appropriate replacements of the Arg and Asp residues. Thus sequence CGGCAAG, also encountered in the HIV genome, could be targeted by an oligopeptide having the sequence Pro-Arg-Pro-Pro-Asp-Pro-Pro-Asn-Pro-Pro-Asn-Pro-Pro-Arg-Ala.
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PMID:Can a polyproline II helical motif be used in the context of sequence-selective major groove recognition of B-DNA? A molecular modelling investigation. 891 63

From a broad screening program, the 4-hydroxycoumarin phenprocoumon (I) was previously identified as a lead template with HIV protease inhibitory activity. The crystal structure of phenprocoumon/HIV protease complex initiated a structure-based design effort that initially identified the 4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical candidate for the potential treatment of HIV infection. Based upon the crystal structure of the 4-hydroxy-2-pyrone III/HIV protease complex, a series of analogues incorporating a 5,6-dihydro-4-hydroxy-2-pyrone template were studied. It was recognized that in addition to having the required pharmacophore (the 4-hydroxy group with hydrogen-bonding interaction with the two catalytic aspartic acid residues and the lactone moiety replacing the ubiquitous water molecule in the active site), these 5,6-dihydro-4-hydroxy-2-pyrones incorporated side chains at the C-6 position that appropriately extended into the S1' and S2' subsites of the enzyme active site. The crystal structures of a number of representative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV protease were also determined to provide better understanding of the interaction between the enzyme and these inhibitors to aid the structure-based drug design effort. The crystal structures of the ligands in the enzyme active site did not always agree with the conformations expected from experience with previous pyrone inhibitors. This is likely due to the increased flexibility of the dihydropyrone ring. From this study, compound XIX exhibited reasonably high enzyme inhibitory activity (Ki = 15 nM) and showed antiviral activity (IC50 = 5 microM) in the cell-culture assay. This result provided a research direction which led to the discovery of active 5,6-dihydro-4-hydroxy-2-pyrones as potential agents for the treatment of HIV infection.
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PMID:Structure-based design of HIV protease inhibitors: 5,6-dihydro-4-hydroxy-2-pyrones as effective, nonpeptidic inhibitors. 891 52

We have previously demonstrated that fibronectin (FN) can bind HIV-1 envelope proteins, in particular gp 120. The aim of the present study was to determine some biological effects of this phenomenon. Pretreating HIV-1 with human FN increased the infectivity of HIV-1, when a low concentration of the virus was used. In contrast, an RGD-containing pentapeptide (Gly-Arg-Gly-Asp-Ser), which is a fundamental binding site of FN, reduced the infectivity of a suspension of HIV-1 at high concentrations of the virus. It is likely that FN bridges the cell surface and the virions, while the RGD-containing pentapeptide may saturate the HIV-1 binding sites for cell surface receptors. Moreover, gp 120 was bound to the FN present on the surface of platelets. The specificity of this binding was confirmed by the inhibition obtained by pretreating platelets with anti-FN antibodies. The consequence of the surface modifications of the platelets could explain the thrombocytopenia that frequently occurs in patients infected with HIV and suggests also the possibility that platelets could be a vehicle for the virus in the circulation.
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PMID:Influence of fibronectin on HIV-1 infection and capability of binding to platelets. 895 48

Antisense oligonucleotides represent an interesting tool for selective inhibition of gene expression. In order to direct oligonucleotides to specific compartments within the cell, we have investigated the possibility of coupling them to a signal peptide Lys-Asp-Glu-Leu (KDEL). This sequence should be able to convey oligonucleotides to the endoplasmic reticulum and from there to the cytosol and the nucleus where their targets are located. On this basis we prepared peptide-oligonucleotide conjugates by coupling, in a single step, a Nalpha-bromoacetyl peptide with an oligonucleotide bearing a thiol group, through a thioether bond. This paper deals with the definition of the optimal pH and temperature conditions leading to an efficient synthesis of peptide-oligonucleotide conjugates: the reaction was quantitative at pH 7.5 within few hours. This method was first set up using a 5',3'-modified dodecanucleotide and a (bromoacetyl)pentapeptide as a conjugation model. Then a 5',3'-modified pentacosanucleotide, complementary to the translation initiation region of the gag mRNA of HIV, was coupled to a (bromoacetyl)dodecapeptide containing a KDEL signal sequence. The anti-HIV activity of the pentacosanucleotide was compared with that of pentacosanucleotide-dodecapeptide conjugates linked through either a thioether bond or a disulfide bridge. The conjugate with a thioether bond has a higher antiviral activity than the peptide-free oligonucleotide and the conjugate linked via a disulfide bond.
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PMID:Synthesis and antiviral activity of peptide-oligonucleotide conjugates prepared by using N alpha-(bromoacetyl)peptides. 897 56

The platelet-activating factor PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthma, HIV pathogenesis, carcinogenesis, and apoptosis. There is substantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried out by specific intra- and extracellular acetylhydrolases (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized. This isoform contains a heterodimer of two homologous catalytic subunits alpha1 and alpha2, each of relative molecular mass 26K, and a non-catalytic 45K beta-subunit, a homologue of the beta-subunit of trimeric G proteins. We now report the crystal structure of the bovine alpha1 subunit of PAF-AH(Ib) at 1.7 A resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21(ras) and other GTPases. The active site is made up of a trypsin-like triad of Ser 47, His 195 and Asp 192. Thus, the intact PAF-AH(Ib) molecule is an unusual G-protein-like (alpha1/alpha2)beta trimer.
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PMID:Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. 898 54

In cell-free proteolytic processing using recombinant HIV-1 protease and Gag precursor polypeptide, certain simple oxim derivatives containing halogenomethylketone and phenyl moieties displayed HIV-1 protease inhibitory activity. Their Ki values ranged from 2.1 microM to 6.3 microM and they did not inhibit significantly other aspartic acid proteases. Both the halogenomethylketone moiety and the oxim structure were essential for the observed inhibition. Molecular modeling analysis suggested that these compounds are recognized by the HIV-1 protease as the P1 and P1' part of the substrate. In addition, one potent derivative showed inhibition of viral maturation in HIV-1IIIB chronically infected Molt-4 cells. These results indicate that it is possible to develop new and specific nonpeptidyl HIV protease inhibitors of low molecular weight.
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PMID:Inhibition of HIV-1 protease by oxim derivatives. 901 61

In order to inhibit the gp 120-CD4 glycoprotein interaction, a key step of the HIV-infection, we have synthesized a series of N-acylated peptides containing sequences identified in both the viral and lymphocytic proteins, (SDFR, SDAR, RFDSAARFDS, DRADSRRS, PSKLNDRADSRRSLWD, ASTTTNYT). An hydrophobic moiety (capryloyl, palmitoyl acrylamidoundecanoyl) was introduced in the last step of interactive synthesis, in homogeneous or solid phase. The acrylogyl-containing compounds were then telomerized under UV irradiation (DPn observed: 2 to 6). The biological evaluation shown an antiviral effect in vitro for telomerized peptides containing amino diacids such as Glu and Asp.
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PMID:Synthesis and biological activity of acylated and telomerized peptides as potential HIV-fixation inhibitors. 905 Feb 8


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