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)

In several models of lymphocyte apoptosis, two alterations of mitochondrial function precede advanced DNA fragmentation: (1) a reduction of mitochondrial transmembrane potential (delta psi m) and (2) an increase in mitochondrial generation of superoxide anion. Here we show that two fluorochromes allow for the identification of analogous mitochondrial perturbations in circulating T lymphocytes from human immunodeficiency virus (HIV)-1+ donors. The first among these fluorochromes, the cationic lipophilic dye DiOC6(3), measures delta psi m; the second marker, hydroethidine (HE), is nonfluorescent, unless it is oxidized by superoxide anions to the product ethidium (Eth). CD4+ or CD8+ cells from clinically asymptomatic HIV-1 carriers contain a significantly elevated percentage of cells endowed with enhanced HE --> Eth conversion and/or reduced DiOC6(3) uptake as compared with normal controls. Phenotypic characterization of (HE --> Eth)high cells from HIV+ donors shows that these cells possess a low delta psi m, thus demonstrating a functional alteration of mitochondria. In addition, (HE --> Eth)high cells display a reduced incorporation of the cardiolipin-specific dye nonyl-acridine orange (NAO), showing a structural defect of the cardiolipin-containing inner mitochondrial membrane. Control experiments involving rotenone, an inhibitor of the respiratory chain complex I, indicate that the reactive oxygen species responsible for HE --> Eth conversion is generated during mitochondrial electron transport. In synthesis, it appears that mitochondrial alterations occur in a significant percentage of circulating T lymphocytes from HIV-1 carriers. The extent of delta psi m reduction, as determined ex vivo, correlates with the frequency of cells undergoing DNA fragmentation after overnight in vitro culture. These observations may be important for the understanding and for the direct ex vivo quantitation of HIV-triggered lymphocyte destruction.
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PMID:Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers. 887 27

The mechanism of the antiviral activity of hypericin was characterized and compared with that of rose bengal. Both compounds inactivate enveloped (but not unenveloped) viruses upon illumination by visible light. Human immunodeficiency and vesicular stomatitis viruses were photodynamically inactivated by both dyes at nanomolar concentrations. Photodynamic inactivation of fusion (hemolysis) by vesicular stomatitis, influenza, and Sendai viruses was induced by both dyes under similar conditions (e.g., I50 = 20-50 nM for vesicular stomatitis virus), suggesting that loss of infectivity resulted from inactivation of fusion. Syncytium formation, between cells activated to express human immunodeficiency virus gp120 on their surfaces and CD4+ cells, was inhibited by illumination in the presence of 1 microM hypericin. Hypericin and rose bengal thus exert similar virucidal effects. Both presumably act by the same mechanism--namely, the inactivation of the viral fusion function by singlet oxygen produced upon illumination. The implications of this photodynamic antiviral action for the potential therapeutic usefulness of both hypericin and rose bengal are discussed.
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PMID:Photodynamic inactivation of infectivity of human immunodeficiency virus and other enveloped viruses using hypericin and rose bengal: inhibition of fusion and syncytia formation. 767 35

Heteroatom fatty acid analogs of myristic acid containing oxygen or sulfur substituted for the alkyl methylene groups inhibit replication of the human immunodeficiency virus (HIV) in infected cells by acting as alternative substrates during the viral protein myristoylation event. In this class of compounds, 12-methoxydodecanoic acid is the most potent compound but is approximately 10(3)-fold less active than azidothymidine. The antiviral activity of 12-methoxydodecanoic acid can be enhanced > 40-fold by preparing L-alpha-phosphatidylethanolamine containing 12-methoxydodecanoic acid in both alkyl chains. In addition, the diacylated L-alpha-phosphatidylcholine analog containing 12-methoxydodecanoic acid in both alkyl chains (i) has a 15-fold better antiviral selectivity, (ii) is 7-fold more potent, and (iii) is 10-100-fold more synergistic with azidothymidine than 12-methoxydodecanoic acid. Because of potent synergism, the antiviral selectivity of the diacylated L-alpha-phosphatidylcholine analog is > 10(4) when coadministered with azidothymidine. Phospholipid conjugates are chiral at the C-2 carbon of the glycerol backbone and most interesting is the observation that both the D- and L-isomers of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, and phosphatidylserine have approximately equal antiviral activity. Phospholipase A2 stereospecifically hydrolyzes only the L isomer of phospholipids and similar activity for both the D- and L- phospholipid isomers suggests that phospholipase A2 is not the rate-limiting enzyme for release of the drugs in vivo.
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PMID:Antiviral phospholipids. Anti-HIV drugs conjugated to the glycerobackbone of phospholipids. 768 28

