UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
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The eukaryotic transcription factor NF-kappa B is involved in the inducible expression of various inflammatory genes as well as in HIV-1 replication. Activation of NF-kappa B is induced by prooxidants and several stimuli eliciting oxidative stress, such as cytokines, lipopolysaccharide, UV irradiation and other mediators. Various antioxidants inhibit NF-kappa B activation in response to these stimuli. In this study, we have investigated the effects of selenium, an integral component of glutathione peroxidase (GPX), on NF-kappa B activation. In selenium-deprived Jurkat and ESb-L T lymphocytes, supplementation of selenium led to a substantial increase of GPX activity. Analysis of DNA binding revealed that NF-kappa B activation in response to TNF was significantly inhibited under these conditions. Likewise, reporter gene assays using luciferase constructs driven by the HIV-1 long terminal repeat showed a dose-dependent inhibition of NF-kappa B controlled gene expression by selenium. The effects of selenium were specific for NF-kappa B, since the activity of the transcription factor AP-1 was not suppressed. These data suggest that selenium supplementation may be used to modulate the expression of NF-kappa B target genes and HIV-1.
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PMID:Selenium-mediated inhibition of transcription factor NF-kappa B and HIV-1 LTR promoter activity. 885 98

MSSP proteins have been identified by their binding to an upstream element of c-myc. Independently, two different approaches yielded two cDNA clones highly homologous to the MSSP cDNAs, suggesting an involvement of MSSP in the regulation of the cell cycle (scr2) and in the repression of HIV-1 and ILR2 alpha-promoter transcription (human YC1). Screening human genomic libraries, we have isolated clones belonging to two different gene loci. Whereas the human MSSP gene 1 turned out to be intronless, the organization of the coding sequence within gene 2 is more complex. It spans more than 60 kb and contains 16 exons (including two alternative first exons), ranging from 48 to 287 bp, respectively. The intron sizes vary from 0.1 to more than 13 kb. Gene 1 has been completely sequenced. A deletion series of its upstream region was conjugated to the luciferase gene, but the transfection of the constructs did not display any promoter activity. Moreover, compared with gene 2 and the cDNA sequences known so far, about 20 point mutations as well as flanking direct repeats have been detected in the MSSP gene 1, showing that it possesses all the characteristics of processed retropseudogenes. Sequence analysis of a 1.7 kb fragment of the 5' flanking region of the MSSP gene 2 revealed that the promoter of gene 2 lacks consensus sequences for TATA and CCAAT boxes, is GC-rich, and contains numerous potential transcription factor binding elements including an Sp1 binding site. DNase I footprinting experiments showed that the putative Sp1 site was bound by proteins. The results of primer extension and S1 mapping analyses suggested the transcription of the gene starts at multiple positions upstream from the initiator methionine codon. Luciferase assays employing progressive deletions of the 1.7 kb promoter region allowed us to define the minimal promoter region of 428 bp (-488/+) and revealed a complex pattern of the transcriptional regulation the human MSSP gene 2. Furthermore, it can be concluded that the MSSP gene 2 encodes both MSSP-1 and MSSP-2, and moreover scr2 and human YC1.
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PMID:Cloning and characterization of the genomic DNA of the human MSSP genes. 887 67

Bacteria and eukaryotic cells respond to cold stress by inducing and enhancing the synthesis of specific arrays of proteins. We describe here cold-induced enhancement of expression for two reporter genes; luciferase and beta-galactosidase, both under the control of HIV-1 LTR sequences, observed in mouse fibroblasts and human HeLa cells respectively. Increased expression of luciferase in fibroblasts when shifted to 25 degrees C was detectable at 30 degrees C but was not observed following cold shock at 4 degrees C. To sustain the cold-induced effect, cells had to be kept at subphysiological temperature. The observed enhancement of luciferase activity did not result from a particular site of integration of the reporter gene and was evident whether cold-stressed cells were stationary or growing. Cold-induced expression of luciferase was evidenced at the protein level, enzymatic activity and RNA level, furthermore, active transcription and translation were required for overexpression. The cold effect which has been generalized with the reporter gene beta-galactosidase appears to be a process involving, at least in part, the HIV-1 LTR sequences and might correspond to an increase in the half-life of mRNA. The cold-dependent enhanced expression of luciferase and beta-galactosidase reported here, together with data describing the activation of HIV-1 LTR by hyperthermia, point out the particular temperature sensitivity of these regulatory sequences. This potential thermal modulation may be useful in the comprehension of regulatory processes in latency and reactivation of viral expression during HIV-1 infection.
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PMID:Low temperature enhancement of reporter genes expression directed by human immunodeficiency virus type 1 long terminal repeat. 894 41

