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

The immunostimulatory activity of a phosphorothioate oligodeoxynucleotide (27 mer) that is antisense to the rev gene of HIV-1 was studied on normal human lymphocytes and on cells from patients with common variable immunodeficiency (CVI). For peripheral blood mononuclear cells from nine normal individuals, the proliferation index (16.8 +/- 12.5) after anti-rev oligomer exposure was proportional to the percentage of peripheral B-cells (r = 0.76, P = 0.02). In five experiments, enriched B- or T-cell populations had proliferation indices of 47.2 +/- 32.9 and 2.4 +/- 1.9, respectively. The addition of T-cells to anti-rev oligomer treated B-cells had no effect (proliferation index = 47.5 +/- 38.1). After anti-rev oligomer stimulation, autoradiography, and counterstaining for B- and T-cell markers, all detectable [3H]thymidine uptake was by CD19-positive cells. Eight of the 14 CVI patients had a proliferation index and secreted levels of IgM and IgG comparable to cells from normal individuals. In contrast to normal cells, the direct correlation between proliferation of peripheral blood mononuclear cells and the percentage of peripheral B-cells was weak in samples from 13 CVI patients (r = 0.4, P = 0.2). These findings indicate that peripheral blood B-cells from about half of CVI patients proliferate and produce immunoglobulin after exposure to anti-rev oligomer. These data demonstrate that under the appropriate circumstances, B-cells of some CVI patients can proliferate and differentiate normally.
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PMID:B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1. 862 Jun 17

RNA-RNA interactions govern a number of biological processes. Several RNAs, including natural sense and antisense RNAs, interact by means of a two-step mechanism: recognition is mediated by a loop-loop complex, which is then stabilized by formation of an extended intermolecular duplex. It was proposed that the same mechanism holds for dimerization of the genomic RNA of human immunodeficiency virus type 1 (HIV-1), an event thought to control crucial steps of HIV-1 replication. However, whereas interaction between the partially self-complementary loop of the dimerization initiation site (DIS) of each monomer is well established, formation of the extended duplex remained speculative. Here we first show that in vitro dimerization of HIV-1 RNA is a specific process, not resulting from simple annealing of denatured molecules. Next we used mutants of the DIS to test the formation of the extended duplex. Four pairs of transcomplementary mutants were designed in such a way that all pairs can form the loop-loop "kissing" complex, but only two of them can potentially form the extended duplex. All pairs of mutants form heterodimers whose thermal stability, dissociation constant, and dynamics were analyzed. Taken together, our results indicate that, in contrast with the interactions between natural sense and antisense RNAs, no extended duplex is formed during dimerization of HIV-1 RNA. We also showed that 55-mer sense RNAs containing the DIS are able to interfere with the preformed HIV-1 RNA dimer.
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PMID:A loop-loop "kissing" complex is the essential part of the dimer linkage of genomic HIV-1 RNA. 864 17

Here we report the design and synthesis of a novel 32-mer peptide, Lys364-378Val445-459.oxidized (named GC-1), which represents a discontinuous epitope from the C3 and C4 domains of gp120 from the HIV-1 IIIB isolate. This peptide induces high titre IgG antibody responses in mice, indicating that it has both B and T cell epitopes. Epitope mapping using reduced GC-1 and appropriate linear peptides demonstrated that a large proportion of the antibodies raised in mice were directed against discontinuous epitope(s). Furthermore, antibodies to GC-1 peptide cross-reacted with purified HIV-1 strain IIIB gp120, indicating the GC-1 mimicked at least one epitope of the native protein. The peptide, which incorporates three gp120 residues Asp 368, Glu 370 and Asp 457, previously shown to be critical for CD4 ligation, bound to the surface of a CD4 transfected human epithelial cell line HeLa, but not to the parent cell line and inhibited binding of recombinant HIV-1 gp120 to recombinant soluble CD4. We have synthesized the first of a series of discontinuous peptides which will be useful for the probing of interactions of HIV-1 gp120 with the CD4 molecule.
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PMID:Design and synthesis of a highly immunogenic, discontinuous epitope of HIV-1 gp120 which binds to CD4+ve transfected cells. 864 38

An electrochemical biosensor for the detection of short DNA sequences related to the human immunodeficiency virus type 1 (HIV-1) is described. The sensor relies on the immobilization and hybridization of the 21- or 42-mer single-stranded oligonucleotide from the HIV-1 U5 long terminal repeat (LTR) sequence at carbon paste or strip electrodes. The extent of hybridization between the complementary sequences is determined by the enhancement of the chronopotentiometric peak of the Co(phen)3(3+) indicator. Numerous factors affecting the probe immobilization, target hybridization, and indicator binding reactions are optimized to maximize the sensitivity and speed the assay time. A detection limit of 4 x 10(-9) M HIV-1 U5 LTR segment is reported following a 30 min hybridization. The hybridization biosensor format obviates the use of radioisotopes common in radioactive methods for the detection of HIV-1 DNA. We also report on the direct adsorptive chronopotentiometric stripping measurements of trace levels of various HIV-1 DNAs.
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PMID:DNA electrochemical biosensor for the detection of short DNA sequences related to the human immunodeficiency virus. 869 62

