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)

A major disadvantage of conventional phototherapy is the requirement for the in situ delivery of stimulating photoenergy subsequent to the binding of photochemicals to target malignant cells, or virus-infected cells, or viruses. This drawback has resulted in considerable limitation in the use of photochemicals in photomedicine. To circumvent this problem, we have investigated the antiviral efficacy of a brominated 1,8-naphthalimide photocompound, termed LY66Br [3-bromo-4-(hexylamino)-N-hexyl-1,8-naphthalimide], which upon exposure to visible light at 420 nm generates independently of oxygen one or more stable antiviral molecular photoproducts (e.g., is 'preactivated'). Human cell lines infected with the human immunodeficiency virus type 1 (HIV-1), or with the human T-lymphotropic virus type-1 (HTLV-I) exposed to photochemical products of LY66Br (P-LY66Br) completely lost their ability to form syncytia in vitro. Photoproducts of P-LY66Br retain full antiviral activity for at least 3 and 6 weeks when stored at room temperature and at -80 degrees C, respectively. Concentrations of P-LY66Br, effective in inhibiting syncytium formation mediated by HIV-1 and HTLV-I, were nontoxic to normal red cell components of whole blood (red blood cell 2,3-diphosphoglyceric acid, adenosine triphosphate, osmotic fragility or blood type antigens). Additionally, no evidence of acute toxicity was demonstrated in mice following an intravenous bolus inoculation to achieve plasma concentration of 600 microM of P-LY66Br. These findings represent the first demonstration of inhibition of retrovirus-induced syncytium formation by a photochemical product, and justify further investigation of the preactivation process of photochemicals in the treatment of systemic viral infections such as the acquired immunodeficiency syndrome (AIDS), in cancer therapy, and in sterilization of banked blood products.
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PMID:Inhibition of retrovirus-induced syncytium formation by photoproducts of a brominated 1,8-naphthalimide compound. 784 75

This study demonstrates that human immunodeficiency virus type 1 (HIV-1) Tat protein amplifies the activity of tumor necrosis factor (TNF), a cytokine that stimulates HIV-1 replication through activation of NF-kappa B. In HeLa cells stably transfected with the HIV-1 tat gene (HeLa-tat cells), expression of the Tat protein enhanced both TNF-induced activation of NF-kappa B and TNF-mediated cytotoxicity. A similar potentiation of TNF effects was observed in Jurkat T cells and HeLa cells treated with soluble Tat protein. TNF-mediated activation of NF-kappa B and cytotoxicity involves the intracellular formation of reactive oxygen intermediates. Therefore, Tat-mediated effects on the cellular redox state were analyzed. In both T cells and HeLa cells HIV-1 Tat suppressed the expression of Mn-dependent superoxide dismutase (Mn-SOD), a mitochondrial enzyme that is part of the cellular defense system against oxidative stress. Thus, Mn-SOD RNA protein levels and activity were markedly reduced in the presence of Tat. Decreased Mn-SOD expression was associated with decreased levels of glutathione and a lower ratio of reduced:oxidized glutathione. A truncated Tat protein (Tat1-72), known to transactivate the HIV-1 long terminal repeat (LTR), no longer affected Mn-SOD expression, the cellular redox state or TNF-mediated cytotoxicity. Thus, our experiments demonstrate that the C-terminal region of HIV-1 Tat is required to suppress Mn-SOD expression and to induce pro-oxidative conditions reflected by a drop in reduced glutathione (GSH) and the GSH:oxidized GSH (GSSG) ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. 785 43

A number of carboxylic acid derivatives of the photoactive terthiophene, alpha-terthienyl, were found to possess impressive UVA-dependent activity against the human immunodeficiency virus, HIV-1; but only when assayed in the absence of serum, indicating that the latter contained interfering components. Good antiviral activity required a high rate of singlet oxygen production, in accordance with previous observations on thiophenes.
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PMID:Photoactive terthiophenes: the influence of serum on anti-HIV (human immunodeficiency virus) activities. 787 Jul 65

Reactive oxygen intermediates like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, then, in the activation and replication of human immunodeficiency virus (HIV)-1 in human cells. Because H2O2 can be converted into the highly reactive OH. at various locations inside the cells, we started to investigate the generation of Reactive oxygen intermediates by photosensitization. This technique is based on the use of a photosensitizer which is a molecule absorbing visible light and which can be located at various sites inside the cell depending on its physicochemical properties. In this work, we used proflavine (PF), a cationic molecule having a high affinity for DNA, capable of intercalating between DNA base pairs. Upon visible light irradiation, intercalated PF molecules oxidize guanine residues and generate DNA single-strand breaks. In lymphocytes or monocytes latently infected with HIV-1 (ACH-2 or U1, respectively), this photosensitizing treatment induced a cytotoxicity, an induction of NF-kappa B, and a reactivation of HIV-1 in cells surviving the treatment. NF-kappa B induction by PF-mediated photosensitization was not affected by the presence of N-acetyl-L-cysteine while strong inhibition was recorded when the induction was triggered by H2O2 or by phorbol 12-myristate 13-acetate. Another transcription factor like AP-1 is less activated by this photosensitizing treatment. In comparison with other inducing treatments, such as phorbol 12-myristate 13-acetate or tumor necrosis factor alpha, the activation of NF-kappa B is slow, being optimal 120 min after treatment. These kinetic data were obtained by following, on the same samples, both the appearance of NF-kappa B in the nucleus and the disappearance of I kappa B-alpha in cytoplasmic extracts. These data allow us to postulate that signaling events, initiated by DNA oxidative damages, are transmitted into the cytoplasm where the inactive NF-kappa B factor is resident and allow the translocation of p50/p65 subunits of NF-kappa B to the nucleus leading to HIV-1 gene expression.
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PMID:Transcription factor NF-kappa B is activated by photosensitization generating oxidative DNA damages. 789 42

