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)

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

Human immunodeficiency virus type 1 (HIV-1) infection has been associated with an increase in the binding of the transcription factor NF-kappa B to its consensus sequence in the viral promoter. Using cultures of primary human fetal astrocytes, we show that exogenous HIV-1 Tat protein, which has been demonstrated to be released from infected cells, is associated with an increase in the binding of this transcription factor to an HIV-1 long terminal repeat kappa B sequence. This effect occurs rapidly and is independent of new protein synthesis. We also demonstrate that extracellular Tat protein is associated with an increase in protein kinase C activity. If Tat functions similarly in other cell types, such findings could relate to some of this protein's previously described physiological effects. These effects include Tat's ability to upregulate the synthesis of specific cytokines and to act as a growth factor.
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PMID:Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. 862 54

A long period of clinical latency before development of symptoms is characteristic of human immunodeficiency virus type 1 (HIV-1) infection. OM10.1, a promyelocyte cell line latently infected with HIV-1, has been developed as a model for studying the mechanism of viral latency and the activation of virus expression. We found that this latently infected cell line with heat shock at 42 degrees C for 2 h resulted in a high level of HIV-1 production without addition of any cytokines. The mechanism of activation was analyzed by using anti-TNF-alpha antibody and various inhibitors. Although the TNF-alpha level in culture supernatants was below the sensitivity of an ELISA assay system, addition of anti-TNF-alpha antibody in culture medium could partially suppress the heat shock induced HIV-1 production. Staurosporine (PKC inhibitor), pentoxifylline (NF-kappa B inhibitor), and Ro5-3335 (HIV-1 Tat inhibitor) also inhibited significantly the heat shock induced virus activation. In particular, staurosporine achieved approximately 90% inhibition of the HIV-1 antigen expression in heat shock-treated OM10.1 at a non-toxic concentration. Although the mechanism of HIV-1 activation with heat shock has not been fully elucidated yet, it is presumed PKC plays an important role in HIV-1 activation. Thus, the present observations will provide a further insight into the pathogenesis of HIV-1 infections.
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PMID:Heat shock induces HIV-1 replication in chronically infected promyelocyte cell line OM10.1. 864 86

Expression of the human immunodeficiency virus (HIV) Nef protein has been linked to both decreased cell surface expression of CD4 and an impairment of signal transduction. The recently reported association of Nef with an unidentified serine kinase provides a clue as to how Nef might exert its effects. Considering the key role of protein kinase C (PKC) in T cell activation, we investigated the possibility that Nef interacts with PKC. Our results, using two approaches for detecting interactions between Nef and PKC isozymes in Jurkat cells, show that Nef interacts preferentially with thetaPKC. The interaction of Nef and thetaPKC is independent of calcium, enhanced by phospholipid activators of PKC and not affected by a PKC pseudosubstrate peptide. Phorbol 12-myristate 13-acetate and phytohemagglutinin stimulation of Jurkat cells expressing Nef fails to produce the usual translocation of thetaPKC from the cytosol to the particulate fraction; translocation of betaPKC and epsilonPKC was unaffected. Indeed, there appears to be a net loss of thetaPKC in Nef-expressing cells following stimulation. The loss of thetaPKC, which may be a result of inhibition of its binding to RACKs due to Nef binding, could contribute to the various impairments of T cell function associated with HIV infection and Nef expression.
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PMID:The HIV nef protein associates with protein kinase C theta. 866 23

A novel cyclic peptide, MS-271, was isolated from the culture broth of an actinomycete, Streptomyces sp. M-271 as an inhibitor of smooth muscle myosin light chain kinase (MLCK). MS-271 inhibited the MLCK from chicken gizzard with an IC50 value of 8 microM. MS-271 did not inhibit cyclic AMP-dependent protein kinase, protein kinase C or calcium/calmodulin-dependent cyclic nucleotide phosphodiesterase at concentrations up to 400 microM. The primary structure of MS-271 was identical to that of siamycin I, an anti-HIV peptide isolated from a microbial source.
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PMID:MS-271, a novel inhibitor of calmodulin-activated myosin light chain kinase from Streptomyces sp.--I. Isolation, structural determination and biological properties of MS-271. 868 31

