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)

We have established a hybridoma clone, designated 2F5, secreting a neutralizing human monoclonal antibody (MAb) specific for gp41 of human immunodeficiency virus type 1 (HIV-1). The epitope of MAb 2F5 was mapped to amino acid sequence Glu-Leu-Asp-Lys-Trp-Ala on the ectodomain of gp41. In this study different in vitro test systems were used to characterize the neutralizing properties of MAb 2F5. In syncytium inhibition assays, fusion inhibition experiments, and neutralization assays on different HIV-susceptible cells (H9, U937, and peripheral blood mononuclear cells) MAb 2F5 showed broad-spectrum neutralizing capacity against HIV-1 laboratory isolates IIIB, MN, RF, and SF2. In addition, primary isolates from AIDS patients were also neutralized.
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PMID:A broadly neutralizing human monoclonal antibody against gp41 of human immunodeficiency virus type 1. 788 24

Peptide T, the HIV envelope-derived fragment Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr, has already been used to successfully treat psoriatic patients without major side-effects. The underlying reason for the positive effect is, however, at present unknown. In the following minireview, we summarize today's knowledge regarding peptide T's interaction with other chemical messenger molecules, such as somatostatin, vasoactive intestinal polypeptide (VIP) and epidermal growth factor (EGF), within the human skin, and, finally, speculate about their relationship to each other. In summary, we believe that the clearance effect of peptide T on psoriasis will open up new avenues with regard to the concept of the pathogenesis of as well as the clinical attendance to this disease.
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PMID:Speculations around the mechanism behind the action of peptide T in the healing of psoriasis: a minireview. 790 47

Peptide mimics of substrates for HIV-proteases were prepared. These "norpeptides" are identical to a fragment of the HIV-polyprotein except that a crucial scissile bond was deleted, and an alpha,beta-disubstituted amino acid spans the P1 and P1 site. Thus all four stereoisomers of Leu psi[]Ala (i.e. H2NCH(CH2iPr)CH(Me)CO2H, 1) were incorporated into Ac-Ala-Arg-Val-Leu psi[]Ala-Glu-Ala-NH2 (all other residues being L-amino acids), and tested with respect to inhibition of HIV-1 and HIV-2 proteases.
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PMID:Evaluation of "norpeptides" as potential inhibitors of HIV-proteases. 792 17

Nuclear antigen 1 (EBNA-1) is one of the key functions of the oncogenic DNA virus, Epstein-Barr virus (EBV), and is the only viral protein consistently expressed in EBV-associated malignancies. EBNA-1 binds in a site-specific manner to the viral DNA and is essential for viral replication, as well as for maintaining the genome as an extrachromosomal episome within infected cells. EBNA-1 is not recognized by the cellular immune system. Here we demonstrate that, in addition to its known DNA binding properties, EBNA-1 can also act as a strong RNA binding protein, interacting with diverse substrates in vitro, including the EBV-encoded RNA polymerase III transcript EBER1 and the HIV-encoded transactivation response (TAR) element. We also show that EBNA-1 can bind exon sequences derived from its own RNA expressed from the Fp promoter, as found in Burkitt's lymphoma-related cells and in nasopharyngeal carcinomas. EBNA-1 has been identified as a component in an RNA complex; moreover, an anti-EBNA-1 antibody 1H4-1, that does not inhibit DNA binding, blocks binding to RNA. Arginine/glycine-containing (so-called 'RGG') motifs have been found in an increasing number of proteins that interact with RNA. The EBV antigen contains three potential 'RGG' motifs located around an internal glycine/alanine-rich repetitive sequence in the protein, and outside the region of EBNA-1 mapped previously as essential for viral DNA replication and other functionally defined properties. These motifs could be involved in the observed binding between EBNA-1 and RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:EBNA-1, the major nuclear antigen of Epstein-Barr virus, resembles 'RGG' RNA binding proteins. 795 53

