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)

Although HIV has been established as the etiologic agent in AIDS, other contributory cofactors may be responsible for selective clinical manifestations of the syndrome. While the pathogenesis remains unclear, the development of immunologic abnormalities observed in some homosexual males with AIDS and AIDS-related complex may be attributed to repeated exposure to allogeneic sperm and seminal plasma components. Accordingly, antibody levels to semen fractions were measured in sera from 338 individuals (295 AIDS, 36 ARC, 16 randomly selected homosexuals, 29 patients with infectious hepatitis, 12 hemophiliacs, 20 rheumatic disease patients, and 24 healthy heterosexual adults). The methods were (i) passive hemagglutination for antibodies to human seminal plasma (HuSePl), and (ii) indirect immunofluorescence (IF) assay on methanol-fixed human sperm noting staining of acrosomal, equatorial, postnuclear, and tail main-piece regions. HuSePl was positive in 31% AIDS sera, while 39% were positive by IF. ARC sera were 30% positive for HuSePl and 38% positive IF. No control sera were positive. Results reveal a significant incidence of antibody to sperm and seminal plasma components in ARC and AIDS patients. Because of the known immunomodulating properties of both, it is possible that these responses may indicate risk factors for disease progression and severity.
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PMID:Sperm and seminal plasma antibodies in acquired immune deficiency (AIDS) and other associated syndromes. 325 34

As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.
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PMID:The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn. 750 11

The fundamental role played by reverse transcriptase (RT) in the replication of retroviruses has made this enzyme a key target in the chemotherapy of HIV infection. Since the replicative cycle of HIV is interrupted by RT inhibitors, the inhibition of HIV RT is currently considered as a useful approach in the prophylaxis and intervention of AIDS. The MeOH and water extracts of 41 medicinal plants used in Egyptian folk medicine were evaluated for their HIV-1 RT inhibitory effects, and inhibitory substances were identified from the fruit of Phyllanthus emblica that showed a potent inhibitory activity to HIV-1-RT. The enzyme activity was determined by the amount of tritium labeled-substrate incorporation into a polymer fraction in the presence of a template-primer. Of the plant materials tested, the fruits of Phyllanthus emblica L. (MeOH extract), Quercus pedunculata (MeOH and water extracts), Rumex cyprius (MeOH and water extracts), Terminalia bellerica (MeOH and water extracts), Terminalia chebula (MeOH and water extracts), and Terminalia horrida (MeOH extract) showed significant inhibitory activity with IC50 of 2-49 mcg/ml. However, in the presence of bovine serum albumin (BSA), the inhibitory potency of most of the extracts, except for P. emblica (MeOH extract) and T. chebula (water extract), was appreciably reduced by nonspecific binding of their ingredients with BSA. Through a bioassay guided-fractionation of the methanol extract of the fruit of P. emblica, putranjivain A (1) was isolated as a potent inhibitory substance with IC50 = 3.9 mcM, together with 1,6-di-O-galloyl-beta-D-glucose (2), 1-O-galloyl-beta-D-glucose (3), kaempferol-3-O-beta-D-glucoside (4), quercetin-3-O-beta-D-glucoside (5), and digallic acid (6). The inhibitory mode of action by 1, 2, and 6 was noncompetitive with respect to the substrate but competitive with respect to a template-primer. Furthermore, the stereochemistry of 1 was established in this paper by nuclear magnetic resonance spectroscopy.
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PMID:Inhibitory effects of Egyptian folk medicines on human immunodeficiency virus (HIV) reverse transcriptase. 754 17

