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)

Adeno-associated virus type 2 (AAV-2), a human parvovirus which is apathogenic in adults, inhibits replication and gene expression of human immunodeficiency virus type 1 (HIV-1) in human cells. The rep gene of AAV-2, which was shown earlier to be sufficient for this negative interference, also down-regulated the expression of heterologous sequences driven by the long terminal repeat (LTR) of HIV-1. This effect was observed in the absence of the HIV-1 transactivator Tat, i.e., at basal levels of LTR-driven transcription. In this work, we studied the involvement of functional subsequences of the HIV-1 LTR in rep-mediated inhibition in the absence of Tat. Mutated LTRs driving an indicator gene (cat) were cointroduced into human SW480 cells together with rep alone or with double-stranded DNA fragments or RNA containing sequences of the HIV-1 LTR. The results indicate that rep strongly enhances the function of negative regulatory elements of the LTR. In addition, the experiments revealed a transcribed sequence element located within the TAR-coding sequence termed AHHH (AAV-HIV homology element derived from HIV-1) which is involved in rep-mediated inhibition. The AHHH element is also involved in down-regulation of basal expression levels in the absence of rep, suggesting that AHHH also contributes to negative regulatory functions of the LTR of HIV-1. In contrast, positive regulatory elements of the HIV-1 LTR such as the NF kappa B and SP1 binding sites have no significant influence on the rep-mediated inhibition.
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PMID:Adeno-associated virus type 2 rep gene-mediated inhibition of basal gene expression of human immunodeficiency virus type 1 involves its negative regulatory functions. 828 57

The transactivator of transcription, Tat, of human immunodeficiency virus type 1 (HIV-1) is required for viral replication. Inhibition of Tat function could have the potential to keep integrated provirus in dormancy. In the presence of Tat, Ro 24-7429, an analog of Ro 5-3335, inhibited expression of indicator genes controlled by the HIV-1 long terminal repeat promoter in transient transfection assays and in a constitutive cell line at noncytotoxic concentrations. Reduction of steady-state mRNA of the indicator gene by the compound correlated with reduction of the gene product in the constitutive cell line. Ro 24-7429 has broad activity against several strains of HIV-1 in different cell lines, peripheral blood lymphocytes, and macrophages (IC90 = 1-3 microM). Importantly, Ro 24-7429 inhibited viral replication in both acute and chronic infection in vitro, a characteristic expected of a Tat antagonist and not shared by viral reverse transcriptase inhibitors. Consistent with this, the compound reduced cell-associated viral RNA and proteins and partially restored cell-surface CD4 in chronically infected cells. After 2 years of continued weekly passage of the virus in fresh CEM cells grown in the presence of the compound at 1 or 10 microM, the virus did not develop resistance to the drug. These results indicate that the compound's action might involve a cellular factor.
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PMID:Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. 834 44

Tat is a transactivator of human immunodeficiency virus type 1 (HIV-1) that stimulates gene expression via an RNA target sequence (TAR) by augmenting transcriptional initiation and/or elongation from the HIV-1 long terminal repeat promoter. Here we show that Tat is able to transactivate the murine cytomegalovirus (MCMV) major immediate-early promoter (MIEP), which lacks sequence similarity with the HIV-1 long terminal repeat TAR element. Surprisingly, deletion of the upstream enhancer region (-610 to -146) of the MCMV MIEP abrogated Tat responsiveness. This result suggests that Tat requires a DNA target for function. Quantitation of RNA and protein indicates that Tat stimulates expression from the MCMV MIEP at both the transcriptional and translational levels. Deletion analysis of the MIEP indicates that there is likely to be interplay between the enhancer region, a sequence upstream of the known enhancer which negatively affects expression, and the Tat protein.
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PMID:TAR-independent transactivation of the murine cytomegalovirus major immediate-early promoter by the Tat protein. 838 74

