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

Deoxyguanylic acids, but not other deoxynucleotides, as short as 3- to 4-mer, were effective in preventing HIV-1-induced cytopathicity. In addition, they prevented giant cell formation of infected Sup-T1 cells, and p24 production in HIV-1 infected H9 cells. Phosphorylation at either the 5'- or 3'-end enhanced these activities. Furthermore, 5'-phosphorylated phosphorothioate tetradeoxyguanylic acid was effective in reducing HIV production in chronically infected cells (H9/IIIB). The search for the target steps of this compound revealed that it inhibits at least 3 steps in the life cycle of HIV: interaction with CD4 (measured by inhibitory effect on the syncytia formation between Sup-T1 and H9/IIIB cells), reverse transcriptase, and step(s) after integration. These results suggest that phosphorylated phosphorothioate tetradeoxyguanylic acid may be a novel candidate for a therapeutic agent of AIDS.
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PMID:Antiviral action of oligodeoxyguanylic acids against human immunodeficiency virus type 1. 754 70

Humoral responses to the HIV-1 envelope were investigated in 30 human volunteers enrolled in a phase I vaccine therapy trial of rgp160 (LAI/LAV) using two techniques that emphasize detection of antibody response against linear (continuous) epitopes: immunoblotting and PEPSCAN. Seven fusion proteins containing large portions from constant regions 1, 2, 3, and 5, and variable region 3 of gp120 and two regions in the transmembrane protein, gp41, were employed in immunoblots to quantitatively measure immune response as a function of immunization. In addition, the entire gp160 (LAI/LAV) envelope protein was constructed in duplicate sets of 211 overlapping 12-mer peptides to fine-map the changes. Immunoblotting defined significant changes in reactivity to epitopes in constant regions; of 28 volunteers completing the trial, the percentage with reactivity against C1 changed from 62 to 100%; for C2, from 0 to 46%; for C3, from 0 to 82%; and for a constant region in gp41, from 25 to 68%. PEPSCAN on a subset (n = 8) of these volunteers identified new reactivity to epitopes throughout the envelope, concentrated in V1, C3, and C5 in gp120 and several peptides in gp41. Completely immunized patients responded to double the number of linear epitopes compared with two patients receiving alum alone. The results verify that the response to rgp160 is significantly broadened after immunization, providing additional evidence that HIV-1-infected volunteers can expand their antibody repertoire against a protein from a pathogen during chronic infection with that same pathogen. These results expand those previously obtained in this patient cohort, by defining explicitly the immunogenic regions recognized postvaccination and by providing methodology for quantitating those changes.
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PMID:Humoral responses to linear epitopes on the HIV-1 envelope in seropositive volunteers after vaccine therapy with rgp160. 754 25

The use of antisense oligodeoxynucleotides as antiviral drugs to combat HIV-1 infection may offer an alternative to traditional pharmacological therapies. We compared the effects of two 28-mer antisense phosphorothioate oligodeoxynucleotides [PS-oligo(dN)] with non-sequence-specific controls on HIV-1 replication in long-term human monocyte/macrophage and PBMC cultures. The anti-rev PS-oligo(dN) was complementary to the messenger RNA (mRNA) sequences derived from the overlapping region of the HIV-1 regulatory genes tat and rev, while anti-gag targeted the translational initiation site of the gag mRNA. In vitro cytotoxicity of the PS-oligo(dN) was evaluated at concentrations ranging from 0.1 to 10.0 microM for a period of 20 days. Cell survival was 100% at 0.1 microM, but decreased to 5% at 10.0 microM in relation to the untreated control cultures. Our data demonstrate that replication of both the T cell-tropic and macrophage-tropic HIV-1 strains in primary cells can be inhibited by PS-oligo(dN) in a sequence-specific and dose-dependent manner at concentrations achievable in vivo. However, the sequence-dependent antiviral activity of the utilized PS-oligo(dN) was limited to a window of specificity at concentrations between 0.25 and 1.0 microM.
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PMID:Antisense phosphorothioate oligodeoxynucleotides alter HIV type 1 replication in cultured human macrophages and peripheral blood mononuclear cells. 754 14

