Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Blocking human immunodeficiency virus (HIV) entry into target cells is an important goal of HIV and acquired immune deficiency syndrome (AIDS) therapies. We have searched for anti-HIV substances from microorganisms using a syncytium formation assay system constructed with HeLa/CD4/Lac-Z and HeLa/T-env/Tat cells. We discovered a novel anti-HIV protein that inhibits syncytium formation, designated as actinohivin, from a cultured broth of a soil isolate, actinomycete strain K97-0003. ESI mass spectrometry of actinohivin isolated from the culture filtrate showed an ion with molecular mass of 12,520.3 Da. The amino acid sequence was determined by N-terminal Edman degradation of the intact protein and peptide fragments formed by endoproteinase digestions. Actinohivin consists of a 114-amino-acid chain that exhibits internal sequence triplication. Actinohivin inhibited both T-cell and macrophage tropic syncytium formation, with IC(50) values of 60 and 700 nM, respectively, and the cytopathic effect of HIV-1(IIIB) in MT-4 cells, with IC(50) value of 230 nM.
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PMID:Actinohivin, a novel anti-HIV protein from an actinomycete that inhibits syncytium formation: isolation, characterization, and biological activities. 1140 2

Extracellular Tat protein, the transactivating factor of the human immunodeficiency virus type 1 (HIV-1), modulates gene expression, growth, and angiogenic activity in endothelial cells by interacting with the vascular endothelial growth factor (VEGF) receptor-2 (Flk-1/KDR). Recombinant Tat protein, produced as glutathione-S-transferase chimera (GST-Tat), activates mitogen-activated protein kinase (MAPK) ERK(1/2) in human, murine, and bovine endothelial cells whereas GST is ineffective. In bovine aortic endothelial cells, GST-Tat and the 165 amino acid VEGF isoform (VEGF165) induce transient ERK(1/2) phosphorylation with similar potency and kinetics. The synthetic peptide Tat(41-60), but not peptides Tat(1-21) and Tat(71-86), causes ERK(1/2) phosphorylation, thus implicating Tat/KDR interaction in the activation of this signalling pathway. Accordingly, GST-Tat induces ERK(1/2) phosphorylation in KDR-transfected porcine aortic endothelial cells but not in parental cells. MAPK kinase inhibitors PD098059 and U0126 prevent ERK(1/2) phosphorylation by Tat. However, they do not affect the angiogenic activity exerted by Tat in the murine Matrigel plug and chick embryo chorioallantoic membrane assays. Blocking of MAPK kinase activity impairs instead the angiogenic response to VEGF165 and to fibroblast growth factor-2 (FGF-2). Our data demonstrate that ERK(1/2) activation following the interaction of HIV-1 Tat protein with endothelial cell Flk-1/KDR receptor does not represent an absolute requirement for a full angiogenic response to this growth factor that appears to utilize mechanism(s) at least in part distinct from those triggered by other prototypic angiogenic growth factors.
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PMID:Activation of endothelial cell mitogen activated protein kinase ERK(1/2) by extracellular HIV-1 Tat protein. 1140 52

We have identified and obtained the full-length clone of RREBP49, a human nuclear factor which specifically interacts with the Rev-responsive element (RRE) sequence of human immunodeficiency virus type 1. Sequence analysis revealed that RREBP49 is highly homologous to hnRNP F protein and contains three repeated RNA-binding domains. Binding assays demonstrated that Rev and RREBP49 bind to different subregions on the RRE sequence and that binding is mutually nonexclusive. Blocking of endogenous RREBP49 expression by an antisense construct increases Rev activity in CV-1 cells, indicating that RREBP49 and Rev may play antagonistic roles in HIV-1 replication. RREBP49 may function as a splicing factor or a nuclear retention factor for unspliced mRNAs. However, only a slight decrease of Rev activity was observed when exogenous RREBP49 was introduced into CV-1 cells by pSVL-RREBP49 expression vector. This may be explained by a high endogenous level of RREBP49 which is above optimal. Alternatively, additional cellular factors may be required for RREBP49-mediated inhibition of Rev. Copyright 1996 S. Karger AG, Basel
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PMID:A Novel hnRNP Specifically Interacts with HIV-1 RRE RNA. 1172 88

We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.
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PMID:Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection. 1209 87

Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.
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PMID:GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia. 1211 68

Human immunodeficiency virus, type 1 (HIV-1) infection of CD4(+) T cells progressively abrogates T cell receptor (TCR).CD3 function and surface expression by specifically interfering with CD3gamma gene transcription. Our data show that the loss of CD3gamma transcripts begins very early after infection and accumulates to a >90% deficiency before a significant effect on surface receptor density is apparent. Blocking TCR.CD3-directed NFAT activation with cyclosporin A provokes a partial re-expression of CD3gamma gene transcripts and surface complexes in a time- and dose-dependent manner. We have identified three NFAT consensus sequences (5'-GGAAA-3') in the 5'-upstream region of the human CD3gamma gene at: -124 to -120 (NFAT(gamma1)), -384 to -380 (NFAT(gamma2)), and +450 to +454 (NFAT(gamma3)) from the first transcription initiation site. Using electrophoretic mobility shift and supershift assays, we show that NFATc2 alone binds to the NFAT(gamma2) motif; however, complexes containing either NFATc2 or NFATc1 plus NF-kappaB p50 bind to the NFAT(gamma1) and NFAT(gamma3) sites. We further demonstrate that NFATc1 and NF-kappaB p50 bind in the same protein.DNA complex and that a fourth Ala added to the core sequence (5'-GGAAAA-3') in NFAT(gamma1), and NFAT(gamma3) is critical for their binding. Finally, we have shown that an increase in the binding of nuclear NFATc2, NFATc1, and NF-kappaB p50 to these three motifs is correlated with a progressive loss of CD3gamma transcripts after HIV-1 infection.
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PMID:Identification of three NFAT binding motifs in the 5'-upstream region of the human CD3gamma gene that differentially bind NFATc1, NFATc2, and NF-kappa B p50. 1237 7