We have previously reported that infection with herpes simplex virus type 1 (HSV-1) activates expression of the human immunodeficiency virus type 1 (HIV-1) provirus in T cells. Activation of the HIV-1 provirus correlated with the activation of binding of 55- and 85-kDa proteins to the kappa B enhancer and binding of the 50-kDa HLP-1 protein to the LBP-1 sequences of the HIV-1 long terminal repeat. Further examination of this system has shown that the inhibition of HSV-1 replication by the antiviral drug acyclovir does not inhibit HSV-1-mediated induction of HIV-1 provirus. Surprisingly, the NF-kappa B and HLP-1 binding activities were substantially inhibited in acyclovir-treated cells. In the transient-transfection assay, ICP0, but not ICP4, activated the HIV-1 long terminal repeat promoter region and the effect of ICP0 was greatly enhanced in the presence of the NF-kappa B binding proteins, suggesting that induction of the HIV-1 provirus involves cooperation between the HSV-1-activated cellular factor, NF-kappa B, and the virus-encoded transactivator, ICP0.
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PMID:Differential contribution of herpes simplex virus type 1 gene products and cellular factors to the activation of human immunodeficiency virus type 1 provirus. 838 40

Hereditary major histocompatibility complex (MHC) class II deficiency (or bare lymphocyte syndrome) is a form of severe primary immunodeficiency with a total lack of MHC class II expression. It is due to a defect in the regulation of MHC class II genes. A novel gene was isolated by complementation cloning, using an MHC class II-negative mutant cell line. This gene (CIITA) functions as a transactivator of MHC class II gene expression and restores expression of all MHC class II isotypes in mutant cells. In addition, CIITA fully corrects the MHC class II regulatory defect of cells from patients with bare lymphocyte syndrome. In this disease we have identified a splicing mutation that results in a 24 amino acid deletion in CIITA, resulting in loss of function of the transactivator. Hence, the CIITA gene is essential for MHC class II gene expression and has been shown to be responsible for hereditary MHC class II deficiency.
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PMID:Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). 840 93

Foamy viruses share complex genome organization with lentiviruses and certain oncoviruses. The open reading frame 3' of env encodes a transcriptional transactivator. Distinct responsive sequences were identified in the long terminal repeats (LTRs) of simian (SFV-1 and SFV-3) and human foamy viruses (HFV). Transactivation of heterologous LTRs was described including those of simian and human immunodeficiency viruses. Foamy viruses persist for the whole lifetime in infected hosts (primates, cats, hamsters, cattle, and probably other mammals). The virus may be orally shed and transmitted, while being latent in various internal organs. Selective viral gene expression in the brains of mice transgenic for HFV has suggested a particular relationship to neural tissue. In latently SFV-3-infected cultured cells, methylation of proviral DNA is apparently involved in the control of latency. Demethylation as well as transfection with the transactivator were shown to be instrumental in viral reactivation. Natural infections with foamy viruses are common, elicit strong immune responses, and seem to be asymptomatic in nonhuman primates. Detection of such infections, however, may not be a triviality in man. While accidental transmission of foamy viruses to man is well documented, reported seroprevalence in human populations and the association of HFV with specific pathology (e.g. thyroiditis de Quervain, amyotrophic lateral sclerosis, and Graves' disease) are controversial and remain to be proven.
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PMID:Foamy viruses. 840 46

We have previously shown that the Tat protein of the human immunodeficiency virus type 1 (HIV-1) is a modular transcriptional activator that can be targeted upstream of either a synthetic promoter or the intact HIV promoter to activate transcription. This activation was shown to be largely dependent on the presence of consensus binding sites for the cellular transcription factor Sp1. Since the use of heterologous promoters may provide further insight into Tat-mediated transactivation, we have analyzed the transactivation of the thymidine kinase promoter of herpes simplex virus by Tat and by the acidic transcriptional transactivator VP16. The effects of mutations of defined upstream promoter elements show that Tat transactivation is dependent on Sp1 binding sites in a site-specific manner. In contrast, transactivation by the acidic transactivator VP16 is completely independent of any of the defined promoter elements upstream of the TATA box. These results suggest that Tat and the classically defined modular acidic transcriptional activators have different modes of transactivation. In addition, the substitution of the HIV-1 TATA box for the thymidine kinase TATA box substantially increases Tat transactivation, indicating that Tat transactivation may also ultimately involve TATA box-associated cellular transcription factors.
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PMID:Activation of a heterologous promoter by human immunodeficiency virus type 1 Tat requires Sp1 and is distinct from the mode of activation by acidic transcriptional activators. 841 86