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear leukocytes (PMNs) are recruited into the genital tract by STD pathogens, such as Chlamydia trachomatis. Semen of HIV-infected men contains HIV associated with mononuclear cells. This study investigated the interaction among PMNs from HIV-uninfected persons, C. trachomatis, and HIV-infected cells and examined the mechanisms for enhanced HIV replication. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in medium without exogenous IL-2. HIV in the cell-free supernatants from cocultures of PMNs and patients' peripheral blood mononuclear cells (PBMCs) was replication competent, as indicated by their capacity to propagate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cells. PMNs from HIV-seronegative donors increased HIV replication over 100-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages. Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture increased HIV replication by an additional ninefold at 24 h, whereas C. trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C. trachomatis serves not only to recruit PMNs, but also to interact with PMNs to increase HIV replication. HIV replication is triggered by contact of HIV-infected cells with PMNs, by the generation of reactive oxygen intermediates (ROIs), and by soluble factors such as TNF-alpha and IL-6. This is based on the findings that production of p24 antigen, IL-6, and TNF-alpha induced by PMNs is abrogated by disrupting or partitioning PMNs from HIV-infected cells; is inhibited by superoxide dismutase and catalase, enzymes that destroy ROIs; is enhanced by differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs is independent of HIV infection of mononuclear cells, since PMNs cocultured with HIV-uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection associated with chlamydia cervicitis may be related to the local recruitment of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen. These observations provide a rationale for strategies to reduce HIV transmission by control of STD.
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PMID:Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis. 769 32

Molecular dynamics simulations of human immunodeficiency virus (HIV)-1 protease with a model substrate were used to test if there is a stable energy minimum for a proton that is equidistant from the four delta oxygen atoms of the two catalytic aspartic acids. The crystal structure of HIV-1 protease with a peptidic inhibitor was modified to model the peptide substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln for the starting geometry. A proton was positioned between the two closet oxygen atoms of the two catalytic aspartic acids, and close to the carbonyl oxygen of the scissile bond in the substrate. All crystallographic water molecules were included. Two molecular dynamics simulations were run: 30 ps with united-atom potentials and 40 ps using the more accurate all-atom potentials. The molecular dynamics used a new algorithm that increased the speed and allowed the elimination of a cut-off for non-bonded interactions and the inclusion of an 8 A shell of water molecules in the calculations. The overall structure of the protease dimer, including the catalytic aspartic acids, was stable during the course of the molecular dynamics simulations. The substrate and a water molecule, that is an important component of the binding site, were stable during the simulation using all-atom potentials, but more mobile when united-atom potentials were used. A Poincare map representation showed that the positions of the proton and its coordinating oxygen atoms were stable for 93% of both simulations, although many of the buried and poorly accessible water molecules exchanged with solvent. The proton has a stable minimum energy position and maintains coordination with all four delta oxygen atoms of the two catalytic aspartic acids and the carbonyl oxygen of the scissile bond of the substrate. Therefore, a loosely bound hydrogen ion at this position will not be rapidly exchanged with solvent, and will rebond to either a catalytic aspartic acid or possibly the substrate. The implications for the reaction mechanism are discussed.
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PMID:Molecular dynamics simulations of HIV-1 protease with peptide substrate. 770 Aug 67

Several recent reports have indicated high levels of reactive oxygen species, causing oxidative stress, in the pathogenesis of HIV infection. Oxidative stress may lead to enhanced HIV replication in infected cells and may also aggravate the immunodeficiency by reduction of cellular immunity and possibly by increased programmed cell death of lymphocytes. Moreover, reduced levels of antioxidants have been found in patients with HIV infection. This raises the question of whether antioxidant therapy might be beneficial in patients with HIV infection. Until now, only a few preliminary, clinical studies have been completed. Further clinical trials are needed to assess the possible role of antioxidants in the treatment of HIV infection.
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PMID:[Can HIV infection be treated with antioxidants?]. 770 93

