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

---

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

Maleylated-human serum albumin (Mal-HSA) inhibited human immunodeficiency virus type-1 (HIV-1) infection of MT-4 cells in vitro. It was also found to inhibit the fusion between uninfected CD4+ cells (Molt-4 clone 8 cells) and HIV-1 infected cells (Molt-4/HIV-1) to form syncytia. To investigate the mechanism of the inhibition, a study was designed to determine whether Mal-HSA could bind to CD4+ cells. Mal-HSA could bind to both MT-4 cells and Molt-4 clone 8 cells with high affinity, Kd = 2.0 nM and Kd = 5.8 nM, respectively. However, Mal-HSA could neither inhibit anti CD4 antibody Leu 3a binding to Molt-4 clone 8 cells nor modulate the expression of CD4 molecules on the surface of the cells. Mal-HSA binding to Molt-4 clone 8 cells was completely inhibited by sulfated polysaccharides bearing anti-HIV activity, such as dextran sulfate, fucoidan and carrageenan. Other HIV-1 susceptible human T-cell lines, such as Molt-4, CEM-5, H-9 and HuT-78 cells, also have Mal-HSA binding sites showing a high affinity, Kd = 0.9 +/- 0.4 nM. Mal-HSA binding proteins of Molt-4 clone 8 cells were identified by ligand blotting as 155 and 220 kDa proteins. Unlike dextran sulfate, Mal-HSA could not inhibit reverse transcriptase activity of HIV-1. These results indicate that Mal-HSA inhibits HIV-1 infection and syncytia formation, and suggest that 155 and/or 220 kDa proteins of target cells are involved in HIV-1 adsorption and/or the membrane fusion between HIV-1 and target cells.
...
PMID:Maleylated human serum albumin inhibits HIV-1 infection in vitro. 128 31

The ROD strain of the human immunodeficiency virus type 2 (HIV-2) was used to produce monoclonal antibodies. Virus grown in CEM cells was partially purified by ultracentrifugation and solubilized in a buffer containing Triton X-100. BALB/c mice were inoculated intraperitoneally with 50 micrograms of solubilized virus preparations mixed 1:1 with complete Freund's adjuvant. Animals were boosted on day 28 and sacrificed on day 31. Spleen cells from the immunized animals were fused with SP20/Ag 14 myeloma cells and cultured in HAT medium. Following selection of the hybrids of interest by an HIV-2 ELISA procedure, hybridomas were cloned twice by limiting dilution. Six clones were found to produce antibodies that reacted with HIV-2 antigens as judged by ELISA. These antibodies were concentrated by ammonium sulfate precipitation, and analyzed by the Western blot procedure. Monoclonal antibodies specifically reactive to an HIV protein of 68 KD were obtained. These antibodies did not react with an HIV-2 band of 55 KD. These data showed that the monoclonal antibodies recognized the carboxy terminal region (the RNAse H domain) of the HIV-2 retrotranscriptase enzyme.
...
PMID:Production of monoclonal antibodies to human immunodeficiency virus type-2. 128 63

