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)

An antisense phosphorothioate oligodeoxynucleotide 27-mer complementary to the rev gene mRNA of the human immunodeficiency virus (HIV-1) was administered to rats through intravenous injections and subcutaneous infusions in order to investigate the disposition of this compound. In addition, nonlethal toxic responses of the rat were evaluated. A biphasic plasma clearance with t1/2 alpha of 20-25 min and t1/2 beta of 27-41 hr was observed. Single doses ranging from 35 to 3257 micrograms were examined, and the plasma concentration and area under the plasma concentration-time curve (AUC) were found to be directly proportional to the dose. Continuous subcutaneous infusion of 50 mg over 28 days was also examined. The oligonucleotide is completely eliminated in the urine over 3 days. Electrophoretic analysis demonstrated that the excreted compound has the same mobility and UV-absorbance profile as the administered compound. Measurement of accumulation and distribution into tissues revealed unique tissue-specific rates and extent of oligonucleotide movement into and out of tissues. Results of the chronic infusion study suggest that uptake into tissue is not saturated, even after 28 days of infusion. Analysis of blood plasma from oligonucleotide-treated animals shows a possible transient elevation in levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), but not alkaline phosphatase (AP), gamma-glutamyltransferase (GT), and bilirubin. The data collectively support the potential utility of phosphorothioate oligonucleotides as therapeutic agents in vivo.
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PMID:Pharmacokinetics of an antisense phosphorothioate oligodeoxynucleotide against rev from human immunodeficiency virus type 1 in the adult male rat following single injections and continuous infusion. 806 15

This report investigates the generation of cytotoxic T lymphocytes (CTL) by in vivo administration of a synthetic antigen linked to a lipid moiety, tripalmitoyl-S-glyceryl cysteine (P3C). The antigen consisted of a 17-mer peptide, derived from the gp120 envelope protein of the human immunodeficiency virus type-1 (HIV-1), in a tetravalent multiple antigenic peptide (MAP) configuration. A single injection of MAP-P3C elicited a long-lasting CTL response in mice. The route of administration was not a determining factor, since intravenous (i.v.) and intraperitoneal (i.p.) priming were both effective. The HIV strain-specific cytotoxic lymphocytes were of the CD8+ subset and class I restricted. A broad cytolytic activity could be achieved by priming with a mixture of homologous peptides from gp120 IIIB and MN strains. Following the administration of the monoclonal antibody GK1.5, resulting in the depletion of the CD4+ T-lymphocyte subpopulation, mice were able to mount a strong CTL response. This finding demonstrates that in priming with a peptide antigen covalently linked to a lipid, such as MAP-P3C, CD4+ cells are not required for the generation of CD8+ cytotoxicity. In contrast, the elimination of macrophages by the carrageenan pretreatment caused suppression of the T-cell lytic activity, suggesting a substantial contribution of the phagocytic cells in mounting CTL response. Taken together, these results may lead to new strategies in designing a human immunodeficiency virus type-1 (HIV-1) vaccine based on synthetic peptides.
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PMID:Cellular immune responses induced by in vivo priming with a lipid-conjugated multimeric antigen peptide. 810 82

Triple helices can be formed on single-stranded oligopurine target sequences by composite oligonucleotides consisting of two oligonucleotides covalently linked by either a hexaethylene glycol linker or an oligonucleotide sequence. The first oligomer forms Watson-Crick base pairs with the target, while the second oligomer engages in Hoogsteen base pairing, thereby acting as a molecular clamp. The triple-helical complex formed by such an oligonucleotide clamp, or "oligonucleotide-loop-oligonucleotide" (OLO), is more stable than either the corresponding trimolecular triple helix or the double helix formed upon binding of the oligopyrimidine complement to the same oligopurine target. Attaching a psoralen derivative to the 5' end of the OLO allowed us to photoinduce a covalent linkage to the target sequence. The psoralen moiety became covalently linked to all three portions of the triplex, thereby making the oligonucleotide clamp irreversible. These crosslinking reactions introduced strong stop signals during DNA replication, as shown on a plasmid containing a portion of the HIV proviral sequence of human immunodeficiency virus. A 16-mer oligopurine sequence corresponding to the "polypurine tract" of human immunodeficiency virus was chosen as a target for a psoralen-OLO conjugate. Three different stop signals for DNA polymerase were observed, corresponding to different sites of polymerase arrest on its template. Even in the absence of photoinduced crosslinking, the psoralen-OLO conjugate was able to arrest DNA replication. The formation of triple-helical structures on single-stranded targets may provide an alternative to the antisense strategy for the control of gene expression.
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PMID:Oligonucleotide clamps arrest DNA synthesis on a single-stranded DNA target. 823 49

