Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retroviral proteins are synthesized as polyprotein precursors that undergo proteolytic cleavages to yield the mature viral proteins. The role of the human immunodeficiency virus (HIV) protease in the viral replication cycle was examined by use of a site-directed mutation in the protease gene. The HIV protease gene product was expressed in Escherichia coli and observed to cleave HIV gag p55 to gag p24 and gag p17 in vitro. Substitution of aspartic acid residue 25 (Asp-25) of this protein with an asparagine residue did not affect the expression of the protein, but it eliminated detectable in vitro proteolytic activity against HIV gag p55. A mutant HIV provirus was constructed that contained the Asn-25 mutation within the protease gene. SW480 human colon carcinoma cells transfected with the Asn-25 mutant proviral DNA produced virions that contained gag p55 but not gag p24, whereas virions from cells transfected with the wild-type DNA contained both gag p55 and gag p24. The mutant virions were not able to infect MT-4 lymphoid cells. In contrast, these cells were highly sensitive to infection by the wild-type virions. These results demonstrate that the HIV protease is an essential viral enzyme and, consequently, an attractive target for anti-HIV drugs.
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PMID:Active human immunodeficiency virus protease is required for viral infectivity. 329 Sep 1

A valine to isoleucine substitution at position 322 within variable region 3 (V3) of envelope of simian immunodeficiency virus was previously shown to compensate for an inactivating valine to glycine mutation at position 448 in constant region 4 (C4) (Morrison et al., Virology 195, 167-174, 1993). Cloned DNA fragments with inactivating C4 mutations were combined with complex mixtures of mutant V3 sequences, and full length genomes were transfected into COS-1 cells. By cocultivating transfected cells with CEM x 174 cells, we were able to identify two additional compensatory V3-C4 combinations. Changing 334 proline to leucine compensated for an inactivating 428 asparagine to lysine mutation and changing 324 isoleucine to leucine compensated for an inactivating 448 valine to glycine mutation. The double mutants replicated efficiently in CEM x 174 cells, rhesus monkey peripheral blood mononuclear cells, and the continuously growing rhesus monkey T cell line 221. Surprisingly, the 324 I-->L and 33 P-->L mutations by themselves impaired SIVmac239 wild-type replication in CEM x 174 cells. These results confirm the cooperation between V3 and C4 sequences and they define additional specific residues participating in this cooperation.
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PMID:Identification of V3 mutations that can compensate for inactivating mutations in C4 of simian immunodeficiency virus. 748 61

Bisheteroarylpiperazines are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). We describe a novel bisheteroarylpiperazine, U-90152 [1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4-[3-(1-methyl eth yl-amino)pyridinyl]piperazine], which inhibited recombinant HIV-1 RT at a 50% inhibitory concentration (IC50) of 0.26 microM (compared with IC50s of > 440 microM for DNA polymerases alpha and delta). U-90152 blocked the replication in peripheral blood lymphocytes of 25 primary HIV-1 isolates, including variants that were highly resistant to 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine, with a mean 50% effective dose of 0.066 +/- 0.137 microM. U-90152 had low cellular cytotoxicity, causing less than 8% reduction in peripheral blood lymphocyte viability at 100 microM. In experiments assessing inhibition of the spread of HIV-1IIIB in cell cultures, U-90152 was much more effective than AZT. When approximately 500 HIV-1IIIB-infected MT-4 cells were mixed 1:1,000 with uninfected cells, 3 microM AZT delayed the evidence of rapid viral growth for 7 days. In contrast, 3 microM U-90152 totally prevented the spread of HIV-1, and death and/or dilution of the original inoculum of infected cells prevented renewed viral growth after U-90152 was removed at day 24. The combination of U-90152 and AZT, each at 0.5 microM, also totally prevented viral spread. Finally, although the RT amino acid substitutions K103N (lysine 103 to asparagine) and Y181C (tyrosine 181 to cysteine), which confer cross-resistance to several nonnucleoside inhibitors, also decrease the potency of U-90152, this drug retains significant activity against these mutant RTs in vitro (IC50s, approximately 8 microgramM).
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PMID:U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. 768 95

