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)

There is compelling evidence that micronutrients can profoundly affect immunity. We surveyed vitamin supplement use and circulating concentrations of 22 nutrients and glutathione in 64 HIV-1 seropositive men and women and 33 seronegative controls participating in a study of heterosexual HIV-1 transmission. We assayed antioxidants (vitamins A, C, and E; total carotenes), vitamins B6 and B12, folate, thiamin, niacin, biotin, riboflavin, pantothenic acid, free and total choline and carnitine, biopterin, inositol, copper, zinc, selenium, and magnesium. HIV-infected patients had lower mean circulating concentrations of magnesium (p < 0.0001), total carotenes (p = 0.009), total choline (p = 0.002), and glutathione (p = 0.045), and higher concentrations of niacin (p < 0.0001) than controls. Fifty-nine percent of HIV+ patients had low concentrations of magnesium, compared with 9% of controls (p < 0.0001). These abnormal concentrations were unrelated to stage of disease. Participants who took vitamin supplements had consistently fewer low concentrations of antioxidants, across HIV infection status and disease stage strata (p = 0.0006). Nevertheless, 29% of the HIV+ patients taking supplemental vitamins had subnormal levels of one or more antioxidants. The frequent occurrence of abnormal micronutrient nutriture, as found in these HIV+ subjects, may contribute to disease pathogenesis. The low magnesium concentrations may be particularly relevant to HIV-related symptoms of fatigue, lethargy, and impaired mentation.
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PMID:Micronutrient profiles in HIV-1-infected heterosexual adults. 862 65

The authors examined the relation between dietary and supplemental micronutrient intake and subsequent mortality among 281 human immunodeficiency type 1 (HIV-1)-infected participants at the Baltimore, Maryland/Washington, DC, site of the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. Subjects completed a semiquantitative food frequency questionnaire at their baseline visit in 1984. Levels of daily micronutrient intake were examined in relation to subsequent mortality over the 8-year follow-up period by using multivariate Cox models, adjusting for age, symptoms, CD4+ count, energy intake, and treatment. The highest quartile of intake for each B-group vitamin was independently associated with improved survival: B1 (relative hazard (RH) = 0.60, 95% confidence interval (CI) 0.38-0.95), B2 (RH = 0.59, 95% CI 0.38-0.93), B6 (RH = 0.45, 95% CI 0.28-0.73), and niacin (RH = 0.57, 95% CI 0.36-0.91). In a final model, the third quartile of beta-carotene intake (RH = 0.60, 95% CI 0.37-0.98) was associated with improved survival, while increasing intakes of zinc were associated with poorer survival. Intakes of B6 supplements at more than twice the recommended dietary allowance were associated with improved survival (RH = 0.60, 95% CI 0.39-0.93), while intakes of B1 and B2 supplements at levels greater than five times the recommended dietary allowance were associated with improved survival (B1: RH = 0.61, 95% CI 0.38-0.98; B2:RH = 0.60, 95% CI 0.37-0.97). Any intake of zinc supplements, however, was associated with poorer survival (RH = 1.49, 95% CI 1.02-2.18). These data support the performance of clinical trials to assess the effects of B-group vitamin supplements on HIV-1-related survival. Further studies are needed to determine the optimal level of zinc intake in HIV-1-infected individuals.
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PMID:Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. 865 Dec 23

Inhibition of the protease in HIV is a potentially useful approach for the treatment of AIDS. In the course of evaluating inhibitors of the HIV-1 protease, we observed a strong synergism between certain inhibitors that might be expected to bind to different sites in this enzyme. The binding affinity of carbobenzyloxyisoleucinylphenylalaninol, for example, is increased 125-fold in the presence of carbobenzyloxyglutaminylisoamylamide. These synergistic effects between inhibitors have specific structural requirements that correlate well with the known substrate preference of the enzyme. The modular basis for this phenomenon remains to be elucidated but it could involve substrate-induced conformational change as part of the reaction mechanism. Similar effects have been reported previously for several zinc proteases. Thus this work extends the observation to a different class of enzymes and suggests that the phenomenon might be widespread.
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PMID:Synergistic binding of inhibitors to the protease from HIV type 1. 867 94

