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)

Proliferation of normal T lymphocytes is impaired by human immunodeficiency virus (HIV) proteins. In this paper, we demonstrate important parts of this mechanism. Initially, HIV-induced impairment of proliferation was shown to be an active process involving induction of protein tyrosine kinases in both CD4 and CD8 T cells. Furthermore, the impairment of cell proliferation was demonstrated to be linked to induction of the inhibitory protein kinase A (PKA) pathway by HIV proteins. This induction of PKA was accompanied by an increase in intracellular cAMP, which is necessary for the activation of PKA. Finally, increases in cAMP/PKA activity were shown to induce biochemical changes that impaired proliferation when cells were stimulated with phytohemagglutinin. This was demonstrated by showing that (i) agents, other than HIV proteins, that increase cAMP/PKA activity (cholera toxoid and 8-bromo-cAMP) also decreased T-lymphocyte proliferation; (ii) exposure of lymphocytes to HIV or cholera toxoid led to decreased membrane activity of the proliferation promoter protein kinase C upon stimulation; and (iii) agents that reduced cAMP generation neutralized the effect of HIV proteins and restored lymphocyte proliferation. These studies show that the HIV-induced augmentation of cAMP/PKA activity may be a key part of the mechanism responsible for all or part of the HIV-induced anergy of T lymphocytes.
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PMID:Human immunodeficiency virus proteins induce the inhibitory cAMP/protein kinase A pathway in normal lymphocytes. 768 26

The paper presents the analysis of T-cell immunity in asthmatics and bronchitis chronics. Immunodeficiency in one-third of them was characterized by thymic failure. T-cell insufficiency was registered in 50% and 37% of atopic and bacterial asthma patients, respectively, in 40% and 25% of those with chronic obstructive bronchitis and nonobstructive one, respectively. Imbalance of immunoregulatory cells in atopic asthma in 87% of relevant patients and in 37% of chronics with obstructive bronchitis was indicated by enhanced suppressor activity. In patients with bacterial asthma and chronic nonobstructive bronchitis (in 40% and 25%, respectively) helper-cell activity rose. A cAMP concentration proved reduced in helper cells and helper + suppressor subpopulations in bacterial asthma and obstructive bronchitis chronics, respectively. Atopic bronchial asthma was associated with low suppressor subpopulation. Variants of immunocorrection in the above conditions are presented for discussion.
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PMID:[The cellular immunity and cyclonucleotide level in the immunoregulatory cells of patients with bronchial asthma and chronic bronchitis]. 790 63

We have studied human immunodeficiency virus type 1 (HIV-1) infection in human SH-SY5Y neuroblastoma cells at various stages of morphological differentiation. Two days' treatment of the cells with retinoic acid (RA) or dibutyryl cAMP (db-cAMP) resulted in the appearance of elongated neurites and enhanced production of 160K to 200K neurofilament proteins as shown by indirect immunofluorescence. DNA synthesis was reduced only in RA-treated cells as detected by 5-bromo-2'-deoxyuridine incorporation. The cells were infected with two T-lymphotropic virus strains (IIIB and NDK) and two fresh isolates (39001 and 46001) from bronchoalveolar lavage samples of AIDS patients. The latter two isolates were unable to form syncytia in infected CD4-positive T-lymphoblastoid C8166 cells which was in contrast to our T-lymphotropic virus strains. Interphase in situ hybridization showed that 14 to 16% of SH-SY5Y cells become positive for HIV-1 DNA. Regardless of the virus strain, morphological differentiation of the cells with RA or db-cAMP inhibited infection by 50% at a single cell in situ resolution. Nested PCR confirmed the presence of proviral DNA in the infected cells. These results show that human neuroblastoma cells, tumour cells of neuroectodermal origin, can be infected by different HIV-1 isolates and that the infection is inhibited by neurotypic cell differentiation.
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PMID:Morphological differentiation of human SH-SY5Y neuroblastoma cells inhibits human immunodeficiency virus type 1 infection. 811 28

The goal of our study was to assess whether the human immunodeficiency virus (HIV) coat protein gp120 induces functional alterations in astrocytes and microglia, known for their reactivity and involvement in most types of brain pathology. We hypothesized that gp120-induced anomalies in glial functions, if present, might be mediated by changes in the levels of intracellular messengers important for signal transduction, such as cAMP. Acute (10 min) exposure of cultured rat cortical astrocytes or microglia to 100 pM gp120 caused only a modest (50-60%), though statistically significant, elevation in cAMP levels, which was antagonized by the beta-adrenergic receptor antagonist propranolol. More importantly, the protein substantially depressed [by 30% (astrocytes) and 50% (microglia)] the large increase in cAMP induced by the beta-adrenergic agonist isoproterenol (10 nM), without affecting that induced by direct adenylate cyclase stimulation by forskolin. Qualitatively similar results were obtained using a glial fibrillary acidic protein (GFAP)-positive human glioma cell line. The depression of the beta-adrenergic response had functional consequences in both astrocytes and microglia. In astrocytes we studied the phosphorylation of the two major cytoskeletal proteins, vimentin and GFAP, which is normally stimulated by isoproterenol, and found that gp120 partially (40-50%) prevented such stimulation. In microglial cells, which are the major producers of inflammatory cytokines within the brain, gp120 partially antagonized the negative beta-adrenergic modulation of lipopolysaccharide (10 ng/ml)-induced production of tumor necrosis factor alpha. Our results suggest that, by interfering with the beta-adrenergic regulation of astrocytes and microglia, gp120 may alter astroglial "reactivity" and upset the delicate cytokine network responsible for the defense against viral and opportunistic infections.
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PMID:Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions. 838 71