The drug Ro5-3335 [7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one] inhibits human immunodeficiency virus type 1 (HIV-1) gene expression at the transcriptional level through interference with Tat-mediated transactivation (M.-C. Hsu, A. D. Schutt, M. Holly, L. W. Slice, M. I. Sherman, D. D. Richman, M. J. Potash, and D. J. Volsky, Science 254:1799-1802, 1991). We confirmed this specific inhibitory effect in a quantitative bioassay based on transactivation of a chimeric gene comprising the HIV-1 long terminal repeat promoter fused to the lacZ gene of Escherichia coli and transfected in a HeLa cell line expressing Tat. Ro5-3335 was found to inhibit HIV-1 long terminal repeat-driven lacZ gene expression at a 50% inhibitory concentration of 0.5 microM. The in vitro anti-HIV-1 activity of Ro5-3335 was highly dependent on the nature of the host cells. The highest selectivity index, 50, was found in phytohemagglutinin-stimulated peripheral blood lymphocytes. The selectivity index was between 1 and 10 in the CD4+ T-cell lines CEM, MOLT-4 (clone 8), and HUT-78. In MT-4 and MT-2 cells, Ro5-3335 had no inhibitory effect on HIV-1 replication. The absence of anti-HIV-1 activity of Ro5-3335 in MT-4 cells was confirmed by using different parameters of virus replication and different multiplicities of infection. In persistently HIV-1-infected HUT-78/IIIB/LAI cells, Ro5-3335 failed to demonstrate any activity at subtoxic concentrations. The cytotoxicity of Ro5-3335 was significantly lower in peripheral blood lymphocytes than in the CD4+ T-cell lines.
...
PMID:Cell type-specific anti-human immunodeficiency virus type 1 activity of the transactivation inhibitor Ro5-3335. 128 90

2',3'-Dideoxy-5-fluoro-3'-thiacytidine (FTC) has been shown to be a potent and selective compound against human immunodeficiency virus type 1 in acutely infected primary human lymphocytes. FTC is also active against human immunodeficiency virus type 2, simian immunodeficiency virus, and feline immunodeficiency virus in various cell culture systems, including human monocytes. The antiviral activity can be prevented by 2'-deoxycytidine, but not by other natural nucleosides, suggesting that FTC must be phosphorylated to be active and 2'-deoxycytidine kinase is responsible for the phosphorylation. By using chiral columns or enzymatic techniques, the two enantiomers of FTC were separated. The (-)-beta-enantiomer of FTC was about 20-fold more potent than the (+)-beta-enantiomer against human immunodeficiency virus type 1 in peripheral blood mononuclear cells and was also effective in thymidine kinase-deficient CEM cells. Racemic FTC and its enantiomers were nontoxic to human lymphocytes and other cell lines at concentrations of up to 100 microM. Studies with human bone marrow cells indicated that racemic FTC and its (-)-enantiomer had a median inhibitory concentration of > 30 microM. The (+)-enantiomer was significantly more toxic than the (-)-enantiomer to myeloid progenitor cells. The susceptibilities to FTC of pretherapy isolates in comparison with those of posttherapy 3'-azido-3'-deoxythymidine-resistant viruses in human lymphocytes were not substantially different. Similar results were obtained with well-defined 2',3'-dideoxyinosine- and nevirapine-resistant viruses. (-)-FTC-5'-triphosphate competitively inhibited human immunodeficiency virus type 1 reverse transcriptase, with an inhibition constant of 2.9 microM, when a poly(I)n.oligo(dC)19-24 template primer was used. These results suggest that further development of the (-)-Beta-enantiomer of FTC is warranted as an antiviral agent for infections caused by human immunodeficiency viruses.
...
PMID:Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. 128 96

2',3'-Dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and shows beneficial effects in AIDS therapy. The compound inhibits mitochondrial DNA (mtDNA) synthesis at a clinically relevant concentration, which could be responsible for the side effects of ddC observed in the clinic. Thymidine (dThd), one of the substrates of mitochondrial deoxypyrimidine kinase (dPyd kinase), was not able to reverse the mitochondrial toxicity of ddC in CEM cells. Furthermore, the cytoplasmic deoxycytidine kinase (dCyd kinase)-deficient CEM cells were highly resistant to the mitochondrial toxicity of ddC. These data suggest a critical role for cytoplasmic dCyd kinase in the mitochondrial toxicity of ddC. The metabolites of ddC, but not ddC itself, were able to inhibit mtDNA synthesis in isolated mitochondria. The potency of the inhibitory effect was in the order of ddCTP greater than ddCDP greater than ddCMP greater than ddC. The lack of inhibition by ddC of mtDNA synthesis could be due to the inefficient ddC phosphorylation in mitochondria. Although the mitochondrial dPyd kinase was reported to phosphorylate ddC, the phosphorylation of ddC in isolated mitochondria was not detectable. The data suggest that ddC is phosphorylated to ddCTP in the cytoplasm and then transported into mitochondria to exert its inhibitory effect on mtDNA synthesis.
...
PMID:The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2',3'-dideoxycytidine. 131 Jun 74