The zinc-bound form of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein, p7, aggregates into particles visible by electron microscopy. The HIV primer tRNA(Lys,3) forms similar high molecular weight complexes with p7 that are also detected by gel mobility shift assays. RNA oligonucleotides of the three stem-loop structures in tRNA(Lys,3) were assayed for the competitive inhibition of p7-tRNA(Lys,3) binding by the intensities of free tRNA(Lys,3) bands on native gels. This reveals that the p7 binds specifically to the central domain of tRNA(Lys,3) where the D and T psi C loops come together, but not the anticodon stem-loop.
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PMID:Chemically synthesised human immunodeficiency virus P7 nucleocapsid protein can self-assemble into particles and binds to a specific site on the tRNA(Lys,3) primer. 869 11

The Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys zinc fingers of retroviral nucleocapsid proteins are prime antiviral targets because of conservation of the Cys and His chelating residues and the absolute requirement of these fingers in both early and late phases of retroviral replication. We previously reported that certain disulfide-substituted benzamides (DIBAs) chemically modify the Cys residues of the fingers, resulting in inhibition of human immunodeficiency virus type 1 (HIV-1) replication (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. O. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995). We now examine the consequences of the interaction of DIBAs with the zinc fingers of the HIV-1 p7 nucleocapsid protein and its Pr55gag precursor. In HIV-1-infected U1 cells, DIBAs inhibited the release of infectious virions, and even under conditions in which virion particles were produced, the particles were noninfectious. DIBAs caused abnormal processing of Gag precursors, and the inhibitory effect on processing was not due to inhibition of the HIV-1 protease enzyme or Pr55gag myristoylation. Rather, the defect in processing was due to the formation of intermolecular cross-linkages among the zinc fingers of adjacent Gag molecules, rendering the precursors no longer recognizable by HIV-1 protease. Likewise, DIBAs caused intermolecular cross-linkage among recombinant Pr55gag packaged into pseudovirions, thereby generating modified precursors that were resistant to the action of protease. Thus, DIBAs chemically modified the mutationally intolerant retroviral zinc fingers in infected cells, interrupting protease-mediated maturation of virions and leading ultimately to the production of compromised virions.
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PMID:Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of gag precursors and result in the release of noninfectious virus particles. 870 44

All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two copies of the conserved sequence motif C-X2-C-X4-H-X4-C. The conserved cysteine and histidine residues coordinate a zinc ion in each such motif. Rice et al. (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. 0. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995) have described a series of compounds which inactivate human immunodeficiency virus type 1 (HIV-1) particles and oxidize the cysteine thiolates in the NC zinc finger. We have characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV). We find that, as with HIV-1, the compounds inactivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles. The killed MuLV particles were found to be incapable of synthesizing full-length viral DNA upon infection of a new host cell. When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprotein does not occur. The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC protein. The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV- I by the compounds. The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutations altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions. This possibility would make the zinc finger an ideal target for antiretroviral agents.
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PMID:Inactivation of murine leukemia virus by compounds that react with the zinc finger in the viral nucleocapsid protein. 876 2

Interaction of the human immunodeficiency virus type 1 (HIV-1) Gag precursor polyprotein (Pr55Gag) with the viral genomic RNA is required for retroviral replication. Mutations that reduce RNA packaging efficiency have been localized to the highly basic nucleocapsid (NC) p7 domain of Pr55Gag, but the importance of the basic amino acid residues in specific viral RNA encapsidation and infectivity has not been thoroughly investigated in vivo. We have systematically substituted the positively charged residues of the NC domain of Pr55Gag in an HIV-1 viral clone by using alanine scanning mutagenesis and have assayed the effects of these mutations on virus replication, particle formation, and RNA packaging in vivo. Analysis of viral clones with single substitutions revealed that certain charged amino acid residues are more critical for RNA packaging efficiency and infectivity than others. Analysis of viral clones with multiple substitutions indicates that the presence of positive charge in each of three independent domains--the zinc-binding domains, the basic region that links them, and the residues that Hank the two zinc-binding domains--is necessary for efficient HIV-1 RNA packaging. Finally, we note that some mutations affect virus replication more drastically than RNA incorporation, providing in vivo evidence for the hypothesis that NC p7 may be involved in aspects of the HIV life cycle in addition to RNA packaging.
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PMID:Charged amino acid residues of human immunodeficiency virus type 1 nucleocapsid p7 protein involved in RNA packaging and infectivity. 879 95

