UMLS:C0021051 - FACTA Search

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Visna virus is a pathogenic lentivirus of sheep that is distantly related to the primate lentiviruses, including the human immunodeficiency virus type 1 (HIV-1). Replication of HIV-1 in cell culture requires the expression of a virus-encoded protein, Tat, which is a potent trans-activator of viral gene expression. Visna virus encodes an analogous Tat protein that greatly increases gene expression directed by the visna viral LTR. This report uses a stable vero cell line that constitutively expresses visna virus Tat to investigate the molecular mechanism of action of Tat on viral gene expression. Transient expression assays, using the visna virus LTR to drive transcription of the bacterial gene for chloramphenicol acetyltransferase (CAT), demonstrate that Tat trans-activates gene expression by increasing steady-state mRNA levels. The increase in steady-state mRNA levels is sufficient to account for the increase in protein observed and is due, in part, to an increase in the rate of transcription initiation. Tat mediates the accumulation of mRNA through AP-4 and AP-1 binding sites located in the U3 region of the LTR. Deletion of the upstream AP-1 and AP-4 binding sites results in a residual low level of trans-activation by Tat. Further experiments, using LTRs with R-U5 sequences deleted to +10, demonstrate AP-1 and AP-4 mediated responses to TAT at the RNA level, but no increase was observed in CAT protein.
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PMID:Molecular mechanisms of visna virus Tat: identification of the targets for transcriptional activation and evidence for a post-transcriptional effect. 131 69

Thirty-one base pairs (bp) containing putative AP-1 and AP-4 binding sequences in the U3 region of feline immunodeficiency virus (FIV) long terminal repeat (LTR) were deleted from an infectious molecular clone of FIV for construction of a mutant virus, and the replication rate and the cytopathogenic activity of the virus were compared with those of the wild type virus in concanavalin-A (Con-A) stimulated primary feline peripheral blood mononuclear cells (fPBMCs). It was found that the replication rate and cytopathogenic activity of the mutant were almost the same as those of the wild type. The deletion of the mutant virus was stable during the infection experiments. From these data, we concluded that the 31 bp fragment in the LTR is not required for the replication of FIV in Con-A stimulated primary fPBMC.
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PMID:Growth properties of a feline immunodeficiency virus mutant which lacks an AP-1 binding site in primary peripheral blood mononuclear cells. 753 37

Functional cis-acting regulatory elements in the bovine immunodeficiency virus (BIV) long terminal repeat (LTR) were identified by deletion mapping and nuclear protein gel shift analysis using three BIV-infectible cell lines, Cf2Th, BLAC-20, and EREp. Deletion mapping studies indicated that putative NF-kappa B, GRE, AP-4, AP-1, CAAT, and ATF/CRE transcription factor elements positively contribute to LTR-directed gene expression in each cell line both in the presence and absence of the viral transactivator Tat. Sp1 and overlapping AP-3 and retroviral core enhancer elements had variable effects on LTR-directed gene expression depending on cell type and presence or absence of Tat. In addition, a sequence spanning the LTR U5 region and the untranslated viral leader was strongly repressive in all cell lines. Tat transactivated the LTR 25-fold over basal levels in a TAR-dependent manner in Cf2Th cells. In contrast, Tat transactivated the LTR only 2.5-fold over basal levels in EREp and BLAC-20 cells in a TAR-independent manner. Probes for putative NF-kappa B, GRE, Sp1, AP-4, AP-1, overlapping AP-3 and retroviral core enhancer, and juxtaposed CAAT and ATF-CRE elements specifically bound nuclear proteins from these three cell lines and HeLa cells, with the stoichiometry of binding being cell-type dependent. Probes for AP-4, AP-1, and juxtaposed CAAT and ATF/CRE elements exhibited greater protein binding with extracts from virally infected cells than with extracts from uninfected cells, suggesting that viral infection can modulate nuclear factor binding. The present studies indicate that several transcription factor elements in the BIV LTR have functional roles and that cell type can strongly determine the role they play in gene expression.
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PMID:cis-acting regulatory elements in the bovine immunodeficiency virus long terminal repeat. 777 92