Syncytium formation, the characteristic cytopathic effect (CPE) of the human immunodeficiency virus (HIV) and cell fusion by Sendai virus, is accelerated by increasing the ambient temperature to values at which normal metabolic activity is inhibited. Uninfected C8166, CEM, and H9 cells were absorbed at 4 degrees C onto monolayers of H9 cells chronically infected with HIV and incubated subsequently at either 37 degrees C or 45 degrees C. Similarly chick and human erythrocytes and Hela cells were agglutinated with Sendai virus at 4 degrees C before incubation at temperatures of up to 50 degrees C. With both viruses the rate of cell fusion was directly related to temperature. Since membrane fluidity is dependent on the phase-transition temperature points of the membrane lipids it is proposed that sufficient membrane fluidity is essential for cell fusion to occur. The implication of these observations on the cytopathology of HIV is discussed.
...
PMID:Temperature enhancement of syncytium formation by HIV and Sendai virus. 131 69

Human monocytes stimulated with phorbol 12-myristate 13-acetate or opsonized zymosan in vitro were viricidal to human immunodeficiency virus type 1 (HIV-1) as measured by the inability of the virus to replicate in CEM cells. Monocytes, when stimulated, release myeloperoxidase (MPO) and produce H2O2; MPO reacts with H2O2 and chloride to form hypochlorous acid, a known microbicidal agent. The viricidal activity of stimulated monocytes was inhibited by the peroxidase inhibitor azide, implicating MPO, and by catalase but not heated catalase or superoxide dismutase, implicating H2O2. Stimulated monocytes from patients with chronic granulomatous disease (CGD) or hereditary MPO deficiency were not viricidal to HIV-1 unless they were supplemented with the H2O2-generating enzyme glucose oxidase or MPO, respectively. The viricidal activity of stimulated, glucose oxidase-supplemented CGD monocytes and MPO-supplemented MPO-deficient monocytes, like that of normal stimulated monocytes, was inhibited by azide and catalase. Monocytesmaintained in culture differentiate into macrophages with loss of MPO and decreased H2O2 production. The viricidal activity of 3- to 9-day monocyte-derived macrophages was decreased unless MPO was added, whereas the loss of viricidal activity by 12-day-old monocyte-derived macrophages was not reversed by MPO unless the cells were pretreated with gamma-interferon. These findings suggest that stimulated monocytes can be viricidal to HIV-1 through the release of the MPO/H2O2/chloride system and that the decreased viricidal activity on differentiation to macrophages results initially from the loss of MPO and, with more prolonged culture, also from a decreased respiratory burst that can be overcome by gamma-interferon.
...
PMID:Viricidal effect of stimulated human mononuclear phagocytes on human immunodeficiency virus type 1. 131 66

2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well as human immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant to deoxycytidine deaminase was found to be the more active antiviral stereoisomer than the (+)-form ((+)-SddC). The (+)-SddC is susceptible to deamination by deoxycytidine deaminase and is 25- and 12-fold more toxic than (-)-SddC in CEM cells in terms of anti-cell growth and anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture of their 5-fluoro analogs ((+/-)-FSddC). Unlike 2',3'-dideoxycytidine, which is a potent inhibitor of mitochondrial DNA synthesis and results in such delayed toxicity as peripheral neuropathy with long term usage, (-)-SddC does not affect mitochondrial DNA synthesis. The (-)form is phosphorylated to (-)-SddCMP and is subsequently converted to (-)-SddCDP and (-)-SddCTP. One additional major metabolite which has been tentatively assigned the name "(-)-SddCMP sialate" was also identified. No significant difference in terms of the profiles of the metabolites was found between 4 and 24 h. There is an appreciable amount of (-)-SddCTP detectable 24 h after removal of the drug. (-)-SddCTP was also found to be approximately 3-fold more potent than (+)-SddCTP in inhibiting human hepatitis B virus DNA polymerase. This is the first nucleoside analog with the unnatural sugar configuration demonstrated to have antiviral activity.
...
PMID:Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication. 132 Nov 32