Pichia pastoris is a methylotrophic yeast increasingly important in the production of therapeutic proteins. Expression vectors are based on the methanol-inducible AOX1 promoter and are integrated into the host chromosome. In most cases high copy number integration has been shown to be important for high-level expression. Since this occurs at low frequency during transformation, we previously used DNA dot blot screens to identify suitable clones. In this paper we report the use of vectors containing the Tn903 kanr gene conferring G418-resistance. Initial experiments demonstrated that copy number showed a tight correlation with drug-resistance. Using a G418 growth inhibition screen, we readily isolated a series of transformants, containing progressively increasing numbers (1 to 12) of a vector expressing HIV-1 ENV, which we used to examine the relationship between copy number and foreign mRNA levels. Northern blot analysis indicated that ENV mRNA levels from a single-copy clone were nearly as high as AOX1 mRNA, and increased progressively with increasing copy number so as to greatly exceed AOX1 mRNA. We have also developed protocols for the selection, using G418, of high copy number transformants following spheroplast transformation or electroporation. We anticipate that these protocols will simplify the use of Pichia as a biotechnological tool.
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PMID:Rapid selection using G418 of high copy number transformants of Pichia pastoris for high-level foreign gene expression. 776 33

3TC (GR109714X) is a cytidine dideoxynucleoside analogue which has been shown to have in vitro activity against a variety of strains of HIV-1 and is currently being investigated in clinical trials as a treatment for HIV infection. An HPLC method for the determination of 3TC in human urine has been developed and validated. The method allows direct injection of urine (10 microliters) using HPLC column switching followed by UV detection. On-line extraction is performed using a Spherisorb-SCX (5 microns, 20 x 4.0 mm) eluted with deionized water at 1 ml min-1. 3TC is retained while the bulk of urine constituents are eluted to waste. The SCX column is then backflushed to a BDS-Hypersil-C18 (5 microns, 250 x 4.6 mm) and eluted with 100 mM acetate pH 4.5-methanol (95:5, v/v) for final separation. 3TC is detected by UV absorbance at lambda = 285. The quantitation range of the assay was 0.5-500 micrograms ml-1. The method has demonstrated sufficient ruggedness to be used in support of 3TC clinical trials. Application to other cytidine analogues including DDC has been demonstrated.
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PMID:Determination of 2'-deoxy-3'-thiacytidine (3TC) in human urine by liquid chromatography: direct injection with column switching. 800 52

Rapid freezing, freeze substitution and low temperature embedding were used to obtain resin-embedded specimens of HIV and SIV for morphological and immunolabelling studies, with particular emphasis on the 'lateral bodies' and p6 protein. HIV- or SIV-infected cells were fixed in 3% paraformaldehyde and cryoprotected with 0.5 M sucrose. Cells were applied to pieces of Whatman No 1 filter paper and impact-frozen onto a liquid nitrogen cooled copper block. Specimens were freeze-substituted at -90 degrees C using one of three different media: (a) absolute methanol, (b) methanol containing 0.5% uranyl acetate, and (c) methanol containing glutaraldehyde, osmium tetroxide and uranyl acetate. Specimens substituted in methanol and uranyl acetate showed both good structural preservation and retention of antigenicity. We found that the use of filter paper for supporting the specimen was an important factor in obtaining good freezing rates and was more practical than freezing mixtures of cells and gelatin. When compared with specimens prepared by conventional fixation and embedding, freeze-substituted virus particles showed a greater uniformity of shape and size and were more dense in appearance. Distinct 'lateral bodies' were not observed in freeze-substituted viruses. The viral protein p6 was widely distributed in the centre of mature virus particles.
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PMID:A morphological and immunolabelling study of freeze-substituted human and simian immunodeficiency viruses. 805 44

Groups of 5'-phosphonates of natural 2'-deoxynucleosides and ribonucleosides were synthesized by condensation of 3'-acetylated 2'-deoxynucleosides or 2',3'-substituted (2',3'-O-isopropylidene, 2',3'-O-methoxymethylene, or 2',3'-O-ethoxymethylene) ribonucleosides. As condensing agents, either N,N'-dicyclohexylcarbodiimide or 2,4,6-triisopropylbenzenesulphonyl chloride were used. Nucleoside 5'-ethoxycarbonyl-phosphonates were converted into corresponding nucleoside 5'-aminocarbonylphosphonates by the action of ammonia in methanol. All compounds were tested for inhibition of several viruses, including human herpes simplex virus type 2 and cytomegalovirus, but showed no activity. A few compounds insignificantly inhibited human immunodeficiency virus type 1 reproduction. Thymidine 5'-hydrogenphosphonate neutralized the anti HIV action of 3'-azido-3'-deoxythymidine, thus indirectly showing that it could be partly hydrolyzed in cell culture to corresponding thymidine.
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PMID:[Ribonucleoside and 2'-deoxyribonucleoside 5'-phosphonates: synthesis and antiviral activity]. 814 53