A monoclonal antibody (vpg15) has been described which can block infection with feline immunodeficiency virus (FIV) and which recognizes the feline homologue of CD9. In order to study the role of feline CD9 in infection with FIV we have molecularly cloned a cDNA encoding feline CD9 by R.A.C.E (rapid amplification of cDNA ends). The amino acid sequence of feline CD9 displays 95.1, 93.8 and 90.7% homology to human, murine and bovine CD9, respectively. Although feline CD9 appears most homologous to human CD9, it has two important features in common with bovine and murine CD9: the presence of a histidine residue at position 192 which is absent from the corresponding position (194) in human CD9; and the absence of two asparagine residues which are found at positions 51 and 52 of human CD9. Feline CD9 is unique in that it lacks a potential N-linked glycosylation site in the first extracellular loop, a feature common to CD9 of other species. Despite the high degree of sequence homology, significant cross-species variation occurred in the two predicted extracellular loops, notably between amino acids 169 to 180 of the second loop. When feline CD9 was expressed on human and murine cells, it was recognized by both the conformation-dependent feline CD9-specific antibody, vpg15, and the cross-species reactive anti-human CD9 antibody, FMC56, confirming that the feline CD9 clone encoded a protein which was synthesized, transported to the cell surface and expressed in a similar conformation to native feline CD9. However, although the vpg15 antibody did not recognize human CD9 when expressed on human epithelial cells, it reacted with human CD9 when expressed on murine fibroblast cells. It is possible therefore, that the conformational epitope recognized by the vpg15 epitope is sensitive to either species- or tissue-specific post-translational modification.
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PMID:cDNA cloning and eukaryotic expression of feline CD9. 775 50

The glycosylation pattern of the external envelope glycoprotein of human immunodeficiency virus type 2 (HIV-2) was studied in dependence on host cells and virus isolates. Strains HIV-2ALT, HIV-2ROD and HIV-2D194, differing in their biological properties and in the amino acid sequences of their env genes, were propagated in MOLT4, HUT78 and U937 cells, in human peripheral blood lymphocytes and monocytes/macrophages in the presence of [6-3H]glucosamine. Radiolabelled viral glycoproteins were isolated from the cell-free supernatants and digested with trypsin. Glycans were sequentially liberated by endo-beta-N-acetylglucosaminidase H and peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase F, and fractionated according to charge and size. Comparison of the oligosaccharide profiles revealed that the envelope glycoproteins of different virus isolates, propagated in the same host cells, yielded very similar glycan patterns, whereas cultivation of an isolate in different host cells resulted in markedly divergent oligosaccharide maps. Variations concerned the proportion of high-mannose-, hybrid- and complex-type substituents, as well as the state of charge and structural parameters of the complex-type species. As a characteristic feature, complex-type glycans of macrophage-derived viral glycoprotein were almost exclusively substituted by lactosamine repeats. Hence, glycosylation of the HIV-2 external envelope glycoprotein seems to be primarily governed by host cell-specific factors rather than by the amino acid sequence of the corresponding polypeptide backbone.
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PMID:Oligosaccharide profiles of HIV-2 external envelope glycoprotein: dependence on host cells and virus isolates. 782 9

Substitution of glycine with glutamic acid at position 48 of the human immunodeficiency virus protease resulted in an enzyme with reduced activity on one of the protease processing sites in the viral Pol polyprotein precursor. Cleavage at this site was restored by a second-site substitution in the substrate replacing an aspartic acid with either glycine or asparagine. These results suggest that the glutamic acid side chain in the mutant protease has an unfavorable charge-charge interaction with this position in the substrate. Cleavage of a processing site in the viral Gag polyprotein precursor with the mutant enzyme was enhanced, and this enhancement was dependent on the presence of an arginine residue in the substrate, again suggesting a charge-charge interaction. The potential for such interactions was confirmed using molecular modeling. The effect of the position 48 substitution was attributed to a 10-fold increase in Km for the processing site in Pol. These results indicate that the addition of a side chain at position 48 can alter the specificity of the HIV-1 protease to substrate in a sequence specific manner and that compensatory changes can be made in the substrate.
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PMID:A side chain at position 48 of the human immunodeficiency virus type-1 protease flap provides an additional specificity determinant. 788 51

We have used a combination of genetic and immunological techniques to explore how amino acid substitutions in the second conserved (C2) domain of gp120 from human immunodeficiency virus type 1 (HIV-1) affect the conformation of the protein. It was reported previously (R. L. Willey, E. K. Ross, A. J. Buckler-White, T. S. Theodore, and M. A. Martin. J. Viol. 63:3595-3600, 1989) that an asparagine-glutamine (N/Q) substitution at C2 residue 267 of HIV-1 NL4/3 reduced virus infectivity, but that infectivity was restored by a compensatory amino acid change (serine-glutamine; S/N) at residue 128 in the C1 domain. Here we show that the 267 N/Q substitution causes the abnormal exposure of a segment of C1 spanning residues 80 to 120, which compromises the integrity of the CD4-binding site. The reversion substitution at residue 128 restores the normal conformation of the C1 domain and recreates a high-affinity CD4-binding site. The gp120 structural perturbation caused by changes in C2 extends also to the C5 domain, and we show by immunological analysis that there is a close association between areas of the C1 and C5 domains. This association might be important for forming a complex binding site for gp41 (E. Helseth, U. Olshevsky, C. Furman, and J. Sodroski. J. Virol. 65:2119-2123, 1991). Segments of the C1 and C2 domains are predicted to form amphipathic alpha helices. We suggest that these helices might be packed together in the core of the folded gp120 molecule, that the 267 N/Q substitution disrupts this interdomain association, and that the 128 S/N reversion substitution restores it.
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PMID:Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1. 793 65

