Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibody responses to 23-valent pneumococcal vaccine were studied in 38 individuals infected with human immunodeficiency virus (HIV), including 6 with asymptomatic infection, 24 with AIDS or AIDS-related complex (ARC) receiving treatment with zidovudine, and 8 untreated AIDS/ARC patients. Antibody responses were significantly higher for asymptomatic persons (aggregate geometric mean, 972 ng of antibody nitrogen (AbN)/ml; P less than .001) and AIDS/ARC patients receiving a median of 12 weeks (range, 4-54) of zidovudine therapy (mean, 369 ng of AbN/ml; P less than .001) when compared with untreated AIDS/ARC patients. Antibody responses among zidovudine-treated AIDS/ARC patients were independent of the dose (mean, 629.2 mg/day; range, 100-1200 mg) or duration of zidovudine therapy. For zidovudine-treated AIDS/ARC patients, persistence of an aggregate antibody response 8 months after vaccination was associated with survival at 14 months after vaccination, whereas waning of response was not. Pneumococcal vaccine should be administered as early as possible in the course of HIV infection. Immunization should be delayed for at least 4 weeks for AIDS/ARC patients initiating zidovudine therapy.
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PMID:Zidovudine improves response to pneumococcal vaccine among persons with AIDS and AIDS-related complex. 189 37

Radiolabeled leukotriene (LT) B4 was incubated with isolated rat hepatocytes in order to assess the metabolism of this chemotactic leukotriene by the liver. At least eight radioactive metabolites were observed, three of which were previously identified as 20-hydroxy-, 20-carboxy-, and 18-carboxy-19,20-dinor-LTB4. A less lipophilic major metabolite (designated HIV) was purified by two reverse phase high performance liquid chromatography separations and was found to exhibit maximal UV absorbance at 269 nm with shoulders at 260 and 280 indicating the presence of a conjugated triene chromophore. Negative ion electron capture gas chromatography/mass spectrometry analysis of the pentafluorobenzyl ester, trimethylsilyl ether derivative of HIV, and positive ion electron ionization mass spectra of the methyl ester trimethylsilyl derivative were consistent with a structure of this metabolite being 16-carboxy-14,15-dihydro-17,18,19,20-tetranor-LTB3. The appearance of this metabolite supports the concept of further beta-oxidation of LTB4 to the carbon 16 which requires the action of 2,4-dienoyl-CoA reductase to remove the 14,15-double bond located two carbon atoms removed from the CoA thioester moiety. One minor metabolite was analyzed by negative ion continuous flow fast atom bombardment mass spectrometry which revealed an ion at m/z 444 which by high resolution mass spectrometry was shown to contain both nitrogen and sulfur. Tandem mass spectrometry suggested the presence of SO3- as well as other fragments corresponding to the amino acid taurine. Incubation of isolated rat hepatocytes with [14C]taurine as well as [3H]LTB4 revealed the incorporation of both radioactive isotopes into this metabolite. The data supported the identification of this metabolite as tauro-18-carboxy-19,20-dinor-LTB4. Amino acid conjugation of leukotrienes has not been previously reported and suggests that such intermediates might participate in enterohepatic circulation of LTB4 metabolites in the intact animal and thus serve as an alternative metabolic route for LTB4 elimination.
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PMID:Metabolism of leukotriene B4 in isolated rat hepatocytes. Involvement of 2,4-dienoyl-coenzyme A reductase in leukotriene B4 metabolism. 216 87

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.
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PMID:Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines. 750 33