Multiple human immunodeficiency virus type 1 (HIV-1) sequences with deletions of NF-kappaB binding sites at both the 5' and 3' long terminal repeats (LTRs) were identified in serial samples collected from an infected individual. The effect of this deletion on the level of transcription was studied by transient transfection of an LTR-driven luciferase reporter gene and by infection with a full-length recombinant HIV-1 containing a luciferase reporter (HIVHXBluc). Detectable levels of gene expression were found in both systems, in the presence or absence of the viral transactivator Tat. Interestingly, a duplication of a putative TCF-1alpha motif was found in place of the NF-kappaB elements in these viruses. Higher transcriptional activity was observed with HXBLTR (NF-kappaB intact) than with the patient's LTR (NF-kappaB deleted), suggesting that the NF-kappaB binding sites may promote optimal levels of viral gene transcription. The ability of these viruses with NF-kappaB deleted to replicate and cause substantial decline in CD4 cell counts demonstrates that the NF-kappaB binding sites are not absolutely required for viral replication or pathogenicity in vivo. These results are consistent with the notion that the HIV-1 LTR possesses functional redundancy which allows it to interact with multiple transcription factors, thereby ensuring viral replication in a variety of cell types.
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PMID:Identification of a replication-competent pathogenic human immunodeficiency virus type 1 with a duplication in the TCF-1alpha region but lacking NF-kappaB binding sites. 899 94

Human immunodeficiency virus type 1 (HIV-1) incorporates several host cell components when budding out of the infected cell. One of the most abundant host-derived molecules acquired by HIV-1 is the HLA-DR determinant of the major histocompatibility complex class II (MHC-II) molecules. The fact that CD4 is the natural ligand of MHC-II prompted us to determine if such virally embedded cellular components can affect the biology of the virus. Herein, we report for the first time that the incorporation of cellular HLA-DR1 within HIV-1 enhances its infectivity. This observation was made possible with virions bearing or not bearing on their surfaces host-derived HLA-DR1 glycoproteins. Such virus stocks were prepared by a transient-expression system based on transfection of 293T cells with a recombinant luciferase-encoding HIV-1 molecular clone along with plasmids encoding the alpha and beta chains of HLA-DR1. Cell-free virions recovered from transfected cells were shown to have efficiently incorporated host-derived HLA-DR1 glycoproteins. Infectivity was increased by a factor of 1.6 to 2.3 for virions bearing on their surfaces host-derived HLA-DR1. The observed enhancement of HIV-1 infectivity was independent of the virus stocks used and was seen in several T-lymphoid cell lines, in a premonocytoid cell line, and in primary peripheral blood mononuclear cells. Finally, we determined that the presence of virion-bound cellular HLA-DR1 is associated with faster kinetics of virus infection. Taken together, these results suggest that HLA-DR-1-bearing HIV-1 particles had a greater infectivity per picogram of viral p24 protein than HLA-DR1-free virions.
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PMID:The presence of host-derived HLA-DR1 on human immunodeficiency virus type 1 increases viral infectivity. 903 23