In an earlier study on minus-strand DNA synthesis catalyzed by murine leukemia virus reverse transcriptase, we described a prominent pause site near the polypurine tract (J. Guo, W. Wu, Z. Y. Yuan, K. Post, R. J. Crouch, and J. G . Levin, Biochemistry 34:5018-5029, 1995). We now report that pausing at this site is due to a stem-loop structure in the RNA template, formed by interaction of a number of bases in the polypurine tract, including the six G's, and a 3' sequence which includes four C's. Addition of human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein to reverse transcriptase reactions reduces pausing by approximately 8- to 10-fold and stimulates synthesis of full-length DNA. Thus, NC functions as an accessory protein during elongation of minus-strand DNA and increases the efficiency of DNA synthesis, in this case, by apparently destabilizing a region of secondary structure in the template. Since NC is associated with genomic RNA in the viral core and is likely to be part of a viral replication complex, these results suggest that NC may also promote efficient DNA synthesis during virus replication. Mutational analysis indicates that the features of HIV-1 NC which are important for reduction of pausing include the basic amino acids flanking the first zinc finger, the zinc fingers, and the cysteine and aromatic amino acids within the fingers. These findings suggest that reverse transcription might be targeted by drugs which inactivate the zinc fingers of HIV-1 NC.
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PMID:Human immunodeficiency virus type 1 nucleocapsid protein reduces reverse transcriptase pausing at a secondary structure near the murine leukemia virus polypurine tract. 879 60

Conservation of the Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys retroviral zinc finger sequences and their absolute requirement in both the early and late phases of retroviral replication make these chemically reactive structures prime antiviral targets. We recently reported that select 2,2'-dithiobisbenzamides (DIBAs) chemically modify the zinc finger Cys residues, resulting in release of zinc from the fingers and inhibition of HIV replication. In the current study we surveyed 21 categories of disulfide-based compounds from the chemical repository of the National Cancer Institute for their capacity to act as retroviral zinc finger inhibitors. Aromatic disulfides that exerted anti-HIV activity tended to cluster in the substituted aminobenzene, benzoate, and benzenesulfonamide disulfide subclasses. Only one thiuram derivative exerted moderate anti-HIV activity, while a number of nonaromatic thiosulfones and miscellaneous disulfide congeners were moderately antiviral. Two compounds (NSC 20625 and NSC 4493) demonstrated anti-cultures. The two compounds chemically modified the p7NC zinc fingers in two separate in vitro assays, and interatomic surface molecular modeling docked the compounds efficiently but differentially into the zinc finger domains. The combined efforts of rational drug selection, cell-based screening, and molecular target-based screening led to the identification of zinc finger inhibitors that can now be optimized by medicinal chemistry for the development of biopharmaceutically useful anti-HIV agents.
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PMID:Evaluation of selected chemotypes in coupled cellular and molecular target-based screens identifies novel HIV-1 zinc finger inhibitors. 880 51

Dietary intake was assessed in a subsample of a cohort of inner-city injecting drug users (IDUs). In this population of predominantly African-American IDUs, including both HIV -1-infected and noninfected men and women, a food frequency questionnaire (FFQ) and a 24-h recall were administered. One hundred seven volunteers participated. Although total caloric intake was consistently higher with the food frequency method, percent of total calories from fat, protein, and carbohydrates were similar between the FFQ and 24-h recall. Spearman's correlations for agreement between the 24-h recall and the FFQ ranged from 0.22 for vitamin E to 0.52 for carbohydrates. HIV-1 seropositives reported higher protein (p = 0.05) and fat (p = 0.02) consumption than seronegatives according to the 24-h recall. The difference in total fat consumption was due to higher intakes of saturated and monounsaturated fats (p = 0.01). Median intakes of vitamins B2 and B12, pantothenic acid (p < or = 0.05), phosphorous (p < or = 0.01), and selenium (p < or = 0.005) were also greater in HIV-1 seropositives. Reported intake of vitamins A and E, calcium, and zinc were below the recommended daily allowances for both HIV-1 seropositives and seronegatives. Although intakes of most nutrients appeared adequate for the group as a whole, extreme ranges were observed and may be the result of imbalanced food selections and day to day variation. Food group analysis indicated low intakes of fruits, vegetables, milk, and milk products. More research is needed to fully understand the implication of dietary habits and nutritional status in the free-living HIV-1-infected and noninfected IDUs.
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PMID:Dietary intake of community-based HIV-1 seropositive and seronegative injecting drug users. 887 58


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