Since early growth response-1 (Egr-1) is required for macrophage differentiation and nitric oxide (NO) is immunosuppressive, we hypothesized that NO would reduce Egr-1 expression in rat lung macrophages. The inflammatory stimuli interferon-gamma and lipopolysaccharide induced an early, transient increase in Egr-1 mRNA (> 5-fold at 2 h) and a sustained, high level of inducible NO synthase mRNA (> 100-fold from 4 to 24 h). The NO metabolites nitrite and nitrate rose > 10-fold in medium from stimulated versus unstimulated cells over 24 h. Concomitant with elevated nitrogen oxides, Egr-1 mRNA levels declined to 80% below unstimulated cells at 24 h. This decline was blocked by an inhibitor of NO production, NG-monomethyl-L-arginine. Further, the NO donor S-nitroso-N-acetylpenicillamine inhibited Egr-1 expression in a dose-dependent manner, producing complete inhibition at 0.5 mM. The effect of S-nitroso-N-acetylpenicillamine was not due to reduced macrophage viability. We conclude that Egr-1 induction precedes inducible NO synthase induction in stimulated rat macrophages and that subsequent NO production reduces macrophage expression of Egr-1. We propose that this mechanism is used to regulate macrophage differentiation in human immunodeficiency virus infection and other inflammatory states.
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PMID:Nitric oxide reduces early growth response-1 gene expression in rat lung macrophages treated with interferon-gamma and lipopolysaccharide. 752 82

A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.
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PMID:Synthesis and biological evaluation of N6-cycloalkyl derivatives of 1-deazaadenine nucleosides: a new class of anti-human immunodeficiency virus agents. 756 37

We report on the preclinical results of an immunotherapeutic approach of AIDS mediated by ex vivo propagated CD4+ and CD8+ T-cells. A mean yield of 6.23 x 10(9) lymphocytes, containing 1.82 x 10(9) CD4+, 3.23 x 10(9) CD8+ T-lymphocytes and 8.39 x 10(6) CD34+ peripheral blood progenitor cells (PBPC) were be obtained by continuous flow cytapheresis (CFC) in 15 asymptomatic HIV infected patients (CD4-count > 350/mm3). The CD4/CD8 ratio (mean: 0.53, SD: +/- 0.15) in the cell concentrates reflected the distribution of the circulating lymphocyte subsets in vivo. Absolute lymphocyte counts decreased at a mean of 404/microliter (25%) immediately after CFC but were replaced from the extravascular pool within one hour. Neither the CD4/CD8 ratio nor p24-antigen and neopterin levels did change significantly after cell separation. No alteration of the number of proviral DNA copies (1/10(3)-1/10(6)) could be detected in peripheral T-helper cells by semiquantitative PCR after lymphapheresis. Cells were cryopreserved in liquid nitrogen without substantial loss of viability or function. Ex vivo propagation of T-cells in a strictly autologous manner in the presence of PHA + IL-2 for 14d resulted in a 50-fold expansion rate (140-fold in healthy controls, p < 0.001). Viral replication could be controlled but not completely eliminated by cocultivation with autologous CD8+ T-lymphocytes as measured by limiting dilution nested PCR (NPCR). The expanded cells showed the typical phenotype of highly activated memory type T-lymphocytes (CD3+ CD45RO+ CD25+ HLA-DR+). The distribution of CD4+ and CD8+ T-cells did not reveal significant changes before and after culture indicating that both subsets were equally expanded. Functionally important membrane or intracellular epitopes which were found to be decreased in HIV infected subjects (CD7, CD55, CD59) before culture were reconstituted after ex vivo propagation of T-cells. The functional importance of the up-regulation of complement regulating epitopes (CD55, CD59) after culture could be proven by a significant inhibition of cytolysis of T-cells in the presence of autologous complement. The majority (75%) of expanded CD8+ T-cells stained positive with mAb TIA-1 which is directed to intracellular granules within cytotoxic T-cells. Furthermore, programmed cell death of expanded T-cells could be prevented by cocultivation with fibroblasts which are believed to secrete a cytokine pattern preventing activated T-cells from apoptosis after withdrawal of IL-2 and other stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Investigations on autologous T-cells for adoptive immunotherapy of AIDS. 757 1