Human immunodeficiency virus type 1 (HIV-1) acquires several host cell membrane proteins when it buds from infected cells. To study the effect of virally incorporated host-derived ICAM-1 glycoproteins on the biology of HIV-1, we have developed a transient expression system that has enabled us to produce virus particles differing only in the absence or the presence of virion-bound ICAM-1. By using a single-round infection assay based on an ICAM-1-negative target T-cell line stably transfected with an HIV-1 long terminal repeat driven luciferase gene construct, we have been able to demonstrate that the acquisition of host-derived ICAM-1 by HIV-1 has functional significance, since it leads to a pronounced increase in viral infectivity (4.6- to 9.8-fold) in an ICAM-1/LFA-1-dependent fashion, as shown by blocking with anti-ICAM-1 and -LFA-1 antibodies. The same potentiating effect on viral infectivity was also observed with monocytoid cells. Studies of the kinetics of infection revealed that the positive effect mediated by virally embedded host cell membrane ICAM-1 is due to an increase in the efficiency of early steps in the viral life cycle. These results provide new insights into how incorporation of host proteins can modulate the biological properties of HIV-1. Our findings have direct clinical relevance, considering that ICAM-1 is expressed on the surface of virus-infected cells and, more importantly, that host-derived ICAM-1 has been shown to be acquired by clinical HIV-1 isolates grown on primary mononuclear cells. These data justify a more complete analysis of the other putative role(s) that virally incorporated ICAM-1 may play in the life cycle of HIV-1, for example, at the level of neutralization sensitivity.
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PMID:Host-derived ICAM-1 glycoproteins incorporated on human immunodeficiency virus type 1 are biologically active and enhance viral infectivity. 909 31

2',3'-Dideoxynucleosides (ddN) and their derivatives are currently used as antiretroviral compounds. Their active agents are the corresponding 2',3'-dideoxynucleoside triphosphates (ddNTPs) generated inside the cell by host kinases. Dinucleoside tetraphosphates (Np4Ns) are molecules of interest in metabolic regulation; their synthesis in vitro can be catalyzed by firefly luciferase. The relative synthesis of diadenosine 5',5'''-P1,P4-tetraphosphate or adenosine(5')tetraphospho(5')adenosine (Ap4A) from ATP is about 100-fold faster than that of di-2',3'-dideoxyadenosine 5',5'''-P1,P4-tetraphosphate or 2',3'-dideoxyadenosine (5')tetraphospho (5')-2',3'-dideoxyadenosine (ddAp4ddA) from ddATP. In the presence of ATPgammaS and ddATP the yield of adenosine(5')tetraphospo(5')-2',3'-dideoxyadenosine (Ap4ddA) was similar to that attained for Ap4A in the presence of ATP. The findings of this work indicate that the presence of a 3'-hydroxyl group is essential for the formation of the luciferase-luciferin-AMP complex, and explains the very low yield of ddAp4ddA in the presence of luciferase, luciferin and ddATP. The absence of 3'-hydroxyl groups in ddAp4ddA greatly hindered their hydrolysis by snake venom phosphodiesterase, asymmetrical dinucleoside tetraphosphatase and by a purified membrane preparation from rat liver. The possibility of using di-2',3'-dideoxynucleoside tetraphosphate (ddNp4ddN) or nucleoside(5')tetraphospho(5')-2',3'-dideoxynucleoside (Np4ddN) as a source of the active retroviral agent ddNTP, for example in HIV infection, is outlined.
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PMID:2',3'-dideoxynucleoside triphosphates (ddNTP) and di-2',3'-dideoxynucleoside tetraphosphates (ddNp4ddN) behave differently to the corresponding NTP and Np4N counterparts as substrates of firefly luciferase, dinucleoside tetraphosphatase and phosphodiesterases. 910 13

Indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) type II are induced in macrophages by interferon (IFN)-gamma and lipopolysaccharide (LPS). Nitric oxide has been previously shown to inhibit IDO activity. We studied whether metabolites of tryptophan via the IDO pathway could alter NOS II activity. In RAW 264.7 cells, the phenolic antioxidant 3-hydroxyanthranilic acid (OH-AA), but not anthranilic acid, inhibited citrulline synthesis by NOS II at sub-millimolar concentrations, when added 1 h before IFN-gamma and LPS. OH-AA inhibited NOS II activity in cytosolic extracts, suggesting a direct action of OH-AA on NOS II protein. Moreover, expression of NOS II mRNA and activation of the nuclear factor kappa B (NF-kappa B) in RAW 264.7 cells were decreased by a pretreatment with OH-AA, but not anthranilic acid, before addition of IFN-gamma and LPS. This pretreatment also inhibited activation of NF-kappa B in response to TNF-alpha in lymphoblastoid J.Jhan5-1 cells. Finally, expression of a long terminal repeat of the human immunodeficiency virus (HIV-LTR)-driven luciferase reporter gene, controlled by NF-kappa B activation, was severely decreased by OH-AA or 3-hydroxykynurenine in J.Jhan5-1 cells. Other tryptophan derivatives were inactive. These data identify OH-AA as an aminophenolic tryptophan derivative inhibiting NF-kappa B activation and impairing both NOS II expression and activity in a millimolar concentration range.
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PMID:Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite. 912 84