Using the process of "antibody antigenization," we engineered two antibody molecules carrying in the third complementarity-determining region of the heavy chain variable domain a 7-mer or a 15-mer peptide epitope of the first extracellular domain (D1) of human CD4 receptor--namely, Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser (SFLTKGPS; positions 42 through 49) and Gly-Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-Ala (GSFLTKGPSKLNDRA; positions 41 through 55). These amino acid sequences are contained in the consensus binding site for the human immunodeficiency virus (HIV) on CD4 receptor. Both antigenized antibodies (AgAbs) bound recombinant gp120 and were recognized by a prototype monoclonal antibody to CD4 whose binding site is within amino acid residues 41-55. AgAbs were then used as immunogens in rabbits and mice to elicit a humoral response against CD4. Only the AgAb carrying the sequence 41GSFLTKGPSKLN-DRA55 induced a response against CD4. The induced antibodies showed specificity for the amino acid sequence of CD4 engineered in the AgAb molecule, were able to inhibit the formation of syncytia between human CD4+ T cells MOLT-3 and 8E5 (T cells that are constitutively infected with HIV), and stained human CD4+ CEM T cells. Four murine monoclonal antibodies were used to analyze the relationship between syncytia inhibition and CD4 binding at the single antibody level, and indicated that recognition of native CD4 is not an absolute requirement for inhibition of syncytia. This study demonstrates that antigenized antibodies can be used as immunogens to elicit site-specific and biologically active immunity to CD4. The importance of this approach as a general way to induce anti-receptor immunity and as a possible new measure to immunointervention in HIV infection is discussed.
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PMID:Active immunity against the CD4 receptor by using an antibody antigenized with residues 41-55 of the first extracellular domain. 826 9

Serologic V3 loop peptide-binding assays have been used to predict divergent human immunodeficiency virus type 1 (HIV-1) strains from the Commonwealth of Independent States (former Soviet Union) that have been subsequently confirmed by sequencing of the V3 region. Initial screening was done by MN V3 peptide binding; 12 parenterally infected HIV-1-positive subjects from Elista and Rostov (group 1) with low-titer MN binding and 6 heterosexually infected HIV-1-positive adults from Byelorussia (group 2) with high-titer MN binding were selected. A consensus sequence from the Elista and Rostov areas was generated; a corresponding 14-mer peptide was synthesized and used in an indirect ELISA to screen sera from 392 individuals from diverse geographic areas. Reactivity to the consensus peptide was 82% in subjects from the homologous areas and 11%-38% in other areas. Antibody binding to a panel of synthetic V3 peptides may be used to predict the presence of diverse strains of HIV-1 within virally heterogenous populations.
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PMID:Identification of human immunodeficiency virus type 1 subtypes and their distribution in the Commonwealth of Independent States (Former Soviet Union) by serologic V3 peptide-binding assays and V3 sequence analysis. 833 67

A 16-mer oligodeoxynucleotide (ODN) which specifically recognizes the polypurine tract (PPT) located upstream of the 3' long terminal repeat (LTR) of human immunodeficiency virus (HIV) proviral DNA via triplex formation is shown to have a dramatic effect on in vitro transcription from the HIV-LTR promoter. In the presence of HeLa cell extracts, a shorter RNA transcript is obtained in the presence of the 16-mer ODN. This truncated RNA lacks about 200 nucleotides from its 3' region. The PPT sequence is not responsible for this effect. Instead, this process involves a purine-rich sequence in the gag mRNA located around position +400. The imperfect hybrid formed between the 16-mer ODN and mRNA is precisely cleaved by RNase H contained in HeLa cell extracts. These data show that sophisticated control experiments must be designed before any conclusion can be drawn on the effect of oligonucleotides used in vitro and in cell cultures.
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PMID:Unexpected effect of an anti-human immunodeficiency virus intermolecular triplex-forming oligonucleotide in an in vitro transcription system due to RNase H-induced cleavage of the RNA transcript. 838 79