UDP-GlcNAc:Gal beta 3GalNAc-R (GlcNAc to GalNAc) beta 1-6-N-acetylglucosaminyltransferase (i.e. core 2 GlcNAc-T) of the O-linked oligosaccharide pathway is developmentally regulated in human T cells, and changes in its activity have been associated with malignancies and the Wiskott-Aldrich immunodeficiency syndrome. Chinese hamster ovary (CHO) cells normally express low levels of core 2 GlcNAc-T activity (8-12 pmol/mg/h) which can be accurately measured with a two-step assay employing purified bovine beta 1-4Gal-T and high specific activity UDP-[3H]Gal to radiolabel the core 2 reaction product. CHO cells treated with 2 mM sodium butyrate for 24 h exhibited a 16-fold increase in core 2 GlcNAc-T activity, whereas several other differentiating agents including dimethyl sulfoxide, retinoic acid, phorbol ester, and cholera toxin had no effect on activity. The addition of butyrate, cholera toxin, or dimethyl sulfoxide to CHO cells slowed cell proliferation and induced changes in cell morphology characteristic of cell differentiation. Induction of core 2 GlcNAc-T by butyrate was blocked by actinomycin D and cycloheximide. Butyrate treatment also elevated cytosolic cAMP levels with a time course which paralleled, but preceded, induction of core 2 GlcNAc-T activity by approximately 8 h. The protein kinase inhibitors H-7 and H-8 blocked butyrate-dependent induction of enzyme activity, whereas the inactive analogue H1004 had no effect. Core 2 GlcNAc-T showed a change in Km for UDP-GlcNAc, from 0.50 mM in untreated cells to 4.54 mM in butyrate + cholera toxin treated CHO cells, but no changes in Km for the synthetic acceptor, Gal beta 1-3GalNAc alpha-para-nitrophenyl. Despite the 9-fold increase in Km for sugar nucleotide, Vmax/Km was 8.8-fold greater in treated compared with untreated cells. These observations suggest that in CHO cells induction of core 2 GlcNAc-T by butyrate treatment requires de novo gene transcription/translation, activation of protein kinase(s), and is associated with changes in the kinetic properties of the enzyme.
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PMID:Regulation of UDP-GlcNAc:Gal beta 1-3GalNAc-R beta 1-6-N-acetylglucosaminyltransferase (GlcNAc to GalNAc) in Chinese hamster ovary cells. 838 71

We examined the effect of chronic human immunodeficiency virus 1 (HIV-1) infection on the growth of human leukemic CEM T cells exposed to compounds which act through several major hormone or hormone-like signal transduction systems. Three were not altered by HIV-1 infection. Micromolar 8-bromo-cAMP inhibited cell growth equally in uninfected and infected cells. At the concentrations tested, neither (Bu)2cAMP nor the stimulator of protein kinase C, phorbol 12-myristate 13-acetate, altered the growth of infected or uninfected cells. The synthetic prostaglandin analog enisoprost also inhibited both equally. However, responses to two basic signal transduction systems, calcium uptake and the glucocorticoid pathway, were influenced by HIV infection. In chronically HIV-infected cells increased sensitivity to lysis by the calcium ionophore A23187 was observed. Additionally, the infected cells contained reduced amounts of glucocorticoid receptor sites and showed a statistically significant shift toward resistance to glucocorticoid-induced apoptosis.
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PMID:Interactions between human immunodeficiency virus infection and hormonal pathways: enhancement of calcium-induced but reduction of glucocorticoid-induced cell death. 839 9

Cytomegalovirus (CMV) infection constitutes a serious threat to patients with acquired immune deficiency syndrome. Recently we reported that human immunodeficiency virus (HIV) infection of CD4+ cells was associated with sustained elevation of cellular levels of cAMP. Moreover, cyclic nucleotide modulators enhanced HIV replication by increasing intracellular levels of cAMP. In this study, the effect of CMV on HIV replication in CMV/HIV mixed infection and its relationship to cAMP were examined. MT-4 cells, CMV strain AD169, and HIV strain IIIB were used. Optimal enhancement (4.4-fold increase) of HIV replication was observed when MT-4 cells were infected with CMV at Day 0 followed by HIV on Day 4 after infection, as determined by reverse transcriptase activity on Day 11 after infection. cAMP (measured by radioimmunoassay) levels in cells infected with CMV alone, HIV alone, or CMV/HIV together were 2-, 3-, and 5-fold above untreated cells, respectively. CMV also enhanced the replication of UV-irradiated HIV 4-fold and this was associated with a 2-fold increase in cAMP as well. Moreover, UV-irradiated CMV enhanced HIV replication 8.8-fold. The same dose of viable and UV-irradiated CMV used in the above experiments increased protein kinase C activity in these cells 3.0- and 8.0-fold, respectively. These findings might suggest that cAMP and protein kinase C are involved in CMV enhancement of HIV replication. These findings may have relevance to the identification of novel target sites for development of antiviral therapeutics.
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PMID:Involvement of cAMP and protein kinase C in cytomegalovirus enhancement of human immunodeficiency virus replication. 841 79