The gene BCL6 encodes a zinc finger protein with similarities to transcription factors. We previously reported that a number of viral genomes, including human immunodeficiency virus type I (HIV-1), contain sequences which are similar to the BCL6 DNA-binding consensus in their promoter regions. Electrophoretic mobility shift assays showed that the full-length BCL6 protein extracted from transfected COS cells and a bacterially expressed truncated protein containing the BCL6 zinc fingers can bind specifically to DNA from the U3 promoter/enhancer region of HIV-1. Transient transfections were performed to analyze the effects of the BCL6 protein on luciferase expression driven by the HIV-1 long terminal repeat (LTR) sequences. Full-length BCL6 significantly repressed luciferase activity compared with multiple controls. We conclude that the BCL6 protein can bind to the HIV-1 promoter-enhancer region and contains a domain upstream of its zinc fingers that can repress transcription from the HIV-1 LTR.
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PMID:BCL6 can repress transcription from the human immunodeficiency virus type I promoter/enhancer region. 913 90

Replication of human immunodeficiency virus type 1 (HIV-1) is increased by different cytokines and T cell activators, also known to modulate tyrosine phosphorylation levels. A novel class of protein tyrosine phosphatase (PTP) inhibitors, peroxovanadium (pV) compounds, were tested for a putative effect on HIV-1 long terminal repeat (LTR) activity. We found that these PTP inhibitors markedly enhanced HIV-1 LTR activity in 1G5 cells, a stably transfected cell line that harbors an HIV-1 LTR-driven luciferase construct. A direct correlation between the extent of tyrosine phosphorylation and the level of HIV-1 LTR inducibility was seen after treatment with three different pV compounds. Transient transfection experiments were carried out in several T cell lines, and after addition of pV, a marked increase in HIV-1 LTR activity was measured. Monocytoid cells were tested using U937-derived cell lines and were also found to be sensitive to the pV-mediated potentiating effect on HIV-1 LTR activity. A significant reduction of the pV-mediated increase in HIV-1 LTR activity was seen in cells transiently transfected with an HIV-1 LTR-driven luciferase construct bearing a mutation in both NF-kappaB binding sites although detectable levels of induction remained. Electrophoretic mobility shift assays allowed the identification of the nuclear translocation of the NF-kappaB p50.p65 heterodimer complex induced by pV compounds. A dominant negative version of the repressor IkappaBalpha mutated on serines 32 and 36 impeded pV-induced NF-kappaB-dependent luciferase activity. Western blot analysis showed a clear diminution in the protein level of IkappaBalpha starting 30 min after pV treatment of Jurkat E6.1 cells which is indicative of its degradation. On the other hand, no increase in tyrosine phosphorylation was observed on IkappaBalpha itself. Finally, we tested the PTP inhibitors on four cell lines latently infected with HIV-1 and showed a consistent pV-mediated increase in virion production. Thus, our studies suggest that pV-mediated activation of HIV-1 LTR activity is controlled by the nuclear translocation of the NF-kappaB transcription factor, which is mediated by IkappaBalpha serine phosphorylation and degradation, but also by a still undefined NF-kappaB-independent pathway.
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PMID:Activation of HIV-1 long terminal repeat transcription and virus replication via NF-kappaB-dependent and -independent pathways by potent phosphotyrosine phosphatase inhibitors, the peroxovanadium compounds. 914 3

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