Rational ligand design is a complex problem that can be divided into three parts: the search for optimal positions and orientations of functional groups in the binding site, the connection of such positions to form candidate ligands, and the estimation of their binding constants. Approaches for addressing the first two parts of the problem are described in the present work. They are applied to the construction of peptide ligands in the binding site of the human immunodeficiency virus 1 (HIV-1) proteinase. The primary objective is to test the method by comparison of the results with the MVT-101 complex structure for which coordinates are available; the results obtained with the liganded and unliganded proteinase structure are used to examine the utility of the latter for binding studies. A secondary objective is to show how to find new inhibitor candidates. The multiple copy simultaneous search (MCSS) method is utilized to search for optimal positions and orientations of a set of functional groups. For peptide ligands, functional groups corresponding to the protein main chain (N-methylacetamide) and to protein side chains (e.g., methanol, ethyl guanidinium) are used. The resulting N-methylacetamide minima are connected to form hexapeptide main chains with a simple pseudoenergy function that permits a complete search of all possible ways of connecting the minima. Side chains are added to the main-chain candidates by application of the same pseudoenergy function to the appropriate functional group minima. A set of 15 hexapeptides with the sequence of MVT-101 is then minimized by a Monte Carlo scheme, which allows for escape from local minima. Comparison of the MCSS results with the structure of MVT-101 in the HIV-1 binding site showed that all of its functional group positions correspond (within 2.4 A) to some (usually more than one) MCSS minima. There were also many other low-energy MCSS minima which do not appear in any known inhibitors, e.g., methyl ammonium minima in the neighborhood of the catalytic aspartates. Among the 15 lowest minima are seven hexapeptides with the same main-chain orientation as the one found by X-ray crystallography for the inhibitor MVT-101 in the binding site and eight with the main chain oriented in the opposite direction; the latter tend to be more stable. [Addendum: These results are in agreement with recent high-resolution crystallographic data provided after the study was completed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase. 834 Sep 18

Several lignans, mostly new, were isolated from Larrea tridentata by assay-guided counter-current chromatography (CCC). Using the secreted alkaline phosphatase bioassay of HIV Tat transactivation and the two-phase hexane-ethyl acetate-methanol-water solvent system, two major components (Gr and Lo) were identified as anti-HIV active principles. The chemical structures of the constituents of Gr (G1-G4) and Lo (L1-L4) were determined by GC-MS and NMR. After optimization of isolation conditions, a large-scale isolation with the chloroform-methanol-water system yielded five constituents (FB1-FB5). The most predominant anti-HIV compound FB2 (denoted Malachi 4:5-6 or mal.4), which occurs in 0.23% yield, was separated from its FB1 isomer (0.13% yield). Compound FB4 and two tricyclic lignans (FB3 and FB5) were also isolated in a substantial amount for further testing of their anti-HIV activities. These compounds may represent a new class of anti-HIV agents with important clinical relevance.
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PMID:Isolation of anti-HIV-1 lignans from Larrea tridentata by counter-current chromatography. 858 Nov 22

The methanol extract from the whole plant of Geum japonicum was found to inhibit the human immunodeficiency virus (HIV-1) protease. Through bioassay-directed fractionation of the extract, a new triterpene acid along with five known triterpene acids, ursolic acid, epipomolic acid, maslinic acid, euscaphic acid, and tormentic acid, were isolated. The structure of the new compound was determined by spectral means including 1H-1H COSY, HMQC, HMBC, and NOE experiments to be 2 alpha, 19 alpha-dihydroxy-3-oxo-12-ursen-28-oic acid (1). Of these compounds, 1, ursolic acid, and maslinic acid showed potent inhibitory activity against HIV-1 protease.
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PMID:Anti-HIV triterpene acids from Geum japonicum. 875 59


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