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)

Programmed cell death (apoptosis) of T-lymphocytes observed in human immunodeficiency virus (HIV) infected individuals could be linked to oxidative stress. Therefore, we have investigated whether reactive oxygen species (ROS) induce apoptosis, which might contribute to the cell loss during progression of HIV-1 infection. ROS were generated in peripheral blood mononuclear cells (PBMC) obtained from HIV-1-positive patients and from healthy controls by stimulation with bacteria or by treatment with hypoxanthine/xanthine oxidase, which has been shown to generate ROS without direct involvement of cytokines. A dose-dependent inhibition of ROS formation correlated with the reduction of apoptosis induced by both bacterial and hypoxanthine/xanthine oxidase stimulation, suggesting that ROS generation was responsible for the induction of apoptosis. In addition, hydrogen peroxide (H2O2) rather than superoxide (O2.-) was observed to induce apoptosis. ROS-dependent apoptosis was shown to be independent of cytokines such as tumor necrosis factor-alpha (TNF-alpha). ROS-induced apoptosis was significantly enhanced in HIV-infected subjects even in the very early stages after infection. Moreover, ROS-mediated apoptosis was not restricted to a particular lymphocyte subset. In view of the diminished oxidative resistance of HIV-infected individuals, our results suggest that ROS-mediated apoptosis might contribute to the deletion of lymphocytes and to the pathogenesis of the disease.
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PMID:Ex vivo induction of apoptosis in lymphocytes is mediated by oxidative stress: role for lymphocyte loss in HIV infection. 911 45

Transactivation of human immunodeficiency virus (HIV) gene expression depends upon the interaction of the viral regulatory protein Tat with the transactivation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all mRNAs. We have used a site-directed RNA-cleaving strategy to determine the neighborhood of the core domain of a Tat fragment in the Tat-TAR complex. We synthesized a 35-amino acid fragment containing arginine-rich RNA-binding domain of Tat(38-72) and attached an EDTA analog to its amino terminus. A derivative of (p-aminobenzyl)-EDTA tetra-tert-butyl ester was synthesized and attached to the amino terminus of the Tat peptide by standard peptide coupling methods. Cleavage from the resin and deprotection of the peptide were carried out in trifluoroacetic acid which also generated unprotected metal binding EDTA moieties. We used this EDTA-Tat conjugate to form a specific complex with TAR RNA. This sequence-specific RNA-binding peptide was converted into a sequence-specific RNA-cleaving peptide by the addition of Fe(II) salt, ascorbate, and H2O2. Hydroxyl radicals generated from the tethered Fe(II) cleaved the TAR RNA backbone in two localized regions. Site-specific cleavage of TAR RNA was observed at the bulge residues (U23, C24, and U25), in the loop region (G34 and A35), and at the strand opposite the bulge (U40 and C41). These results demonstrate that, in the three-dimensional structure of the Tat-TAR complex, the Phe38 of Tat(38-72) is located in the proximity of the bulge region and two nucleotides from the loop sequence.
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PMID:Probing the proximity of the core domain of an HIV-1 Tat fragment in a Tat-TAR complex by affinity cleaving. 937 65

The effect on normal vaginal flora of three intravaginal microbicides potentially active against human immunodeficiency virus type 1 was examined. Volunteers received dextrin sulfate (D2S), nonoxynol-9 (N-9), or docusate sodium in separate placebo-controlled studies. High vaginal swabs were obtained for bacterial culture before and after microbicide application. D2S did not affect the vaginal flora. However, lactobacilli decreased by > or = 10(2) cfu/mL in 9 (56%) of 16 women given N-9 and in 5 (63%) of 8 women given docusate sodium. Women using N-9 were also significantly more likely to become colonized abnormally (usually with aerobic gram-negative rods) than were those using placebo, as were women using docusate sodium. Women with reduced lactobacilli were less likely to regain normal flora than were those whose lactobacilli were unaffected. However, coliform colonization occurred whether lactobacilli produced H2O2 or not. Continuous use of N-9 could induce susceptibility to urinary and gynecological infection. It is essential that potential microbicides are examined for activity against normal vaginal flora.
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PMID:Effect on normal vaginal flora of three intravaginal microbicidal agents potentially active against human immunodeficiency virus type 1. 959 30