Vif is a 23-kDa protein encoded by human immunodeficiency virus, type 1 (HIV-1) which is important for virion infectivity. Here, we describe the phosphorylation of HIV-1 Vif and its role in HIV-1 replication. In vivo studies demonstrated that Vif is highly phosphorylated on serine and threonine residues. To identify phosphorylation sites and characterize the Vif kinase(s), Vif was expressed in Escherichia coli and purified for use as a substrate in in vitro kinase assays. The purified Vif protein was phosphorylated in vitro on serine and threonine residues by a kinase(s) present in both cytosol and membrane fractions. Phosphorylation of Vif was stimulated by phorbol 12-myristate 13-acetate and inhibited by staurosporine and hypericin, a drug with potent anti-HIV activity. The Vif kinase(s) was resistant to inhibitors of protein kinase C, cAMP-dependent kinase, and cGMP-dependent kinase, suggesting that it is distinct from these enzymes. To identify the phosphorylation sites, 32P-labeled Vif was digested by V8 protease and the peptides were resolved by reverse-phase high performance liquid chromatography. Radioactive peptide sequencing identified three phosphorylation sites within the C terminus, Ser144, Thr155, and Thr188. Two-dimensional tryptic phosphopeptide mapping indicated that these sites are also phosphorylated in vivo. Both Ser144 and Thr188 are contained in the recognition motifs (R/KXXS*/T* and R/KXXXS*/T*) used by serine/threonine protein kinases such as cGMP-dependent kinase and PKC. Ser144 is present in the motif SLQXLA, which is the most highly conserved sequence among all lentivirus Vif proteins. Mutation of Ser144 to alanine resulted in loss of Vif activity and >90% inhibition of HIV-1 replication. These studies suggest that phosphorylation of Vif by a serine/threonine protein kinase(s) plays an important role in regulating HIV-1 replication and infectivity.
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PMID:Phosphorylation of Vif and its role in HIV-1 replication. 862 71

We have recently elucidated the nature and function of transcription factors present in Jurkat, glial and neuronal cells that interact with modulatory region B, the nuclear receptor responsive element, in the long terminal repeat of human immunodeficiency virus type 1 (HIV-1). Considering the key role that the combination of host cell proteins plays in HIV-1 gene transcription, it appears essential to characterize proteins interacting with the adjacent region A. In vitro experiments revealed that the 5'-TGATTGGC-3'motif of region A is the target for at least three distinct proteins, one belonging to the nuclear factor I family, while two others are related to the cAMP response element binding (CREB) protein family. One of these proteins, present in DNA-protein complex C2, is formed by distinct polypeptides of relative molecular mass 43 000 and 50 000. We have purified the 43 kDa protein, which is distinct from CREB-43, and have shown that renatured p43 is able to specifically interact with site A. Transient expression experiments with vectors containing wild-type or mutant motif A revealed that basal HIV-1 gene transcription in Jurkat cells is regulated by antagonistic effects of the site A binding proteins.
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PMID:Characterization of nuclear proteins that bind to the regulatory TGATTGGC motif in the human immunodeficiency virus type 1 long terminal repeat. 909 27

Stable human cell lines expressing the human immunodeficiency virus type I (HIV-I) Nef protein from inducible promoters were used to analyze the phosphorylation status of Nef in vivo. Nef phosphorylation in both HeLa and Jurkat cells was stimulated by phorbol ester treatment. Phosphoamino acid analysis revealed a predominance of phosphoserine with a small proportion of phosphothreonine. Treatment of cells with selective protein kinase inhibitors revealed that Nef phosphorylation was markedly reduced by bisindolylmaleimide, an inhibitor of protein kinase C, but was unaffected by inhibitors of mitogen-activated protein kinase kinase or cAMP-dependent kinase. These data implicate protein kinase C in Nef phosphorylation in vivo, and thus confirm and extend earlier in vitro data. Phosphorylation of a nonmyristoylated Nef mutant was impaired, suggesting that membrane targeting of Nef was required for phosphorylation. This was expected given that activated protein kinase C translocates from the cytosol to the plasma membrane. However, analysis of the subcellular localization of phosphorylated wild-type Nef revealed that both the cytosolic and membrane-associated pools of Nef were phosphorylated to an equivalent extent. Thus the significance of myristoylation for Nef function may be in influencing protein conformation, although these data could be explained by a transient and dynamic interaction between myristoylated Nef and the plasma membrane.
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PMID:Protein kinase C-mediated phosphorylation of HIV-I nef in human cell lines. 913 71


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