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)

The effect of the appearance of drug-resistant human immunodeficiency virus type 1 (HIV-1) on viral RNA load was studied in patients treated with the reverse transcriptase inhibitor lamivudine. During the first 12 weeks of treatment, HIV-1 RNA concentrations and amino acid changes in codon 184, causing high-level resistance to lamivudine, were determined in longitudinal serum samples from HIV-1 p24 antigen-positive and -negative patients. A marked decline in the amount of HIV-1 RNA (approximately 95% below baseline) and HIV-1 p24 antigen was observed within 2 weeks, followed by a rise that coincided with the appearance of lamivudine-resistant viruses in serum (isoleucine mutants initially, which were subsequently replaced by valine variants). After 12 weeks, a partial antiviral effect was observed despite the presence of a complete codon 184 mutant virus population in serum. This study shows that the rapid appearance of drug-resistant virus in serum is followed by an increase in viral RNA load.
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PMID:Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). 753 72

A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT). A different structure-antiviral activity relationship was found, depending on the nature of the mutated amino acid in the HIV-1 RT. The results show that 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)uracil, and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)-2-thiouracil remain active against the majority of viruses containing single mutations which confer resistance to nonnucleoside RT inhibitors.
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PMID:Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains. 754 Mar 84

Initial studies suggested that major histocompatibility complex class I-restricted viral epitopes could be predicted by the presence of particular residues termed anchors. However, recent studies showed that nonanchor positions of the epitopes are also significant for class I binding and recognition by cytotoxic T lymphocytes (CTLs). We investigated if changing nonanchor amino acids could increase class I affinity, complex stability, and T-cell recognition of a natural viral epitope. This concept was tested by using the HLA-A 0201-restricted human immunodeficiency virus type 1 epitope from reverse transcriptase (pol). Position 1 (P1) amino acid substitutions were emphasized because P1 alterations may not alter the T-cell receptor interaction. The peptide with the P1 substitution of tyrosine for isoleucine (I1Y) showed a binding affinity for HLA-A 0201 similar to that of the wild-type pol peptide in a cell lysate assembly assay. Surprisingly, I1Y significantly increased the HLA-A 0201-peptide complex stability at the cell surface. I1Y sensitized HLA-A 0201-expressing target cells for wild-type pol-specific CTL lysis as well as wild-type pol. Peripheral blood lymphocytes from three HLA-A2 HIV-seropositive individuals were stimulated in vitro with I1Y and wild-type pol. I1Y stimulated a higher wild-type pol-specific CTL response than wild-type pol in all three donors. Thus, I1Y may be an "improved" epitope for use as a CTL-based human immunodeficiency virus vaccine component. The design of improved epitopes has important ramifications for prophylaxis and therapeutic vaccine development.
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PMID:Amino-terminal alteration of the HLA-A*0201-restricted human immunodeficiency virus pol peptide increases complex stability and in vitro immunogenicity. 754 95

During replication of human immunodeficiency virus type 1 (HIV-1), proteolytic cleavage of Gag and Gag-Pol precursor proteins into different functional protein subunits is catalyzed by the viral proteinase, and this enzyme is the target of the antiviral proteinase inhibitor, Ro 31-8959. We investigated in vitro which HIV mutants with reduced sensitivity to Ro 31-8959 emerged during proteinase inhibition treatment; from three different HIV-1 strains, comparable progeny virus resistant to proteinase inhibitor were found, whereas the same experimental protocol detected no resistant HIV-2 mutants. Molecular analysis of the mutations underlying resistance revealed a multistep mechanism in which an amino acid exchange was common to all resistant isolates, and in all experiments preceded further exchanges at position 90 (leucine to methionine) and/or at position 54 (isoleucine to valine). For wild-type strains the 90% inhibitory concentrations of Ro 31-8959 were close to 20 nM, whereas HIV-1 mutants with all 3 amino acid exchanges had more than 50-fold increased 90% inhibitory concentrations (above 1000 nM). The primary event (Gly-48 to valine) occurs at the hinge of the flaps of the proteinase, thus hampering entry of the inhibitor to the active center and suggesting steric hindrance. Detailed knowledge of this stereotypic process could open inhibitor design, thus preventing conceivable escape of resistant virus on proteinase inhibitor action.
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PMID:Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959. 757 26