Phenylarsine oxide (PAO), which is described as an inhibitor of tyrosine phosphatase activity, inhibits H2O2 release from human peripheral blood mononuclear cells (PBMCs) as measured by electrochemistry. Since human immunodeficiency virus type 1 (HIV-1) replication is known to be favored under oxidative stress conditions, ex vivo experiments using uninfected PBMCs, primary monocytes or a latently infected promonocytic U1 cell line show that HIV-1 replication and reactivation, monitored by p24 antigen measurement, are inhibited by PAO in a time- and concentration-dependent manner. These observations can be linked with the inhibition of NF-kappa B activation when uninfected monocytes are induced by either tumor necrosis factor alpha (TNF-alpha) phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS).
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PMID:Phenylarsine oxide inhibits ex vivo HIV-1 expression. 986 1

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) introduced in association with the luciferase reporter gene into Jurkat T cells was strongly activated by a combination of human neutrophils and phorbol myristate acetate (PMA). Activation was not observed when normal neutrophils were replaced by neutrophils which lack a respiratory burst, ie, from a patient with chronic granulomatous disease (CGD), was strongly inhibited by catalase, was potentiated by vanadate, was stimulated by relatively low concentrations of azide, and was inhibited by selective inhibitors of protein kinase C (PKC). The PMA affected activation in three ways: (1) by directly activating the LTR in Jurkat LTRluc; (2) by inducing a respiratory burst in neutrophils with the formation of H2O2; and (3) by increasing the sensitivity of Jurkat LTRluc to the activating effect of H2O2. When PMA was replaced by opsonized zymosan as the neutrophil stimulus, activation of the LTR was low unless azide was added. Activation in the presence of azide was not seen when CGD neutrophils were used or when catalase was added, suggesting that azide acts by inhibiting the degradation of H2O2. These findings indicate that activation of the HIV-1 LTR in Jurkat T cells can be induced by H2O2 released by neutrophils, particularly when PKC is concomitantly activated.
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PMID:Activation of the human immunodeficiency virus-1 long terminal repeat by respiratory burst oxidants of neutrophils. 986 80

We investigated the role of the two highly conserved cysteine residues, cysteines 67 and 95, of the human immunodeficiency virus type 1 (HIV-1) protease in regulating the activity of that protease during viral maturation. To this end, we generated four HIV-1 molecular clones: the wild type, containing both cysteine residues; a protease mutant in which the cysteine at position 67 was replaced by an alanine (C67A); a C95A protease mutant; and a double mutant (C67A C95A). When immature virions were produced in the presence of an HIV-1 protease inhibitor, KNI-272, and the inhibitor was later removed, limited polyprotein processing was observed for wild-type virion preparations over a 20-h period. Treatment of immature wild-type virions with the reducing agent dithiothreitol considerably improved the rate and extent of Gag processing, suggesting that the protease is, in part, reversibly inactivated by oxidation of the cysteine residues. In support of this, C67A C95A virions processed Gag up to fivefold faster than wild-type virions in the absence of a reducing agent. Furthermore, oxidizing agents, such as H2O2 and diamide, inhibited Gag processing of wild-type virions, and this effect was dependent on the presence of cysteine 95. Electron microscopy revealed that a greater percentage of double-mutant virions than wild-type virions developed a mature-like morphology on removal of the inhibitor. These studies provide evidence that under normal culture conditions the cysteines of the HIV-1 protease are susceptible to oxidation during viral maturation, thus preventing immature virions from undergoing complete processing following their release. This is consistent with the cysteines being involved in the regulation of viral maturation in cells under oxidative stress.
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PMID:Conserved cysteines of the human immunodeficiency virus type 1 protease are involved in regulation of polyprotein processing and viral maturation of immature virions. 988 17

In the course of our studies on oxidative stress as a component of pathological processes in humans, we showed that microintrusion into cells with microcapillary and ultramicroelectrochemical detection could mimic many types of mechanical intrusion leading to an instant (0.1 s) and high (some femtomoles) burst release of H2O2. Specific inhibitors of NADPH enzymes seem to support the assumption that this enzyme is one of the main targets of our experiments. Also, human immunodeficiency virus type 1 (HIV-1) gp160 inhibits the cooperative response of uninfected T cells as well as Tat protein release by infected cells does. In this study, we analyzed in real time, lymphocyte per lymphocyte, the T-cell response following activation in relation to the redox state. We showed that the immunosuppressive effects of HIV-1 Tat and gp160 proteins and oxidative stress are correlated, since the native but not the inactivated Tat and gp160 proteins inhibit the cellular immune response and enhance oxidative stress. These results are consistent with a role of the membrane NADPH oxidase in the cellular response to immune activation.
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PMID:Amplification of the inflammatory cellular redox state by human immunodeficiency virus type 1-immunosuppressive tat and gp160 proteins. 988 50