The glycosphingolipid galactosylceramide (GalCer), which binds gp120 with high affinity and specificity, is a potential alternative receptor for human immunodeficiency virus type 1 (HIV-1) in some CD4-negative neural and epithelial human cells, including the human colonic epithelial cell line HT-29. In the present study, we demonstrate that synthetic multibranched peptides derived from the consensus sequence of the HIV-1 V3 loop block HIV-1 infection in HT-29 cells. The most active peptide was an eight-branched multimer of the motif Gly-Pro-Gly-Arg-Ala-Phe which at a concentration of 1.8 microM induced a 50% inhibition of HIV-1 infection in competition experiments. This peptide was not toxic to HT-29 cells, and preincubation with HIV-1 did not affect viral infectivity, indicating that the antiviral activity was not due to a nonspecific virucidal effect. Using a high-performance thin-layer chromatography binding assay, we found that multibranched V3 peptides recognized GalCer and inhibited binding of recombinant gp120 to the glycosphingolipid. In addition, these peptides abolished the binding of an anti-GalCer monoclonal antibody to GalCer on the surface of live HT-29 cells. These data provide additional evidence that the V3 loop is involved in the binding of gp120 to the GalCer receptor and show that multibranched V3 peptides are potent inhibitors of the GalCer-dependent pathway of HIV-1 infection in CD4-negative mucosal epithelial cells.
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PMID:Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line. 798 25

Integrase is the only viral protein necessary for integration of retroviral DNA into chromosomal DNA of the host cell. Biochemical analysis of human immunodeficiency virus type 1 (HIV-1) integrase with purified protein and synthetic DNA substrates has revealed extensive information regarding the mechanism of action of the enzyme, as well as identification of critical residues and functional domains. Since in vitro reactions are carried out in the absence of other viral proteins and they analyze strand transfer of only one end of the donor substrate, they do not define completely the process of integration as it occurs during the course of viral infection. In an effort to further understand the role of integrase during viral infection, we initially constructed a panel of 24 HIV-1 mutants with specific alanine substitutions throughout the integrase coding region and analyzed them in a human T-cell line infection. Of these mutant viruses, 12 were capable of sustained viral replication, 11 were replication defective, and 1 was temperature sensitive for viral growth. The replication defective viruses express and correctly process the integrase and Gag proteins. Using this panel of mutants and an additional set of 18 mutant viruses, we identified nine amino acids which, when replaced with alanine, destroy integrase activity. Although none of the replication-defective mutants are able to integrate into the host genome, a subset of them with alterations in the catalytic triad are capable of Tat-mediated transactivation of an indicator gene linked to the viral long terminal repeat promoter. We present evidence that integration of the HIV-1 provirus is essential not only for productive infection of T cells but also for virus passage in both cultured peripheral blood lymphocytes and macrophage cells.
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PMID:Human immunodeficiency virus type 1 integrase: effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells. 798 32

Between hypervariable regions V1 and V2 of human immunodeficiency virus type 1 (HIV-1) gp120 lies a cluster of relatively conserved residues. The contribution of nine charged residues in this region to virus infectivity was evaluated by single-amino-acid substitutions in an infectious provirus clone. Three of the HIV-1 mutants studied had slower growth kinetics than the wild-type virus. The delay was most pronounced in a mutant with an alanine substituted for an aspartic acid residue at position 180. This aspartic acid is conserved by all HIV-1 isolates with known nucleotide sequences. Substitutions with three other residues at this position, including a negatively charged glutamic acid, all affected virus infectivity. The defect identified in these mutants suggests that this aspartic acid residue is involved in the early stages of HIV-1 replication.
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PMID:The highly conserved aspartic acid residue between hypervariable regions 1 and 2 of human immunodeficiency virus type 1 gp120 is important for early stages of virus replication. 798 52