HIV-1 gp41 independently of CD4 binds to human T cells, B cells and monocytic cells. Since PMA downmodulates CD4 (HIV receptor) expression and inhibits HIV-1 dependent syncytia formation, we wanted to examine whether PMA could affect gp41 binding protein expression on human cells. The strong binding of HIV-1 recombinant soluble gp41 (rsgp41; Env aa539-684) to monocytes (CD14+) and B-lymphocytes (CD19+) and B lymphoblastoid cells (Raji) could be clearly decreased by treating the cells with PMA for 48 h, while the weak binding to T lymphocytes was slightly increased by this treatment. The PMA inhibitory- and enhancing-effects could be avoided by pretreatment with staurosporine (protein kinase C inhibitor). The PMA treatment of Raji and U937 (monocytic) cells resulted in a 50-60% decrease of gp41 binding proteins (gp41bps) detectable in cell lysates of these cells in comparison with lysates of buffer-treated cells, while in the case of H9-cells PMA treatment resulted in an increase of available gp41bps by about 35% in comparison with buffer-treated H9. Staurosporine pre-treatment could prevent these effects of PMA. Further studies of rsgp41-eluates from these buffer-treated or PMA-treated cells demonstrated that PMA modulated mainly expression of rsgp41bps of 37, 45, 50 and 62 kDa. These results indicate that PMA exerts different effects on human T, B and monocytic cells. Production by and expression on cells of HIV-1 gp41bps appear to depend on protein kinase C, supporting that the four proteins on human cells may act as receptor proteins for HIV-1 gp41.
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PMID:HIV-1 gp41 binding to human T- and B-lymphocytes and monocytes is modulated by phorbol myristate acetate (PMA). 880 14

The replication of human immunodeficiency virus type 1 (HIV-1) requires cellular components to interact with regulatory elements located in the long terminal repeat (LTR) as well as viral proteins Tat and Rev. Several well known signaling transduction inhibitors were tested to determine their effects on the Tat-mediated transactivation using a transfection assay with the bacterial chloramphenicol acetyltransferase gene under the control of the HIV-1 LTR. The protein kinase C inhibitors curcumin and staurosporine, but not a tyrosine kinase inhibitor herbimycine A, inhibited Tat-mediated LTR-driven transactivation. Two antimalarial drugs quinacrine and chloroquine, that are also arachidonic acid metabolism inhibitors, were found to inhibit the Tat-mediated LTR-driven gene expression. Another inhibitor of arachidonic acid metabolism 4-bromophenacyl bromide was also found to inhibit Tat-mediated gene expression driven by HIV-1 LTR. However, the antimalarial drug quinine elicited no effects on Tat-mediated transactivation. These results suggest that the anti-arachidonic acid metabolism properties of quinacrine and chloroquine may be responsible for their ability to inhibit Tat-mediated LTR-regulated gene expression.
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PMID:Inhibition of HIV-1 Tat-mediated transactivation by quinacrine and chloroquine. 880 83