Lactobacilli, a component of the normal vaginal flora, can activate the human immunodeficiency virus (HIV)-1 long terminal repeat (LTR) in the Jurkat T lymphocyte and THP-1 macrophage cell lines. Activation of the LTR in Jurkat cells was strongly enhanced by vanadate and inhibited by catalase, implicating H2O2. In contrast, activation in THP-1 cells occurred in the absence of vanadate and was unaffected by catalase. The active material partitioned into the phenol layer on hot aqueous phenol extraction. Lactobacilli also increased tumor necrosis factor-alphaand interleukin-1betaproduction and activated NF-kappaB in THP-1 cells and increased tumor necrosis factor-alphaproduction by human monocytes. Human vaginal fluid specimens had comparable properties, which correlated with their bacterial content. These findings suggest the presence in vaginal fluid of agent(s) derived from indigenous bacteria that can activate the HIV-1 LTR, cytokine production, and NF-kappaB in cells of macrophage lineage, with possible influence on vaginal physiology and host defense.
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PMID:Lactobacilli and vaginal host defense: activation of the human immunodeficiency virus type 1 long terminal repeat, cytokine production, and NF-kappaB. 995 72

Monocytes are precursors of tissue macrophages, which are major targets of human immunodeficiency virus type 1 (HIV-1) infection. Although few blood monocytes are infected, their resulting activation could play a key role in the pathogenesis of HIV disease by modulating their transendothelial migration and inducing the production of reactive oxygen species (ROS). ROS participate in chronic inflammation, HIV replication, and the apoptosis of immune system cells seen in HIV-infected subjects. Published data on monocyte activation are controversial, possibly because most studies have involved monocytes isolated from their blood environment by various procedures that may alter cell responses. We therefore used flow cytometry to study, in whole blood, the activation and redox status of monocytes from HIV-infected patients at different stages of the disease. We studied the expression of adhesion molecules, actin polymerization, and cellular levels of H2O2, Bcl-2, and thioredoxin. Basal H2O2 production correlated with viral load and was further enhanced by bacterial N-formyl peptides and endotoxin. The enhanced H2O2 production by monocytes from asymptomatic untreated patients with CD4(+) cell counts above 500/microliter was associated with a decrease in the levels of Bcl-2 and thioredoxin. In contrast, in patients with AIDS, Bcl-2 levels returned to normal and thioredoxin levels were higher than in healthy controls. Restoration of these antioxidant and antiapoptotic molecules might explain, at least in part, why monocyte numbers remain relatively stable throughout the disease. Alterations of adhesion molecule expression and increased actin polymerization could play a role in transendothelial migration of these activated monocytes.
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PMID:Redox and activation status of monocytes from human immunodeficiency virus-infected patients: relationship with viral load. 1023 14

The alveolar macrophage (AM) oxidative burst response is an important component of microbicidal effector cell function against a variety of potential pathogens in the lungs, although the role against Pneumocystis carinii has not been fully investigated. The goals of this study were to characterize the P. carinii-mediated oxidative burst of AMs from healthy individuals, and to examine the oxidative burst of AMs from human immunodeficiency virus (HIV)-infected persons. For healthy individuals, the AM oxidative burst (measured as hydrogen peroxide [H(2)O(2)] production) increased in a time- and concentration-dependent manner in response to P. carinii or to the major surface glycoprotein of P. carinii, gp-A (0.01 to 10 microg/ml), required physical contact of P. carinii with AMs, and was not dependent on organism viability. Enzymatic removal of the surface-associated molecules of P. carinii reduced the oxidative burst to 43% of control (P = 0.01). Blocking the AM mannose receptor reduced the P. carinii-mediated oxidative burst response to 37% of control (P = 0.01). Compared with AMs from healthy individuals, P. carinii-mediated H(2)O(2) production was significantly reduced in AMs from asymptomatic HIV-positive (HIV+) persons with CD4+ counts < 200 cells/mm(3) (249+/-43 relative fluorescence units [RFU] versus 130+/-44 RFU; mean +/- standard error of the mean, P = 0.038) and HIV+ persons with active P. carinii pneumonia (78+/-40 RFU; P = 0.014), but preserved for HIV+ persons with CD4+ counts > 200 cells/mm(3). Importantly, H2O2 production in response to phorbol myristate acetate or serum-opsonized zymosan particles was preserved in all groups studied. Thus, AM oxidative burst, mediated in part via P. carinii gp-A and AM mannose receptor may represent an important host response to P. carinii. A specific impairment of P. carinii-mediated AM oxidative burst in persons with advanced HIV infection may contribute to the pathogenesis of P. carinii pneumonia.
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PMID:Alveolar macrophages from human immunodeficiency virus-infected persons demonstrate impaired oxidative burst response to Pneumocystis carinii in vitro. 1101 9


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