Systematic replacement of the P4-P2 subsites of substrate-based human immunodeficiency virus type 1 protease (HIV-1 PR) inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere (Cha-psi [H.E.]-Ala) at positions corresponding to the scissile sites of substrates was carried out. The structure-activity relationship revealed that compounds with the combination of hydrophilic P3 and beta-branched hydrophobic P2 amino acids generally showed strong inhibitory activity against HIV-1 PR. In particular, compounds 4 (Boc-Orn-Val-Cha-psi [H.E.]-Ala-NHBun; Bu(n) = n-butyl, Ki = 11 nM) and 6 (Z-Orn-Val-Cha-psi [H.E.]-Ala-NHBun, Ki = 8 nM) exhibited good enzyme selectivity, possessing no significant inhibitory activities toward closely related aspartic proteases, pepsin, cathepsin D, and renin. As a possible model system for (anti-Mo-MSV/MLV complex (Mo-MSV = Moloney murine sarcoma virus; MLV = murine leukemia virus)) activity was investigated. Both compounds were found to inhibit moderately the focus formation of Mo-MSV/MLV complex in NIH3T3 cells (compound 4, IC50 = 1.8 microM; compound 6, IC50 = 1.0 microM).
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PMID:Studies of human immunodeficiency virus type 1 (HIV-1) protease inhibitors. III. Structure-activity relationship of HIV-1 protease inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere. 800 98

The most preferred residue in the substrates of human immunodeficiency virus (HIV-1) protease is glutamic acid in the P2' position. The catalytic importance of this charged residue has been studied to obtain a detailed insight into the mechanism of action, which will promote drug design to combat the virus. To this end, we have synthesized Lys-Ala-Arg-Val-Leu*Phe(NO2)-Glu-Ala-Nle (substrate E) and its counterpart containing the neutral Gln (substrate Q) in place of Glu. Kinetic analyses have shown that the specificity rate constants (kcat/Km) display bell-shaped pH dependencies for both substrates, but the pH-independent limiting value is 35-40-fold higher with substrate E than with substrate Q. In contrast to the pH-rate profiles of kcat/Km, there is a striking difference between the pH dependencies of Km and kcat for the two substrates. This indicates different ground state and transition state stabilizations in the two reactions. Solvent kinetic deuterium isotope effects show that the rate-limiting step for the hydrolysis of substrate E is a chemical step coupled with proton transfer whereas with substrate Q it is a physical step, presumably a conformational change. Accordingly, the charged residue in P2' alters the rate-limiting step and the nature of the enzyme-substrate complex, resulting in different mechanisms for the two substrates.
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PMID:Substrate-dependent mechanisms in the catalysis of human immunodeficiency virus protease. 804 36

The protease encoded by the human immunodeficiency virus-1 (HIV-1) is essential for the processing of viral polyproteins into mature viral proteins. The 99-residue protease from HIV-1 contains two generally conserved cysteine residues, one of which (Cys-67) is located on the solvent-exposed surface. It was shown previously that Cys-67 of the native enzyme reacted with 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB, Ellman's reagent) at pH 6.2, causing a reversible inactivation of the protease. However, there was no reaction when the protein was denatured in 6 M guanidine hydrochloride, implying that the native conformation rendered Cys-67 more reactive. To investigate the structural basis of the lowered pKa in the native protein, we synthesized a 17-residue peptide matching the sequence of residues 59-75. The reactivity of this synthetic peptide with DTNB mimicked that of the protease, being more reactive in the absence of 6 M guanidine hydrochloride than in its presence. It was possible that His-69 or Lys-70 could facilitate ionization of the SH group of Cys-67, which is required for reaction with DTNB. Apparently both residues are important, because increased reactivity of the native peptide was eliminated when either His-69 or Lys-70 were changed to Ala. Replacement of His-69 by Glu reversed the reactivity, so that the native peptide was less reactive than that denatured in guanidine hydrochloride. Thus, the reactivity of Cys-67 is modulated by the charges on residues 69 and 70 in the protein. The presence of His-69 and Lys-70 renders the native protease especially susceptible to oxidation and disulfide formation. The resulting reversible inactivation of the protease may be important in the normal regulation of the viral life cycle, a suggestion supported by the strong conservation of the residues in this region.
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PMID:Reactivity of cysteine-67 of the human immunodeficiency virus-1 protease: studies on a peptide spanning residues 59 to 75. 805 89


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