L-735,524 is a potent, orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease currently in a Phase II clinical trial. We report here the three-dimensional structure of L-735,524 complexed to HIV-2 protease at 1.9-A resolution, as well as the structure of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2 protease is found to be essentially identical to that of HIV-1 protease. In the crystal lattice of the HIV-2 protease complexed with L-735,524, the inhibitor is chelated to the active site of the homodimeric enzyme in one orientation. This feature allows an unambiguous assignment of protein-ligand interactions from the electron density map. Both Fourier and difference Fourier maps reveal clearly the closure of the flap domains of the protease upon L-735,524 binding. Specific interactions between the enzyme and the inhibitor include the hydroxy group of the hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl groups of the essential Asp-25 and Asp-25' enzymic residues and the amide oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of Ile-50 and Ile-50' via an intervening water molecule. A second bridging water molecule is found between the amide nitrogen N2 of L-735,524 and the carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to binding, an equally significant contribution to affinity arises from hydrophobic interactions between the protease and the inhibitor throughout the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme. Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site.
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PMID:Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. 792 52

Although the etiology of multiple sclerosis (MS) is unknown, there is compelling evidence that its pathogenesis is mediated through the immune system. Molecular mimicry, i.e., crossreactivity between self-antigens and viral proteins, has been implicated in the initiation of autoimmunity and MS. Based on homology to human T cell lymphotropic virus type I (HTLV-I) a novel human retrotransposon was cloned and found to constitute an integral part of the coding sequence of the human transaldolase gene (TAL-H). TAL-H is a key enzyme of the nonoxidative pentose phosphate pathway (PPP) providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid biosynthesis. Another fundamental function of the PPP is to maintain glutathione at a reduced state and, consequently, to protect sulfhydryl groups and cellular integrity from oxygen radicals. Immunohistochemical analyses of human brain sections and primary murine brain cell cultures demonstrated that TAL is expressed selectively in oligodendrocytes at high levels, possibly linked to production of large amounts of lipids as a major component of myelin, and to the protection of the vast network of myelin sheaths from oxygen radicals. High-affinity autoantibodies to recombinant TAL-H were detected in serum (25/87) and cerebrospinal fluid (15/20) of patients with MS. By contrast, TAL-H antibodies were absent in 145 normal individuals and patients with other autoimmune and neurological diseases. In addition, recombinant TAL-H stimulated proliferation and caused aggregate formation of peripheral blood lymphocytes from patients with MS. Remarkable amino acid sequence homologies were noted between TAL-H and core proteins of human retroviruses. Presence of crossreactive antigenic epitopes between recombinant TAL-H and HTLV-I/human immunodeficiency virus type 1 (HIV-1) gas proteins was demonstrated by Western blot analysis. The results suggest that molecular mimicry between viral core proteins and TAL-H may play a role in breaking immunological tolerance and leading to a selective destruction of oligodendrocytes in MS.
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PMID:Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis. 796 52

N-acetyl-L-cysteine (NAC) has been proposed as a therapeutic agent for AIDS patients because it reduces human immunodeficiency virus type 1 (HIV-1) replication in stimulated T cells. However, NAC and glutathione enhanced acute HIV-1 replication in monocyte-derived macrophages. Buthionine sulfoximine did not affect NAC-mediated enhanced HIV-1 replication, indicating that the NAC-mediated effects are glutathione-independent. Superoxide dismutase and the hydroxyl radical scavengers dimethylthiourea and thiourea, but not urea, inhibited acute HIV-1 replication in macrophages. NAC reduced ferricytochrome c and increased dose-dependently Fe(III)-citrate and Fe(III)-EDTA-catalyzed hydroxyl radical formation in a system using glucose and glucose oxidase. Dimethylthiourea and thiourea, but not urea and superoxide dismutase, dose-dependently inhibited NAC-mediated enhancement of HIV-1 replication. These data suggest that oxygen radicals play an important role in self-sustained HIV-1 replication in macrophages and that oxygen radical scavengers other than NAC should be considered as therapeutic agents for AIDS patients.
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PMID:Role for oxygen radicals in self-sustained HIV-1 replication in monocyte-derived macrophages: enhanced HIV-1 replication by N-acetyl-L-cysteine. 799 46