A 16-base pair oligo(purine)-oligo(pyrimidine) sequence present in the coding region of two HIV 1 proviral genes (pol and nef) was chosen as a target for triplex-forming oligonucleotides in in vitro transcription assays. Inhibition of transcription elongation was observed with triplex-forming oligonucleotide-acridine conjugates (Acr-15-TCG:5'-Acr-T4CT4G6-3' and Acr-9-TC:5'-Acr-T4CT4-3' where C is 5-methylcytosine) under conditions where the unsubstituted oligomers did not exhibit any inhibitory effect. Both SP6 bacteriophage RNA polymerase and eukaryotic RNA polymerase II were physically blocked by such a triplex barrier. The polymerase arrest is caused by the triple-helical complex involving the hydrogen-bonded oligonucleotide stabilized by the intercalated moiety and not solely by the acridine molecule specifically intercalated at the duplex-triplex junction. The stability of the triple-helical complex formed by the 15-mer containing thymines, cytosine, and guanines (15-TCG) and involving the formation of six contiguous C.GxG base triplets was strongly enhanced in the presence of a benzopyridoindole derivative (BePI), which intercalates in triplex structures. This improvement of the binding affinity led to an increased inhibition of transcription elongation. The present results demonstrate the necessity to use triplex-forming oligonucleotides with high binding affinity and a long residence time on their double-stranded target to efficiently inhibit transcription elongation. These data provide a rational basis for the optimization and the development of triplex-forming oligonucleotides as transcriptional blockers, even when they are targeted to the transcribed portion of a gene, downstream of the transcription initiation site.
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PMID:Specific inhibition of in vitro transcription elongation by triplex-forming oligonucleotide-intercalator conjugates targeted to HIV proviral DNA. 875 10

Human immunodeficiency virus type 1 (HIV-1) Gag-specific cytotoxic T lymphocyte (CTL) responses were studied in seven seropositive long-term asymptomatic individuals (CDC A1) with stable CD4 counts for more than 8 years. Using a set of partially overlapping peptides covering the whole Gag, five 15-20-mer peptides were found to contain CTL epitopes. Further characterization of these epitopes revealed a new HLA-A25-restricted CTL epitope in p24, p24(203-212) ETINEEAAEW. This region of Gag is highly conserved in clades B and D of HIV-1. Naturally occurring amino acid sequences, containing p24(203)D (consensus HIV-1 clades A, C, F, G and H) or p24(204)I (HIV-2ROD) were not recognized by CTL recognizing the index peptide. No virus variants with mutations in this sequence were found in peripheral blood mononuclear cells from the HIV-1-infected individual concerned during the 8 year observation period, indicating that the virus had not escaped from the observed CTL response.
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PMID:Fine-specificity of cytotoxic T lymphocytes which recognize conserved epitopes of the Gag protein of human immunodeficiency virus type 1. 876 Apr 12

Oligopeptides derived from the gag polyprotein (Pr55gag) of human immunodeficiency virus type 1 (HIV-1) segment were used to evaluate the extension of the putative binding region for the complex of Pr55gag and the human cytosolic peptidyl prolyl cis/trans isomerase (PPIase) 18 kDa cyclophilin (Cyp18). Five N-terminally acetylated, C-terminally amidated oligopeptides containing one (HIV-1 Gag218-224; 1), two (HIV-1 Gag218-226 and HIV-1 Gag217-224; 2 and 3, respectively), three (HIV-1 Gag217-226; 4) or four (HIV-1 Gag213-237; 5) proline residues were synthesized. Using competition experiments with a standard substrate the binding affinities to Cypl8 of the synthesized peptides were determined. The IC50 value of 184 microM for the 25-mer peptide 5 was fivefold or more lower than those of the peptides 1-4 lacking one or more prolines. Failure of competition in assays containing enzymes of other PPIase families by millimolar concentrations of 5 revealed a Cyp18 specific interaction involving the active site of the enzyme. In its far UV circular dichroism, aqueous solutions of 5 display properties of random coil conformation, but spectra were also consistent with a small contribution of proline specific secondary structures. However, a proline-rich peptide typical of forming left-handed polyproline II helices did not compete for the active site of Cypl8. The results demonstrate that the putative binding region of HIV-1 gag polyprotein has a certain degree of binding affinity to the PPIase site of Cyp18, and may add a previously unrecognized topological component to the known subsite specificity of cyclophilins.
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PMID:Extended binding sites of cyclophilin as revealed by the interaction with HIV-1 Gag polyprotein derived oligopeptides. 883 Jun 60