Retrovirus minus strand strong stop transfer (minus strand transfer) requires reverse transcriptase-associated RNase H, R sequence homology, and viral nucleocapsid protein. The minus strand transfer mechanism in human immunodeficiency virus-1 was examined in vitro with purified protein and substrates. Blocking donor RNA 5'-end cleavage inhibited transfers when template homology was 19 nucleotides (nt) or less. Cleavage of the donor 5'-end occurred prior to formation of transfer products. This suggests that when template homology is short, transfer occurs through a primer terminus switch-initiated mechanism, which requires cleavage of the donor 5' terminus. On templates with 26-nt and longer homology, transfer occurred before cleavage of the donor 5' terminus. Transfer was unaffected when donor 5'-end cleavages were blocked but was reduced when internal cleavages within the donor were restricted. Based on the overall data, we conclude that in human immunodeficiency virus-1, which contains a 97-nt R sequence, minus strand transfer occurs through an acceptor invasion-initiated mechanism. Transfer is initiated at internal regions of the homologous R sequence without requiring cleavage at the donor 5'-end. The acceptor invades at gaps created by reverse transcriptase-RNase H in the donor-cDNA hybrid. The fragmented donor is eventually strand-displaced by the acceptor, completing the transfer.
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PMID:Mechanism of minus strand strong stop transfer in HIV-1 reverse transcription. 1249 70

The human survivin gene belongs to the family of inhibitor of apoptosis proteins (IAP) and is involved in apoptosis inhibition and regulation of cell division. The survivin gene is the only member of the IAP family whose expression is known to be regulated through the cell cycle. Survivin expression reaches the highest levels during the G(2)/M transition and then is rapidly degraded during the G(1) phase. Here we report that the human immunodeficiency virus type 1 (HIV-1) upregulates Survivin expression via survivin promoter transactivation. Vpr, an HIV-1 accessory protein that induces cell cycle arrest in G(2)/M, is necessary and sufficient for this effect. Blocking Vpr-induced G(2)/M arrest leads to elimination of the survivin promoter transactivation by Vpr. Our results suggest that Survivin may be actively involved in regulating cell viability during HIV-1 infection.
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PMID:Upregulation of survivin by HIV-1 Vpr. 1251 Jan 54

Cyclin-dependent kinase inhibitors (CDKIs) have been shown to block human immunodeficiency virus and herpes simplex virus. It is hypothesized that CDKIs block viral replication by inhibiting transcription of specific cellular genes. Here we find that three CDKIs, flavopiridol, purvalanol A, and methoxy-roscovitine, block Moloney murine leukemia virus (MLV) transcription events. Using gene expression microarray technology to examine the inhibitory effects of CDKIs, we observed a cellular gene, the pre-B-cell leukemia transcription factor 1 (Pbx1) gene, down-regulated by CDKI treatment. The PBX consensus element (PCE), TGATTGAC, is conserved in the long terminal repeats of several murine retroviruses, including Moloney MLV. Mutations in the PCE completely inhibited viral transcription whereas overexpression of PBX1 and a PBX1-associated protein, PREP1, enhanced viral transcription. The interaction between the PCE and PBX1-PREP1 proteins was confirmed by gel shift experiments. Blocking PBX1 protein synthesis resulted in a significant decrease in viral transcription. Collectively, our results represent the first work demonstrating that the homeodomain proteins PBX1 and PREP1 are cellular factors involved in Moloney MLV transcription regulation.
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PMID:Identification of homeodomain proteins, PBX1 and PREP1, involved in the transcription of murine leukemia virus. 1252 89

Considerable evidence suggests that human immunodeficiency virus (HIV)-infected macrophages and/or lymphocytes may mediate sexual transmission of HIV. We and others have previously demonstrated that when vitally stained donor mouse lymphocytes or macrophages are placed in the vaginas of mice, some of the stained cells can later be found in the iliac lymph nodes. The aim of this study was to assess the extent of mononuclear cell trafficking from the vagina and to test the possibility that carrageenan formulation, a sulfated polysaccharide formulation containing 3% PDR98-15 carrageenan (PC-515; FMC Biopolymer, Rockland, ME), a vaginal microbicide, would prevent vaginal transmigration of macrophages. When supravitally stained mouse macrophages and T cells were inoculated into the vagina of recipient mice, discrete numbers of donor cells migrated to the recipient iliac and inguinal lymph nodes and spleen. When recipient mice were preinoculated with the carrageenan formulation, the number of macrophages in lymph nodes and spleen was reduced by >90%. In contrast, a methylcellulose formulation, which is believed to be inactive, did not significantly reduce migration to the lymphoid organs. Our findings suggest that the carrageenan formulation blocks cell trafficking of macrophages from vagina and that blocking does not result from cytotoxicity. Blocking cell trafficking may help to prevent sexual transmission of HIV.
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PMID:Carrageenan formulation prevents macrophage trafficking from vagina: implications for microbicide development. 1277 28


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