Nuclear protein binding sites in the long terminal repeat (LTR) of feline immunodeficiency virus (FIV) were identified by the method of DNase I footprinting. Using nuclear protein extracts from a feline T lymphoma cell line, several discrete footprints were generated upstream of the transcriptional initiation site (-50 to -150). The specificity of protein binding was examined by competition with oligonucleotides representing consensus DNA binding sites for known transcription factors. Binding to AP-1 (-124) and ATF (-58) motifs was observed, with cross-competition between these sites. A strong footprint signal was also detected over a tandemly repeated C/EBP motif (-94, -86) and an adjacent weaker footprint was found to be specific for an NF1 motif (-72/-63). The effect on FIV LTR promoter activity of progressively deleting these nuclear factor binding sites was examined by linking LTR deletion mutants to the chloramphenicol acetyltransferase (CAT) gene. Deletion of the AP-1 site caused a 10- to 25-fold loss of CAT activity whereas deletion past the ATF site reduced activity virtually to background levels. The effects of deleting the C/EBP and NF1 sites were less marked and varied according to cell type. Transactivation of the LTR was assayed using constructs linked to a CAT reporter gene. The full-length FIV LTR was not significantly trans-activated. However, the expression of a deleted LTR construct lacking the AP-4/AP-1 site but retaining C/EBP and ATF sites was partially restored by co-infection with FIV or by co-transfection with an infectious molecular clone of FIV (FIV-PPR). These results show that host transcription factors responsive to cellular activation have a major role in regulating FIV expression, and suggest that virus-coded trans-activators acting through U3 may play a role in some cellular environments.
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PMID:Cis- and trans-regulation of feline immunodeficiency virus: identification of functional binding sites in the long terminal repeat. 812 51

Sequences of 31 bp containing putative AP-1 and AP-4 binding sequences in the U3 region of the feline immunodeficiency virus (FIV) long terminal repeat (LTR) were deleted and the basal promoter activity of the LTR was measured by the chloramphenicol acetyltransferase (CAT) assay. The activity of the FIV LTR was reduced in Felis catus whole foetus 4 (fcwf-4) cells and Crandell feline kidney cells by this deletion. Cotransfection of murine c-Fos or c-Jun expression plasmids with the FIV LTR-CAT reporter plasmid into fcwf-4 cells revealed that FIV LTR could be activated by c-Fos but not c-Jun in the cells. The mutated LTR was introduced into an infectious molecular clone of FIV and the replication rate and the cytopathogenic activity of the mutant were compared with those of the wild-type in two feline CD4-positive T lymphoblastoid cell lines. It was found that the rate and activity of the mutant were almost the same as those of the wild-type. From these data, we conclude that the 31 bp fragment is important for achieving maximal expression of the FIV genome, but not required for the replication of FIV in feline T lymphocytes.
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PMID:The AP-1 binding site in the feline immunodeficiency virus long terminal repeat is not required for virus replication in feline T lymphocytes. 839 13

Approximately 38% of human immunodeficiency virus type 1 (HIV-1)-infected patients within the Vancouver Lymphadenopathy-AIDS Study have proviruses bearing partial 15- to 34-nucleotide duplications upstream of the NF-kappaB binding sites within the 5' long terminal repeat (LTR). This most frequent naturally occurring length polymorphism (MFNLP) of the HIV-1 5' LTR encompasses potential binding sites for several candidate transcription factors, including TCF-1alpha/hLEF, c-Ets, AP-4, and Ras-responsive binding factor 2 (RBF-2) (M. C. Estable et al., J. Virol. 70:4053-4062, 1996). RBF-2 and an apparently related factor, RBF-1, bind to at least four cis elements within the LTR which are required for full transcriptional responsiveness to protein-tyrosine kinases and v-Ras (B. Bell and I. Sadowski, Oncogene 13:2687-2697, 1996). Here we demonstrate that representative MFNLPs from two patients specifically bind RBF-2. In both cases, deletion of the MFNLP caused elevated LTR-directed transcription in cells expressing RBF-2 but not in cells with undetectable RBF-2. RBF-1, but not RBF-2, appears to contain the Ets transcription factor family member GABPalpha/GABPbeta1. Taken together with the fact that every MFNLP from a comparative study of over 500 LTR sequences from 42 patients contains a predicted binding site for RBF-2, our data suggest that the MFNLP is selected in vivo because it provides a duplicated RBF-2 cis element, which may limit transcription in monocytes and activated T cells.
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PMID:Naturally occurring human immunodeficiency virus type 1 long terminal repeats have a frequently observed duplication that binds RBF-2 and represses transcription. 965 89