Spatial orientations of bulky DNA adducts can influence the extent of resistance to digestion by exonucleases and translesion synthesis by HIV-1 reverse transcriptase (HIV-1 RT). In order to determine how different diastereomers of benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide (BPDE)-adducted DNAs influence the activity of these enzymes, 11-mer and 33-mer oligodeoxyribonucleotides were synthesized bearing site-specific and stereospecific BPDE adducts at adenine N6 on position two of the human N-ras codon 61. Phosphodiesterase I, which hydrolyzes DNA in the 3'-->5' direction, exhibited greater resistance opposite the lesion with C10-R BPDE-adducted templates than the corresponding C10-S adducts. However, the opposite stereoselective resistance to digestion was observed with phosphodiesterase II, which hydrolyzes DNA in the 5'-->3' direction. These results are complemented by the in vitro replication pattern exhibited with HIV-1 RT. Primer extension reactions under conditions defining single encounters between polymerase and substrate revealed adduct-dependent termination one base 3' to each of the lesions. When experimental conditions were altered to permit multiple encounters, HIV-1 RT was able to replicate past the damaged site on four of the six adducted templates, exhibiting little pausing opposite the lesion. Analyses of the replication pattern past these lesions revealed two general categories of replication blockage, which, like the exonucleolytic digestion data, were also based on the C10-R and C10-S configuration of the stereoisomers. Thus, the chirality of BPDE-dA adducts modulates enzymatic functions. Furthermore, the (+)- and (-)-anti-trans-BPDE-dA modified templates exhibited the most facile bypass, while the (+)- and (-)-anti-cis-BPDE adducts were most blocking.
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PMID:Impact of the stereochemistry of benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide-deoxyadenosine adducts on resistance to digestion by phosphodiesterases I and II and translesion synthesis with HIV-1 reverse transcriptase. 883 43

Four 25-mer oligonucleotides containing m4T(T*) with the 3'-->5' sequences A-T*-A, A-T*-C, G-T*-G and G-T*-C, together with four oligonucleotides containing the same sequences with unmodified T, were studied for the effect of the immediate 5' and 3' bases flanking m4T on in vitro replication. Under enzyme-limiting conditions, all m4T-containing oligomers showed a varying sequence-dependent blockage at the base 3' to m4T. However, with time and high concentrations of dNTP's, full replication beyond m4T did occur with Klenow fragment (Kf), although substantial blockage remained, particularly in the case when the sequence was 3'-A-T*-A-5'. The extent of blockage at the base 3' to m4T, compared to complete replication using Kf, followed the order A-T*-A > A-T*-C >> G-T*-C > or = G-T*-G. Two other DNA polymerases, HIV-RT and Sequenase, which, unlike Kf, do not have 3' proofreading activity differ, agreed with data obtained with Kf. We conclude that the extent of complete replication of m4T-containing oligomers is primarily a function of the 3' flanking base with a lesser effect of the 5' base and requires specific dGTP insertion opposite m4T. These data suggest that a 5' G . C pair favors the formation of the following T*-G and this latter step is rate-limiting. However, once a T*-G pair is formed, rapid elongation to full length transcripts occurs.
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PMID:Replication of O4-methylthymine-containing oligonucleotides: effect of 3' and 5' flanking bases on formation and extension of O4-methylthymine . guanine basepairs. 884 83

A hairpin ribozyme (HR112) and two hammerhead ribozymes (RZ115 and RZ119) containing a 5'C(UUCG)G3' loop were designed to cleave the long terminal repeat (LTR) of HIV-1. When the ribozyme catalyzed RNA cleavage reaction for a chemically synthesized 19 mer (LTR 19) was measured, the t 1/2 value of LTR 19 mediated by RZ115 was smaller than that of the RZ119 case. Moreover, the transformed CEM cells harboring the gene encoding these ribozymes were challenged with a HIV-1IIIB strain, two ribozymes, HR112 and RZ119 possessed strong anti-HIV-1 activity. However, the anti-HIV-1 activity displayed by RZ115 was weak. On the basis of secondary structure predictions of the RNA transcribed with the gene encoding ribozymes, the secondary structure of the transcribed RNA with RZ115 sequences was observed to be different from those with the other ribozymes. It has been demonstrated that the secondary structures of transcribed RNAs can possibly influence the anti-HIV-1 activity.
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PMID:Design and anti-HIV-1 activity of ribozymes that cleave HIV-1 LTR. 884 84


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