The human immunodeficiency virus type-1 (HIV-1) Tat protein stimulates transcriptional elongation. Tat is introduced to the transcription machinery by binding to the transactivation response region (TAR) RNA stem-loop encoded by the 5' leader sequence found on all HIV-1 mRNAs. We have used multidimensional heteronuclear NMR to determine the structure of the TAR RNA in the presence of the ADP-1 polypeptide, a 37-mer that carries the minimal RNA recognition region of the Tat protein and closely mimics Tat binding specificity. In the presence of a variety of ligands, including ADP-1, related basic peptides and the amino acid derivative argininamide, the bulge region of TAR undergoes a local conformational rearrangement and forms a more stable structure. The structure of TAR in the bound form has been determined from over 1000 NMR-derived constraints. The U23 residue at the 5' end of the bulge is positioned near G26 and A27 in the major groove, rather than stacked on A22 as in the free TAR. U23 and G26 are brought into close proximity by contacts to the guanidinium group and side-chain amide group of a common arginine residue. However, the interaction of this guanidinium group with TAR is not the only source of binding specificity. Besides NOEs to the arginine residue participating in the conformational change, ADP-1 shows additional intermolecular NOEs to TAR, suggesting that there are multiple points of contacts between TAR RNA and residues from the basic and core regions of Tat. These structural results provide important clues towards the identification of small molecular mass and/or peptidomimetic inhibitors of the essential Tat-TAR interaction.
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PMID:The structure of the human immunodeficiency virus type-1 TAR RNA reveals principles of RNA recognition by Tat protein. 756 92

HIV infection induces antibodies that mediate neutralization of cell-free virus and may protect against viral infection. Neutralizing human mAb that bind to the third hypervariable domain (V3) of gp120 have been generated from PBL of HIV-seropositive subjects. Twelve such mAb recognize 9 different epitopes spanning an 11 amino acid stretch at the tip of the V3MN loop. The epitopes of an additional two mAb have not been precisely determined but occur within a 15-mer peptide around the tip of the V3 loop. Eleven of 13 mAb are reactive with at least one other V3 peptide besides MN, indicating that cross-reactivity is a common phenomenon amongst anti-V3 antibodies. All the mAb achieved 50% neutralization of HIVMN at antibody concentrations of 12 to 4700 ng/ml. Two mAb, which recognized epitopes at the top of the V3 loop, GPGR and GRAF, neutralized strains as divergent as MN and IIIB. The affinities of all mAb tested were shown to be substantially higher for the rgp120 than for a 23-mer peptide from the V3 loop of the homologous strain. A significant inverse correlation was demonstrated between affinities and the 50% neutralizing doses for HIVMN.
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PMID:Repertoire of neutralizing human monoclonal antibodies specific for the V3 domain of HIV-1 gp120. 767 79

A 134-mer peptide corresponding to the N-terminal sequence of p24 (residues 146-279 of the gag gene product of the LAV strain) was chemically synthesized using highly optimised protocols on an ABI 430A synthesizer. The crude peptide was obtained by treating the peptide-resin with HF, then purified by a combination of size exclusion and RP-HPLC. One hundred milligram of 90% pure 134-mer can be obtained within a month. Both mice and rabbit polyclonal antisera raised against a commercial preparation of recombinant p24, and a pooled sera from HIV-1 infected individuals reacted strongly with the 134-mer peptide in ELISA. Both mice and rabbits immunized with the free peptide emulsified in Freund's complete adjuvant generated strong anti-peptide and anti-p24 antibody responses as judged by immunoblots and ELISAs. Immunodominant epitopes were mapped to residues 201-227 (LKETINEEAAEWDRVHPVHAGPIAPG). These B-cell epitopes had previously been identified by mouse monoclonal antibodies raised against HIV-1 virus or gag gene products. Furthermore, murine T-cell lines generated against the 134-mer peptide were found to respond to two short peptides, P24B (residues 195-215) and P24D1 (residues 268-279). These two T-cell epitopes were previously reported as human helper T-cell and CTL epitopes, respectively. These results clearly indicate that the synthetic 134-mer peptide could elicit both T- and B-cell responses to HIV-1 similar to those obtained with the natural viral gag protein, and could be useful for the development of a synthetic HIV vaccine.
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PMID:Synthesis and immunological characterization of a 134-mer synthetic peptide corresponding to the N-terminal half of the HIV-1 nucleoprotein, p24. 767 66

Most synthetic HIV-1 gp120 V3 loop peptides that are used as immunogens in experimental HIV-1 vaccine studies are modeled from the naturally occurring viral gp120 V3 loops. In experimental animals these immunogens generally elicit type (or variant)-specific neutralizing antibodies that are not broadly reactive among HIV-1 variants. In an attempt to find a more general structure for the V3 loop, we have obtained candidates that mimic V3 loop sequences by screening random epitopes displayed in a fusion phage 15-residue epitope library. Human monoclonal antibody 447-52D, a highly potent and broadly reactive virus-neutralizing antibody that recognizes the conserved V3 loop tip motif GPXR, was the probe. By using a screening method that was designed specifically for this work, we identified hundreds of reactive phage clones, 70 of which were sequenced. Over 98% of the epitopes contain the motif GPXR, yet none of the 70 are an identical match to any V3 variant loop described to date. One of these sequences was synthesized as the beta-maleimidopropionyl 15-mer peptide, covalently conjugated to a carrier and used to immunize rabbits. High anti-peptide titers were obtained in all animals with three of four individual responses also binding to a peptide that is representative of the "North American consensus" V3 loop. The sera from these three positive rabbits neutralized HIV-1 variant SF-2 in vitro. In addition, one of them was capable of neutralizing variant AL-1. Both of these variants are considered to have V3 loops of the North American consensus type. Thus, neutralizing responses were obtained by use of an immunogen that was selected for its ability to bind a broadly reactive human monoclonal antibody rather than modeled from an HIV-1 gp120 V3 loop sequence.
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PMID:Identification of HIV vaccine candidate peptides by screening random phage epitope libraries. 768 12