The Rev proteins of primate immunodeficiency viruses are essential transactivators for the switch from early to late phase in the viral replication cycle. By mutational analysis, a putative activation domain (AD) has been assigned to the carboxy-terminus. This leucine-rich stretch of amino acids proved to be essential for the transactivating properties of HIV-1 Rev. Some mutants in the AD transdominantly inhibit the function of wild-type Rev protein very efficiently. We identified a similar domain structure for SIVmac239 Rev by sequence comparison and in vitro mutagenesis. The leucine/isoleucine residues of the SIVmac239 Rev activation domain appeared to be of similar importance for function. The mutants of these residues in the SIV AD displayed a dominant negative phenotype on both HIV-1 and SIVmac 239 rev-responsive elements (RRE). The prokaryotically expressed wild-type and mutant proteins were analyzed for RNA-binding properties in a gel-shift assay in vitro. This assay revealed a similar binding pattern of wild-type and transdominant proteins on either RRE.
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PMID:The activation domain of simian immunodeficiency virus SIVmac239 Rev protein is structurally and functionally analogous to the HIV-1 Rev activation domain. 764 23

The transmembrane protein of human immunodeficiency virus type 1 (HIV-1) contains a leucine zipper-like (hydrophobic heptad) repeat which has been predicted to form an amphipathic alpha helix. To evaluate the potential of the hydrophobic heptad repeat to induce protein oligomerization, this region of gp41 has been cloned into the bacterial expression vector pRIT2T. The resulting plasmid, pRIT3, expresses a fusion protein consisting of the Fc binding domain of monomeric protein A, a bacterial protein, and amino acids 538 to 593 of HIV-1 gp41. Gel filtration chromatography demonstrated the presence of oligomeric forms of the fusion protein, and analytical centrifugation studies confirmed that the chimeric protein formed a higher-order multimer that was greater than a dimer. Thus, we have identified a region of HIV-1 gp41 which is capable of directing the oligomerization of a fusion protein containing monomeric protein A. Point mutations, previously shown to inhibit the biological activity of the HIV-1 envelope glycoprotein, have been engineered into the segment of gp41 contained in the fusion protein, and expressed mutant proteins were purified and analyzed via fast protein liquid chromatography. A point mutation in the heptad repeat, which changed the central isoleucine to an alanine, caused a significant (> 60%) decrease in oligomerization, whereas changing the central isoleucine to aspartate or proline resulted in almost a complete loss of oligomerization. Deletions of one, two, or three amino acids following the first isoleucine also resulted in a profound decrease in oligomerization. The inhibitory effects of the mutations on oligomer formation correlated with the effects of the same mutations on envelope glycoprotein-mediated fusion. A possible role of the leucine zipper-like region in the fusion process and in an oligomerization event distinct from assembly of the envelope glycoprotein complex is discussed.
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PMID:Oligomerization of the hydrophobic heptad repeat of gp41. 770 97

A 17-amino acid arginine-rich peptide from the bovine immunodeficiency virus Tat protein has been shown to bind with high affinity and specificity to bovine immunodeficiency virus transactivation response element (TAR) RNA, making contacts in the RNA major groove near a bulge. We show that, as in other peptide-RNA complexes, arginine and threonine side chains make important contributions to binding but, unexpectedly, that one isoleucine and three glycine residues also are critical. The isoleucine side chain may intercalate into a hydrophobic pocket in the RNA. Glycine residues may allow the peptide to bind deeply within the RNA major groove and may help determine the conformation of the peptide. Similar features have been observed in protein-DNA and drug-DNA complexes in the DNA minor groove, including hydrophobic interactions and binding deep within the groove, suggesting that the major groove of RNA and minor groove of DNA may share some common recognition features.
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PMID:A peptide interaction in the major groove of RNA resembles protein interactions in the minor groove of DNA. 776 51