The antiviral activity of antisense oligodeoxynucleotide phosphorothioates complementary to the tat gene, the gag mRNA, and the rev mRNA were studied in a long-term infection model. Three antisense oligonucleotides directed to the splice-acceptor site of the tat gene failed to suppress human immunodeficiency virus type 1 replication at 1 microM concentration in long-term culture. In contrast, two oligodeoxynucleotide phosphorothioates (28-mer) complementary to the gag and the rev mRNAs inhibited viral replication for > 80 days, and the antiviral activity was sequence- and length-dependent. In addition, after pretreatment of cells we could reduce the concentration of the antisense oligodeoxynucleotides by > 10-fold and still maintain the inhibition of viral replication. These results suggest that chemotherapy for human immunodeficiency virus type 1 infection with antisense oligodeoxynucleotide phosphorothioates may be achieved by an initial high-dose treatment followed by a lower maintenance dose.
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PMID:Long-term treatment of human immunodeficiency virus-infected cells with antisense oligonucleotide phosphorothioates. 848 3

Although having variability in primary sequence, the v3 loop of gp120 in pathogenic strains of human immunodeficiency virus type-1 (HIV-1) is positively charged and known to interact with sulfated polysaccharides. Because the interaction of sulfated polysaccharides with the v3 loop inhibits HIV infection in vitro, we investigated the interaction of the v3 loop with phosphodiester (PO) and phosphorothioate (PS) oligodeoxynucleotides (oligos). In a solid-phase ELISA assay, a PS 28-mer homopolymer of cytidine, SdC28, blocked the binding of the v3 loop-specific monoclonal antibody (mAb) 9284 to rgp120 more potently than did dextran sulfate. In addition, like dextran sulfate, SdC28 appeared to bind specifically to the v3 loop, because neither compound inhibited the binding of other anti-gp120 mAbs. In contrast to PS oligos, PO oligos did not inhibit mAb 9284 binding. The length dependence of the interaction of PS oligos with the v3 loop was studied by using a series of PS oligos. A discrete loss of inhibiting activity occurred as a function of decreasing PS oligo length, which was most marked between PS oligos of 18-mer and 12-mer in length. We further probed the chemical nature of the interaction of oligos with gp120 by measuring the gp120 binding affinities of PS and PO oligos of various lengths. We employed a 5'-32P-labeled alkylating oligo, ClRNH32P-OdT15, and determined that the Km of gp120 binding is 4 microM. We also determined values of competition constant (Kc) for PS competitors of ClRNH32P-OdT15 binding. The binding constant (= 1/Kc) for PS oligos showed a discrete increase in gp120 binding for PS oligos > 12- to 18-mer in length, with no further increment beyond an 18-mer. Given the important role of the v3 loop in HIV-1 pathogenicity, these data suggest that therapeutic trials of PS oligos should be considered.
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PMID:Phosphorothioate oligodeoxynucleotides bind to the third variable loop domain (v3) of human immunodeficiency virus type 1 gp120. 849 4

A 15-mer C-5 propyne modified phosphorothioate oligodeoxynucleotide antisense to rev was approximately 5-fold more effective in providing viral inhibition compared to a 28-mer unmodified phosphorothioate oligodeoxynucleotide targeted to the same sequence and previously shown to inhibit HIV-1 in a sequence-dependent manner. The antiviral effect was obtained by lipofection or simple addition of 0.2-1 microM modified oligodeoxynucleotide to the culture medium of H9 cells chronically infected with the HIV-1LAI isolate of human immunodeficiency virus type 1. We conclude that C-5 propyne oligodeoxynucleotides in accordance with previous findings by others are superior to unmodified phosphorothioates in providing inhibition of HIV-1 in a sequence-dependent manner and that this inhibition can be conferred by oligodeoxynucleotides in free solution.
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PMID:Inhibition of HIV-1 in vitro by C-5 propyne phosphorothioate antisense to rev. 858 62

From an extract of a Streptomyces culture, we identified and purified a novel compound, NP-06, which is active against human immunodeficiency virus (HIV) in vitro. Analyses indicate that NP-06 is a hydrophobic 21-mer oligopeptide, N terminally cyclized through the side chain of Asp-9, containing two intramolecular cystine linkages with a molecular weight of 2,163.4. The 50% inhibitory concentrations were 2.8 and 1.3 microM when NP-06 was tested for in vitro anti-HIV-1 activity in ATH8 cells and phytohemagglutinin-activated peripheral blood mononuclear cells, respectively, NP-06 appears to block the early stage of HIV-1 infection, most likely at the stage of virus-cell fusion.
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PMID:NP-06: a novel anti-human immunodeficiency virus polypeptide produced by a Streptomyces species. 861 94


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