A minimal kinetic mechanism for HIV reverse transcriptase (RT)-catalyzed RNA-dependent and DNA-dependent DNA polymerization was determined by pre-steady-state kinetic methods to be: [formula: see text] where E, TP, dNTP, and PPi are RT, template-primer, 2'-deoxynucleoside 5'-triphosphate, and inorganic pyrophosphate, respectively. Defined sequence template-primers that encode for incorporation of dTTP were prepared by annealing either a 44-mer RNA template or a 44-mer DNA template (of the same sequence) to a 21-mer DNA primer (r44:d21-mer and d44:d21-mer, respectively). The values of the above kinetic constants were determined for dTMP and 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP) incorporation into both template primers. The kcat and Km values calculated from these kinetic constants were similar to the values directly determined from steady-state experiments. Further, the net rate constants for processive incorporation of three successive nucleotides into the r44:d21-mer were similar indicating that a rate-determining step did not follow catalysis. A 20-fold difference in the rate constants (kp) for incorporation of dTMP into the r44:d21-mer versus the d44:d21-mer was largely responsible for the difference in the calculated processivity numbers of 340 and 5, respectively. Finally, the rate constant for pyrophosphorolysis of the 3'-AZTMP-terminated r44:d21-mer (kpyro) was similar to the rate constant for dissociation of the chain-terminated template primer from the enzyme (koff) indicating that millimolar concentrations of intracellular inorganic pyrophosphate would be required for pyrophosphorolysis of AZTMP-terminated retroviral genomes.
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PMID:Human immunodeficiency virus reverse transcriptase. A kinetic analysis of RNA-dependent and DNA-dependent DNA polymerization. 768 54

The human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) heterodimer (M(r) = 66,000 and M(r) = 51,000) has been photoaffinity labeled using 4-thiodeoxyuridine triphosphate (S4-dUTP) as a probe. A nascent polymerization complex was assembled from a single-stranded DNA template, a 12-mer DNA primer, and the necessary dNTPs (one of which was alpha-32P-labeled) to extend the primer to produce the n-1 product. The photoaffinity probe was then uniquely added at the 3'-terminal position of the extended primer bound at the catalytic site and photolyzed. The larger subunit (p66) was exclusively derivatized. The unique radioactive peptide resulting from proteolysis was isolated and identified by amino acid sequencing.
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PMID:Active site labeling of HIV-1 reverse transcriptase. 768 13

Replication of retroviral RNA into double-stranded DNA provirus involves initiation of plus-strand DNA synthesis at the polypurine tract, PPT, by the reverse transcriptase (RT). The PPT is highly conserved among the known HIV-1 retroviral isolates. It occurs twice, once within the coding region of the integrase and the other one adjacent to the 3' LTR. The data presented show that two antisense oligonucleotides, a 20-mer and a 40-mer, complementary to the PPT induce complete blocks of DNA synthesis whereas an antisense oligonucleotide outside the PPT is only slightly inhibitory. Previously polypurine sequences have been used by several groups for triplex-formation. During replication the HIV-polypurine tract, PPT, is present in a RNA-DNA hybrid. Therefore triple-helix formation consisting of RNA-DNA and a third DNA strand covering the PPT region was tested here by protection against RNase H cleavage in vitro. Incubation with a pyrimidine oligonucleotide in parallel orientation to the PPT-RNA shows some protection. GT-pyrimidine-purine mixed oligonucleotides (25-mer) led to protection against RNase H up to 50% independent of their orientation. The data suggest that triple-helix formation may have taken place with the PPT in vitro. Therefore, this highly conserved structure may prove useful in nucleic acid based anti-viral therapy with antisense or triple-helix approaches. Furthermore, the influence of HIV-1 nucleocapsid (NC) protein, NCp15, on reverse transcription is reported. The data show a two- to three-fold stimulatory effect of the NCp15 on RNA directed DNA synthesis.
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PMID:The polypurine tract, PPT, of HIV as target for antisense and triple-helix-forming oligonucleotides. 768 36


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