The 1400 kb genomic sequence between the markers D16S406 and D16S423 on chromosome 16p13.3 has been recently sequenced and the interval contains a transcription factor, AP-4, that was identified as a ligand for immunoglobulin-kappa promoter E-box elements,(1)suggesting that AP-4 may be related to immunodeficiency diseases. In addition, chromosome 16p13.3 includes a number of genes including the PKD1 gene,(2,3)the autosomal dominant polycystic kidney disease (ADPKD) gene. ADPKD is characterized by progressive development and enlargement of renal cysts.(4)The size and genomic complexity of the PKD1 gene makes it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. To increase the number of polymorphic markers in the region around AP-4 gene, we performed database searches of 1400 kb of genomic sequence (from contig NT000677 to NT001573: http://www.ncbi.gov/genome/seq.cgi) across the 16p13.3. A number of dinucleotide or tetranucleotide repeats were found, and 20 microsatellites that contain more than 15 contiguous repeats were chosen for further investigation.
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PMID:Characterization of microsatellite markers adjacent to AP-4 on chromosome 16p13.3. 1173 4

The sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present in the cytosolic tails of the proteins. A subset of these signals conform to the [DE]XXXL[LI] consensus motif and mediate sorting via interactions with heterotetrameric adaptor protein (AP) complexes. However, the identity of the AP subunits that recognize these signals remains controversial. We have used a yeast three-hybrid assay to demonstrate that [DE]XXXL[LI]-type signals from the human immunodeficiency virus negative factor protein and the lysosomal integral membrane protein II interact with combinations of the gamma and sigma1 subunits of AP-1 and the delta and sigma3 subunits of AP-3, but not the analogous combinations of AP-2 and AP-4 subunits. The sequence requirements for these interactions are similar to those for binding to the whole AP complexes in vitro and for function of the signals in vivo. These observations reveal a novel mode of recognition of sorting signals involving the gamma/delta and sigma subunits of AP-1 and AP-3.
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PMID:Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes. 1469 Nov 37

Chemoattractant-like receptor 1 (CMKLR1) is a functionally unknown ("orphan") G-protein coupled receptor. It has been implicated in osseous and cartilage development, and it also has a pathophysiological role as one of the minor coreceptors involved in human immunodeficiency virus type I (HIV-1)/simian immunodeficiency virus (SIV) infection of CD4(+) immune cells. Here we report the cloning of the mouse cmklr1 gene, the characterization of its genomic structure for comparison with the human gene, and the mapping and functional analysis of its 5' flanking sequence. The gene was found to contain three exons intercepted by one larger and one smaller intron. The overall structure resembles the human orthologue. The promoter lacks classical TATA and CCAAT boxes but contains several GC-rich regions as well as AP-4 elements, C/EBP motifs, and GATA-1 and GATA-2 binding sites. Promoter function was analyzed in mouse neuroblastoma (NB4 1A3) cells, endogenously expressing CMKLR1, as well as in mouse embryonic fibroblastic (3T3 clone A31) cells not expressing CMKLR1. 5' Deletion analysis and luciferase reporter gene assays of the promoter indicated that a 280-bp sequence adjacent to the transcription start site (established through 5'-RACE) is essential for initiating transcription. Within this region it was possible to identify four potential Sp1-binding sites that may be active in the transcription of the gene. Thus, we show that the mcmklr1 gene has several conserved features in common with its human counterpart, which suggests that they are regulated in a similar manner. The promoter does not seem to be tissue specific but other elements or enhancers may be missing. The results provide a necessary basis for further studies of the gene regulation and function of this chemoattractant-like receptor and will be useful when manipulating the gene in the development of transgenic animal models.
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PMID:Genomic organization and promoter analysis of the gene encoding the mouse chemoattractant-like receptor, CMKLR1. 1501 96

Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase (HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immunoprecipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.
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PMID:Transcriptional repression of human immunodeficiency virus type 1 by AP-4. 1654 Apr 71

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