We wanted to study the effect of sputum induction on forced expiratory volume in one second (FEV1) and on oxygen saturation in normal controls, asymptomatic human immunodeficiency virus (HIV)-seropositive individuals, and HIV-seropositive patients under investigation for suspected Pneumocystis carinii pneumonia (PCP). Over a five month period, sputum induction with ultrasonically nebulized 3% saline was performed on 110 HIV-seropositive patients with suspected PCP, 10 asymptomatic HIV-seropositive patients, and 15 normal controls. Oxygen saturation (peak, trough and change in oxygen saturation (delta O2)) was measured throughout the procedure using pulse oximetry, and these results compared with the chest radiograph and the final pulmonary diagnosis. In addition, the effect of sputum induction on FEV1 was measured in the 15 control subjects and 10 asymptomatic HIV-seropositive patients. Compared with bronchoalveolar lavage, sputum induction had a diagnostic sensitivity for PCP of 76%. Chest radiography was 79% sensitive, and had specificity of 83%. Patients with PCP had lower peak and trough oxygen saturation values compared with the non-PCP group (mean peak 95 vs 97%; mean trough 88 vs 91%), and greater falls in O2 saturation during the procedure (mean delta O2 7.6 vs 5.5%). One subject desaturated to 76%, requiring supplemental oxygen. Sputum induction caused significant but temporary falls in FEV1 both in control and HIV-seropositive groups (mean maximum fall in FEV1 10.4 vs 12.5%). We conclude that although sputum induction causes significant falls in oxygen saturation and FEV1, it remains sensitive and safe, and provides a useful alternative to bronchoscopy for the diagnosis of PCP.
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PMID:Effect of sputum induction on arterial oxygen saturation and spirometry in HIV-infected patients. 801 1

Although the current risk of posttransfusion infection is very low in North America and Western Europe, there continues to be considerable interest in measures to inactivate residual viruses in blood components. The human immunodeficiency virus is of greatest concern, but hepatitis C virus is also considered to be a significant problem. HTLV-I and -II and HBV may also be transmitted by transfusion, although infrequently. It is likely that effective inactivation methods will have to reduce viral titers by about 6 orders of magnitude, including both viruses found free in plasma and those in intracellular compartments. Although it would be most desirable to have a single procedure to inactivate viruses in all blood components, it appears that different methods may be required for plasma, red cells and platelets. To date, the most promising approach for platelets appears to be photochemical inactivation. In general, photoactive compounds fall into two major groups: photodynamic dyes which are activated by visible light and act by oxygen dependent generation of reactive molecular species; and ultraviolet-activated intercalating compounds which form covalent adducts with nucleic acids. We have found that photodynamic inactivators are unable to inactivate viruses in platelet concentrates without damaging the platelets. On the other hand, we have shown that aminomethyl trimethyl psoralen (AMT), when activated by long-wavelength ultraviolet light (UVA) can inactivate more than 5 logs of model viruses and HIV while platelet in vitro properties are maintained. Further, unlike photodynamic inactivators, AMT is able to inactivate cell-associated and intracellular viruses and also prevents the replication of integrated HIV genome sequences, as demonstrated by PCR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Viral inactivation in platelet concentrates. 804 13

Monocyte and macrophage dysfunction may be important for both immunopathogenesis and clinical manifestations in subgroups of patients with primary hypogammaglobulinaemia. In the present study we examined the ability to generate reactive oxygen species (ROS) in isolated monocytes from these patients by two different methods: superoxide dismutase (SOD) inhibitable cytochrome c reduction by O2- and nitroblue tetrazolium (NBT) reduction. Monocyte from patients with common variable immunodeficiency (CVI) demonstrated significantly enhanced ROS generation both unstimulated and stimulated (unopsonized zymosan and phorbol myristate acetate (PMA)). The enhanced oxidative burst response in CVI patients was found both with and without serum containing medium. Furthermore, serum from CVI patients did significantly enhance the oxidative burst response in monocytes from healthy blood donors compared with the effect of control serum. The enhanced ROS generation in CVI patients was significantly correlated with elevated serum levels of neopterin, reduced numbers of CD4+ lymphocytes in peripheral blood and occurrence of splenomegaly. In contrast to the CVI group, monocytes from patients with X-linked agammaglobulinaemia (XLA) did not show enhanced ROS generation. The increased oxidative burst response in monocytes from CVI patients most probably reflects in vivo activation of these cells. Our observations indicate the presence of a subgroup of CVI patients characterized by chronic immune activation particularly of monocytes. The enhanced ROS generation might be involved in immunopathogenesis (e.g. T cell dysfunction) and in the pathogenesis of clinical manifestations (e.g. malignancies and autoimmune disorders) in these patients.
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PMID:Enhanced generation of reactive oxygen species in monocytes from patients with common variable immunodeficiency. 805 Jan 70


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