Variable regions with sequence length variation in the human immunodeficiency virus type 1 envelope exhibit an unusual pattern of codon usage with AAT, ACT, and AGT together composing > 70% of all codons used. We postulate that this distribution is caused by insertion of AAT triplets followed by point mutations and selection. Accumulation of the encoded amino acids (asparagine, serine, and threonine) leads to the creation of new N-linked glycosylation sites, which helps the virus to escape from the immune pressure exerted by virus-neutralizing antibodies.
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PMID:Insertion of N-linked glycosylation sites in the variable regions of the human immunodeficiency virus type 1 surface glycoprotein through AAT triplet reiteration. 793 44

The human immunodeficiency virus type 1 (HIV-1) encoded Vpu is a small integral membrane phosphoprotein that functions in the enhancement of viral particle release and has more recently been shown to cause degradation of CD4 at the endoplasmic reticulum. We have demonstrated earlier that Vpu is phosphorylated by the ubiquitous casein kinase-2 (CK-2) in HIV-1 infected cells. The phosphoacceptor sites targeted by CK-2 in Vpu, however, have not been demonstrated and it was unclear whether Vpu was phosphorylated at one or more of its four serine residues. In this study we characterized the CK-2 phosphoacceptor sites in Vpu using recombinant CK-2 for in vitro phosphorylation of recombinant Vpu protein as well as synthetic peptides of Vpu. Phosphorylation of both Ser52 and Ser56 was demonstrated by in vitro phosphorylation using three 54-residue peptides comprising the entire hydrophilic part of Vpu and containing single serine to asparagine transitions in either position 52 or 56. The Km values of CK-2 to these peptides were established, revealing a preferential phosphorylation of Ser56. The Km values are: Ser56 = 31 microM; Ser 52 = 156 microM; wild type = 27 microM. In addition, we studied phosphorylation of Vpu by endogenous CK-2 following in vitro translation in rabbit reticulocyte lysate of wild-type Vpu or a mutant, Vpum2/6, carrying serine to asparagine changes at amino acid positions 52 and 56. The in vivo phosphorylation of Vpu was studied in transiently transfected human embryonic kidney (293) cells. In this system, the mutant Vpum2/6 was not phosphorylated, indicating that the seryl residues of Vpu at amino acid positions 52 and 56, but not those at positions 23 and 61, are phosphorylated by CK-2. The two CK-2 phosphorylation sites are conserved in all known Vpu sequences and represent the consensus Ser52GlyAsn(Glu/Asp)Ser(Glu/Asp)Gly(Glu/Asp)59. Prediction of the secondary structure revealed a conserved alpha-helix-turn-alpha-helix motif for the hydrophilic C-terminal part of Vpu. A structural model for Vpu is proposed in which the membrane anchor precedes a region comprising two amphipathic alpha-helices of opposed polarity, joined by a strongly acidic turn that protrudes into the cytoplasm and contains the CK-2 phosphorylation sites. Possible functional and structural homologies of Vpu to the membrane channel-forming M2 protein of influenza A viruses are discussed.
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PMID:The human immunodeficiency virus type 1 encoded Vpu protein is phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56 within a predicted alpha-helix-turn-alpha-helix-motif. 810 1

The transmembrane envelope glycoprotein (gp41) of human immunodeficiency virus type 1 possesses four consensus sites (Asn-X-Ser/Thr) for the incorporation of N-linked sugars situated on the extracellular domain of the molecule. The purpose of this investigation was to determine the significance of each of these sites in relation to the structure and function of the viral envelope glycoprotein. Each of the four sites was removed by in vitro mutagenesis of gp160 sequence in the non-infectious viral clone pEVd1443, so that amino acids 616, 621, 642 and 679 were each changed from asparagine to serine. The effects of mutagenesis were assessed by syncytium assay after wild-type or mutant envelope clones had been transfected into CD4+ HeLa cells. Removal of the glycosylation site at position 642 resulted in the synthesis of precursor gp160 that was neither cleaved, to give gp120 and gp41, nor transported to the plasma membrane of transfected cells. A consequence of these events was that envelope mutant 642 failed to induce syncytia between neighbouring cells in which it had been expressed. The results of this study indicate that N-linked glycosylation of Asn-642 in the glycoprotein produced by the pEVd1443 expression system is necessary for the correct intracellular processing of gp160 to yield surface-expressed, fusogenic gp41.
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PMID:Deletion of a single N-linked glycosylation site from the transmembrane envelope protein of human immunodeficiency virus type 1 stops cleavage and transport of gp160 preventing env-mediated fusion. 820 3


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