The human immunodeficiency virus, type 1 (HIV-1) genome encodes a 15-kDa accessory gene product, Vpr, that is essential for virus replication in primary monocytes/macrophages. Being present in the virion, Vpr is believed to function in the early phases of HIV-1 replication, including nuclear migration of the pre-integration complex and/or transcription of the provirus genome. By gel filtration analysis of highly purified Vpr protein and its mutants, we demonstrate that HIV-1 Vpr exists as an oligomer. The N-terminal domain of Vpr (amino acids (aa) 1-42) is sufficient for oligomerization; however, deletion of aa 36-76 from Vpr disrupts oligomerization, suggesting that aa 36-42 are critical for Vpr oligomerization. As a result of Vpr oligomerization, basic aa residues within Vpr aa 1-73 are highly resistant to trypsin digestion, while those within Vpr aa 74-96 are easily accessible. Mutations within the leucine-/isoleucine-rich domain (aa 60-81), which was previously identified to be involved in Vpr interaction with a host cellular protein, rendered Arg62 more susceptible to trypsin digestion. Thus, the Vpr oligomeric structure must be extended into this domain. These results suggest a novel feature of HIV-1 Vpr that may be important for its functions.
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PMID:Biochemical mechanism of HIV-1 Vpr function. Oligomerization mediated by the N-terminal domain. 779 8

Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral resistance and provide information that may prove useful in designing the next generation of protease inhibitors.
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PMID:Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. 781 32

Pepstatin A, a pentapeptide with the molecular weight of 686, is a naturally occurring inhibitor of aspartyl proteases secreted by Streptomyces species. Above a critical concentration of 0.1 mM at low ionic strength and neutral pH, it can polymerize into filaments which may extend over several micrometers. After negative staining, these filaments show a helical substructure with characteristic diameters ranging from 6 to 12 nm. Selected images at higher magnification suggest the filaments are composed of two intertwined 6 nm strands. This is in agreement with the optical diffraction analysis which additionally established a periodic pitch of 25 nm for the helical intertwining. Rotary shadowing of the pepstatin A filaments clearly demonstrated the right-handedness of the helical twist. In physiological salt solution or at higher concentrations of pepstatin A, a variety of higher order structures were observed, including ribbons, sheets and cylinders with both regular and twisted or irregular geometries. Pepstatin A can interact with intermediate filament subunit proteins. These proteins possess a long, alpha-helical rod domain that forms coiled-coil dimers, which through both hydrophobic and ionic interactions form tetramers which, in turn, in the presence of physiological salt concentrations, polymerize into the 10 nm intermediate filaments. In the absence of salt, pepstatin A and intermediate filament proteins polymerize into long filaments with a rough surface and a diameter of 15-17 nm. This polymerization appears to be primarily driven by nonionic interactions between pepstatin A and polymerization-competent forms of intermediate filament proteins, resulting in a composite filament. Polymerization-incompetent proteolytic fragments of vimentin, lacking portions of the head and/or tail domain, failed to copolymerize with pepstatin A into long filaments under these conditions. These peptides, as well as bovine serum albumin, were found to stick to the surface of pepstatin A filaments, ribbons and sheets. Independent evidence for direct association of pepstatin A with intermediate filament subunit proteins was provided not only by electron microscopy but also by UV difference spectra. Pepstatin A loses its ability to inhibit the aspartyl protease of the human immunodeficiency virus type 1 following polymerization into the higher order structures described here. The amazing fact that pepstatin A can spontaneously self-associate to form very large polymers seems to be a more rare event for such small peptides. The other examples of synthetic or naturally occurring oligopeptides discussed in this review which are able to polymerize into higher order structures possess a common property, their hydrophobicity, often manifested by clusters of valine or isoleucine residues.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pepstatin A: polymerization of an oligopeptide. 805 47


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