The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using 3J(H,H) coupling constants and quantitative NOE experiments. No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3). However, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially. In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain. Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing alpha-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo. This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong alpha-glucosidase I activity. Compound 4 is a good inhibitor of intestinal alpha-glucohydrolases, alpha-glucosidase II, and Golgi alpha-mannosidases I and II, but its N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested. In the case of 2,5-dideoxy-2,5-imino-D-mannitol (DMDP, 7), which is a potent beta-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency toward beta-galactosidase as well. N-Alkylation of compounds 4 and 7, known well as potent yeast alpha-glucosidase inhibitors, resulted in a serious loss of inhibitory activity toward yeast alpha-glucohydrolases. Activity of these nine analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells. Compounds 2 and 3, which are better inhibitors of alpha-glucosidase I than 1, proved active with EC50 values of 69 and 49 micrograms/mL in MT-4 cells and 100 and 37 micrograms/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1. The change in potency and specificity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.
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PMID:N-alkylated nitrogen-in-the-ring sugars: conformational basis of inhibition of glycosidases and HIV-1 replication. 760 1

Cryptococcus neoformans is responsible for pulmonary and meningal infections in HIV patients. The lack of effective cellular cooperation caused by the low level of CD4+ cells, and the resistance of C. neoformans to phagocytosis allows growth and persistence of the yeast in the host. We describe here an in-vitro model of intracellular replication of C. neoformans inside J774-A.1 macrophages, and the determination of the intracellular antifungal activity of amphotericin B and fluconazole alone or in association with IFN-gamma. The maximum inhibitory effect was observed with one MIC of amphotericin B and 100 or 1000 IU/mL of IFN-gamma. amphotericin B alone (at 1 x MIC), or either 1 x or 50 x MIC of fluconazole in normal or IFN-gamma activated macrophages, did not eradicate the ingested yeast. A potential underlying mechanism of the synergy of amphotericin B in IFN-gamma primed macrophages was investigated by measurement of nitrite level and by use of the NO synthase competitive inhibitor, NG-monomethyl L-arginine (NMMA). One MIC of amphotericin B was able to activate the synthesis of nitrogen reactive intermediates in IFN gamma-primed macrophages. NMMA treated infected macrophages responded less well to IFN-gamma priming, resulting in a moderate inhibition in subsequent amphotericin B exposure.
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PMID:Synergic inhibitory activity of amphotericin-B and gamma interferon against intracellular Cryptococcus neoformans in murine macrophages. 773 Feb 21

A number of heterobicyclic compounds such as 1,3,5-thiazine, thiazolidinone, pyrimidine, pyrimidinedione, imidazole, quinazolinone and 1,2,4-triazinone derivatives have been sythesized by reaction of 1,6-dihydro-3(2H)-thioxo-6-spiro-(9'- fluorene)-1,2,4-triazin-5(4H)-one (1) with sulphur/nitrogen compounds in neutral or alkaline media. Structure elucidation of the new compounds have been carried out with the help of elemental analysis and spectral data. Some of these compounds were tested for in vitro anti HIV and anticancer activities.
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PMID:Synthesis of some new heterobicyclic compounds containing spiro-1,2,4-triazine moiety as potential anti-HIV and anticancer agents. 783 66

A number of heterobicyclic compounds such as 1,3,5-thiazine, thiazolidinone, pyrimidine, pyrimidinedione, imidazole, quinazolinone and 1,2,4-triazinone derivatives have been synthesized by interaction of 1,6-dihydro-3 (2H)-thioxo-6-spiro-(9'-fluorene)-1,2,4-triazin-5(4H)-one (1) with sulphur/nitrogen compounds in neutral or alkaline medium. Structure elucidation of the new compounds has been carried out with the help of elemental analysis and spectral data. Some of these compounds were tested for in vitro anti HIV and anticancer activities.
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PMID:Synthesis of some new heterobicyclic compounds containing spiro-1,2,4-triazine moiety as potential anti HIV and anticancer agents. 791 84


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