We postulated that changes in the cell surface display of molecules that facilitate cell-cell and cell-matrix adhesions may reflect the changing immunosurveillance capacity of blood monocytes during progression of human immunodeficiency virus (HIV) infections. In Centers for Disease Control (CDC) stage A patients, whose monocytes' ability to phagocytose bacteria and generate reactive oxygen intermediates is often increased, the frequency of monocytes expressing CD49d, HLA-DP, HLA-DQ, and an activation epitope of CD11a/CD18 was increased and monocyte transendothelial migration was unimpaired. In CDC stage B/C patients, whose monocytes' ability to phagocytose bacteria and migrate across confluent endothelial monolayers was diminished, surface expression of CD49e and CD62L and the percentage of monocytes expressing CD18, CD11a, CD29, CD49e, CD54, CD58, CD31, and HLA-I were significantly decreased. Incubating normal donor monocytes with immune complexes in vitro reproduced the phenotypic and functional abnormalities seen in stage B/C patients. By contrast, in vitro stimulation with subcellular particulates released by apoptotic lymphocytes reproduced changes seen in stage A patients' monocytes. Although circulating monocytes appear to be activated at all stages, these data suggest that the high levels of circulating immune complexes, found predominantly in the later stages of HIV infection, may be particularly instrumental in reducing the monocyte's capacity to maintain surveillance against infection.
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PMID:Phenotypic and functional changes in peripheral blood monocytes during progression of human immunodeficiency virus infection. Effects of soluble immune complexes, cytokines, subcellular particulates from apoptotic cells, and HIV-1-encoded proteins on monocytes phagocytic function, oxidative burst, transendothelial migration, and cell surface phenotype. 770 78

Military and civilian medical organisations have long recognised that an oxygen-carrying volume expander which is easy to store, transport and administer could be life-saving for trauma victims. Concern over fatal blood-borne pathogens including hepatitis and human immunodeficiency virus (HIV), as well as a shrinking donor pool further highlight the need for such a product. A variety of substances that transport oxygen and augment intravascular volume in the absence of red cells are emerging as possible "blood substitutes" for use in humans. These include haemoglobin solutions, liposome encapsulated haemoglobin (LEH) and perfluorocarbons. The purpose of this review is to discuss issues related to the various oxygen-carrying volume-expanding solutions by addressing the following questions: 1) What are the ideal properties of an oxygen-carrying volume expander? 2) What types of oxygen-carrying solutions are under development? 3) How does the efficacy of these compounds compare to their limitations and side effects? and 4) What are the potential clinical applications of these products?
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PMID:Haemoglobin-based blood substitutes: what's on the horizon? 771 Feb 40

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.
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PMID:Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA. 773 19

Between February and April 1991, six adults were admitted to the New York Hospital because of measles pneumonitis. The diagnosis was confirmed by serology and/or viral culture. Uncommon clinical features among patients with this diagnosis included thrombocytopenia, hepatitis, myositis, and hypocalcemia. All patients were markedly hypoxic (initial alveolar--arterial oxygen gradients while the patients were breathing room air, 40-61 mm Hg); four required support with mechanical ventilation. All patients received therapy with intravenous ribavirin (20-35 mg/[kg.d]) for 1 week. The respiratory status of five patients (one of whom was positive for human immunodeficiency virus [HIV]) who were treated early (days 2-5 of illness) promptly improved; all abnormal parameters eventually returned to baseline. Treatment of the sixth patient, who was presumed to be HIV-infected, was initiated on hospital day 22; this patient died of progressive oxygenation failure on day 38. We conclude that life-threatening measles pneumonitis in adults may be more common that previously appreciated, regardless of the patient's immune status. Therapy with intravenous ribavirin was well tolerated by our patients and was associated with reversal of respiratory compromise.
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PMID:Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. 864 18


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