Human immunodeficiency viruses types 1 and 2 encode transactivator proteins, named Tat-1 and Tat-2, that stimulate transcription directed by the viral long terminal repeat sequences. The Tat-1 and Tat-2 proteins are related in protein sequence and mechanism of transactivation. We expressed Tat proteins by in vitro translation and found, as expected, that both Tat-1 and Tat-2 were monomers. Unexpectedly, we found that the Tat-1 and Tat-2 proteins displayed significantly different tertiary structures. As determined by velocity sedimentation and gel filtration, Tat-1 acted as a compact structure and Tat-2 acted as an extended, asymmetric structure. Additionally, we found that the in vitro-expressed Tat-2 protein was significantly less susceptible to aggregation than the Tat-1 protein. This observation led us to overexpress Tat-2 in Escherichia coli and develop a simple and rapid method to purify monomer Tat-2 to approximately 50% purity. These results suggest that large amounts of Tat-2 protein can be purified in suitable form for biochemical and biophysical studies of Tat protein structure.
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PMID:Rapid purification of monomer HIV-2 Tat protein expressed in Escherichia coli. 842 5

Human T-cell leukemia virus type I (HTLV-I) Rex and human immunodeficiency virus type 1 (HIV-1) Rev are essential gene products required for the replication of these two pathogenic human retroviruses. Both Rex and Rev act at a posttranscriptional level by binding to highly structured RNA-response elements, the Rex-response element in HTLV-I and the Rev-response element in HIV-1. Using a sensitive in vivo assay of protein-protein interaction, we now demonstrate that the HTLV-I Rex and HIV-1 Rev proteins readily form homomultimeric complexes in the absence of their cognate RNA-response elements yet fail to form heteromultimeric complexes with each other. Dominant negative mutations have been identified in both the rex and rev genes which presumably specify a critical activation or effector domain in each of these viral transactivators. Surprisingly, these dominant negative mutants of Rex and Rev fail to interact in vivo. These findings raise the possibility that the binding of nonfunctional monomers rather than functional multimers underlies the transdominant phenotype of these Rex and Rev mutants. Further, it seems likely that the assembly of functional and stable multimers of Rex and Rev in vivo may depend not only on the intrinsic multimerization domains of these proteins but also on the binding of a bridging cellular cofactor to the related activation domains present in each viral transactivator.
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PMID:Dominant negative mutants of human T-cell leukemia virus type I Rex and human immunodeficiency virus type 1 Rev fail to multimerize in vivo. 847 55

Long terminal repeat (LTR) of human immunodeficiency virus (HIV) type 1 is activated by thyroid hormone (T3) receptor alpha (T3R alpha) in the absence of ligand. Addition of T3 reverses this effect. This activity is mediated by a high affinity T3 response element (T3RE) within the HIV-1 LTR, termed the HIV-T3RE (bases -74 to -50), which coincides with the Sp1 element as demonstrated by mobility shift, DNaseI footprinting, and methylation interference analyses. HIV-T3RE mediates ligand-independent activation of transcription by T3R alpha when linked to a heterologous promoter. In addition, the viral transactivator Tat synergizes with T3R alpha to activate the HIV-1 LTR in the absence of T3, which is relieved in its presence. These findings have implications for the possible control of HIV-1 LTR activity by T3.
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PMID:A unique thyroid hormone response element in the human immunodeficiency virus type 1 long terminal repeat that overlaps the Sp1 binding sites. 853 64


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