2',3'-Dideoxyguanosine (ddGuo) is a selective inhibitor of the replication of human immunodeficiency virus in vitro and the most active antihepadnavirus nucleoside analog known in vitro and in vivo, in a Peking duck model. However, the exact route by which this and related guanosine analogs are anabolized to their putative active metabolites in target cells is controversial. The anabolic pathway for the activation of ddGuo was investigated with the use of mutant human lymphoid CCRF-CEM and WI-L2 cell lines deficient in known nucleoside kinases. Uptake of ddGuo by human lymphoid cells and subsequent conversion to mono-, di-, and triphosphorylated metabolites is dose dependent and occurs proportionately to the exogenous concentration of drug. Studies with kinase-deficient CCRF-CEM and WI-L2 mutants revealed that at least two different routes of metabolism are operating in these cells to initiate the phosphorylation of ddGuo to its active dideoxynucleotides, one being deoxycytidine (dCyd) kinase and the other a cytosolic-5'-nucleotidase acting in the anabolic direction as a phosphotransferase. The evidence for this included 1) a lower but significant accumulation of drug anabolites in dCyd kinase-deficient mutants, 2) a lack of cross-resistance of the kinase-deficient mutants to growth inhibition by ddGuo, compared with that by the related analogs dideoxycytidine and arabinosylcytosine, known substrates for dCyd kinase, and 3) identification of different phosphorylation activities for ddGuo in extracts of wild-type cells and kinase-deficient mutants. Knowledge of the enzyme systems involved in anabolism of ddGuo analogs should be important for both new drug design and optimal therapeutic application.
...
PMID:Metabolic pathways for the activation of the antiviral agent 2',3'-dideoxyguanosine in human lymphoid cells. 132 48

2',3'-Dideoxy-3'-thiacytidine (cis-(+/-)-SddC) was found to have potent activity against hepatitis B virus and human immunodeficiency viruses in culture. Recent studies by us identified (-)-SddC as the stereoisomer responsible for the antiviral effect and showed that the cytotoxicity was mainly caused by (+)-SddC. Metabolism studies showed that these drugs were converted to their monophosphates, diphosphates, and triphosphates. The enzyme responsible for the formation of monophosphates was identified to be cytoplasmic deoxycytidine kinase in CEM cells. Uptake studies showed that the intracellular concentration of (-)-SddC and its metabolites was approximately 5-fold higher than that of (+)-SddC metabolites. (-)-SddCTP was more potent than (+)-SddCTP in inhibiting hepatitis B virus replication; (+)- and (-)-SddCTP exhibited minimal inhibition on polymerases alpha and delta, more inhibition on beta, and strong inhibition on gamma. In all cases, (+)-SddCTP was found to be more inhibitory than (-)-SddCTP to all four polymerases. (+)-SddCMP competed with dCTP for incorporation into DNA by DNA polymerase gamma and beta and served as a chain terminator; however, similar incorporation was not detected using other polymerases. The selective inhibition of DNA synthesis in isolated mitochondria by (+)- and (-)-SddCTP suggests a stereospecificity on the mitochondrial uptake of deoxynucleoside triphosphates.
...
PMID:Biochemical pharmacology of (+)- and (-)-2',3'-dideoxy-3'-thiacytidine as anti-hepatitis B virus agents. 133 Oct 54


1 2 3 4 5 6 7 8 9 10 Next >>

---