Several recent reports support the hypothesis that apoptosis occurring in leukocytes of human immunodeficiency virus type 1 (HIV-1)-infected individuals is important in progression to AIDS. Specifically, apoptosis of uninfected bystander cells appears critical in the pathogenesis of disease. Here, we present evidence that protease-defective, gp120-containing HIV-1 (L-2) particle preparations specifically induce apoptosis in cells obtained from a subset of promonocytic U937-derived subclones. The rate of apoptosis induction was inversely correlated with the susceptibility of the U937 subclones to wild-type HIV-1 infection. Three types of apoptosis experiments were performed: DNA content analysis by flow cytometry, apoptotic nuclear degradation by fluorescent microscopy and DNA fragmentation analysis by agarose gel electrophoresis. Kinetic analysis revealed that there was a slower induction of apoptosis by L-2 particle preparations than with tumor necrosis factor (TNF)-alpha or anti-Fas antibody. However, there were no significant differences in the initial binding rates of L-2 particles as well as the binding of TNF-alpha or anti-Fas antibody to the U937 subclones. The basal level of protein kinase C activity was higher in high-type subclones compared with low-type subclones. These results suggest that U937 cells can be divided into at least two subpopulations, one that permits a productive HIV-1 infection but is not subjected to L-2 particle preparation-induced apoptosis, while the other poorly replicates HIV-1 and is subjected to L-2 mediated apoptosis, although at a slower rate than found with TNF-alpha or anti-Fas antibody.
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PMID:Induction of apoptosis by protease-defective particle preparations of human immunodeficiency virus type 1 is specific to a subset of U937-derived subclones. 894 63

We have recently described the cDNA and predicted protein structure of a natural soluble CD4 ligand, IL-16. IL-16 is chemotactic for CD4+ T cells and induces functional IL-2 receptors in CD4+ T cells. The binding of IL-16 to CD4 results in activation of p56(lck), whose adaptor function is essential for the chemotactic response. Subsequently, increases in intracellular Ca2+ and phosphatidylinositol 1,4,5-trisphosphate occur, as does translocation of protein kinase C from cytosol to membrane. Because of the similarities between these signals and functions and those noted for the CD4 ligand HIV-1 gp120, we investigated the potential regulatory effects of IL-16 on CD3/TCR-mediated lymphocyte activation. Preincubation of human T cells with IL-16 up to 24 h before activation with plate-bound anti-CD3 Abs reduced T cell activation by 80%, as monitored by IL-2R expression and [3H]thymidine uptake. If IL-16 was added following anti-CD3 activation, no suppression was noted. The suppressive effects of preincubation with IL-16 were not rescued by the addition of rIL-2 and were not the result of priming for anti-CD3-induced apoptosis. In addition, IL-16 had no effect on surface expression of CD3 or CD4. However, IL-16 did reduce the magnitude of the anti-CD3-induced intracellular Ca2+ increase. These studies indicate that while the interaction of CD4 with its natural ligand, IL-16, results in Ag-independent chemotaxis and IL-2R expression, this pro-inflammatory state is associated with subsequent transient inhibition of responsiveness via the CD3/TCR complex.
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PMID:IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation. 895 68

The CD4 molecule acts as a receptor for class II MHC molecules to stabilize Ag recognition by the TCR and as a high affinity receptor for HIV-1. In this study, we investigated the effect of oxidative stress on the level of CD4 expression on cultured peripheral blood T lymphocytes (PBL blasts). As previously reported, we observed that the surface CD4 was down-regulated by PMA. Unexpectedly, treatment of PBL blasts with hydrogen peroxide (H2O2) or a sulfhydryl oxidative reagent, diamide, almost completely inhibited PMA-induced CD4 down-regulation, although these oxidants per se did not affect the level of CD4 expression. We next assessed the serine phosphorylation of CD4, which is reported to be an indispensable process for PMA-induced CD4 endocytosis. PMA could induce the serine phosphorylation even in the presence of oxidants. We also found that these oxidants had an additive effect on PMA-induced dissociation between CD4 and p56(lck), which is known to be another necessary step for CD4 endocytosis. These results indicate that in T cells, oxidants inhibit protein kinase C-mediated CD4 down-regulation due to perturbing a signaling process other than the above two steps, implying that oxidative stress may tune the functions of CD4+ T cells and their susceptibility to HIV-1 through the control of CD4 expression.
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PMID:Inhibition of protein kinase C-mediated CD4 down-regulation by oxidative stress in T lymphocytes. 895 81


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