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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase sites were mapped in the 5'-long terminal repeat of HIV-1 DNA by agarose and sequencing gel electrophoresis. Topoisomerase II sites were observed in the absence and presence of teniposide and amsacrine in the transcription initiation region and the TATA box, consistent with a possible role of topoisomerase II in transcription. The NF-kB and Sp1 regions were poorly cleaved. Topoisomerase I sites were relatively unfrequent even in the presence of camptothecin. They were absent in the core promoter and were concentrated in the TAR and the upstream region near the junction with the host DNA.
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PMID:DNA topoisomerases I & II cleavage sites in the type 1 human immunodeficiency virus (HIV-1) DNA promoter region. 781 Dec 42

The quantity and quality of human immunodeficiency virus type 1 (HIV-1) gene expression is controlled in large part by the action of two small nuclear viral regulatory proteins termed Tat and Rev. Tat is unique among transcriptional trans-activators in that it acts via a structured RNA target sequence, termed TAR, to induce high levels of transcription from the HIV-1 long terminal repeat promoter element. The activity of the viral Rev protein is also unprecedented in that this protein functions to induce the nuclear export of a specific class of viral RNA species that are otherwise sequestered in the nucleus by the action of cellular factors. Like Tat, Rev also interacts with a highly specific cis-acting target sequence termed, in this case, the Rev Response Element. In this review, I provide an outline of our current understanding of the roles and mechanisms of action of these two novel RNA-sequence-dependent regulatory proteins.
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PMID:RNA-sequence-mediated gene regulation in HIV-1. 781 57

Each of the two stem-loop structures in the HIV-2 TAR (TAR-2) RNA element contains a dinucleotide bulge that specifies a binding site in vitro for the HIV-2 Tat transactivator protein. A TAR-2 RNA with both bulges deleted is very weakly transactivated in vivo by the HIV-2 Tat protein. To gain insight into general features of Tat protein:TAR RNA interactions, we have analyzed the significance of the dinucleotide bulges in TAR-2 RNA for in vitro binding and in vivo transactivation by the related HIV-1 Tat protein. The HIV-1 Tat protein has been shown previously to bind efficiently to wild-type TAR-2 RNA and fully transactivates the HIV-2 LTR. We found that the 5' proximal bulge and the 3' distal bulge appear to specify a high and low affinity binding site in vitro, respectively, for the HIV-1 Tat protein. Wild-type TAR-2 RNA was found to be able to bind HIV-1 Tat proteins simultaneously at each bulge binding site in vitro. A TAR-2 RNA with both bulges deleted was greatly defective for in vitro binding by the HIV-1 Tat protein. Surprisingly, the TAR-2 RNA with both bulges deleted was efficiently transactivated in vivo by the HIV-1 Tat protein, indicating that the HIV-1 Tat protein (but not HIV-2 Tat protein) is able to strongly activate transcription of a TAR RNA with no apparent bulge binding site.
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PMID:HIV-1 Tat protein is able to efficiently transactivate the HIV-2 LTR through a TAR RNA element lacking both dinucleotide bulge binding sites. 783 24

The Human Immunodeficiency Virus type 1 (HIV-1) Tat protein is a potent activator of transcription directed by the long terminal repeat (LTR), an essential step in the life-cycle of HIV-1. While interaction of Tat with an RNA element encoded by downstream LTR sequences (termed TAR) is commonly considered essential to activation, numerous recent reports have implicated upstream transcription elements within the LTR as participants in mediating this activation. We have recently demonstrated that Tat activation occurs independent of the TAR element in certain cells derived from the central nervous system (CNS), and that this activation is mediated by the kappa B domain of the LTR. Further, CNS-derived cells were found to contain kappa B-binding activity capable of both interacting with Tat and activating LTR transcription in vitro. The present study demonstrates that the kappa B-binding transcription factor derived from CNS cells consists of a component indistinguishable from prototypical Nuclear Factor-kappa B (NF-kappa B) (in size, mobility on native gel, kinetics of activation and cognate binding sequence) as well as a supershifting component that is dissociable under certain conditions. The supershifting activity is found to stabilize binding of the presumed NF-kappa B to DNA. Further, only the form of NF-kappa B which is associated with this supershifting activity is capable of binding Tat. We hypothesize a model in which Tat utilizes this interaction to activate HIV-1 through the NF-kappa B domain of the LTR in circumstances where TAR is absent. This model has implications with respect to the ability of Tat to alter cellular gene expression and perhaps contribute to the array of problems seen in HIV-1 infection such as altered immune status, CNS toxicity, and the formation of tumors.
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PMID:A CNS-enriched factor that binds to NF-kappa B and is required for interaction with HIV-1 tat. 783 36

Noncoding sequences regulate the function of mRNA and DNA. In animal mRNAs, iron responsive elements (IREs) regulate the synthesis of proteins for iron storage, uptake and red cell heme formation. Folding of the IRE was indicated previously by reactivity with chemical and enzymatic probes. 1H- and 31P-NMR spectra now confirm the IRE folding; an atypical 31P-spectrum, differential accessibility of imino protons to solvents, multiple long-range NOEs and heat stable subdomains were observed. Biphasic hyperchromic transitions occurred (52 and 73 degrees C). A G-C base pair occurs in the hairpin loop (HL) (based on dimethylsulfate, RNAse T1 previously used, and changes in NMR imino proton resonances typical of G-C base pairs after G/A substitution). Mutation of the hairpin loop also decreased temperature stability and changed the 31P-NMR spectrum; regulation and protein (IRP) binding were previously shown to change. Alteration of IRE structure shown by NMR spectroscopy, occurred at temperatures used in studies of IRE function, explaining loss of IRP binding. The effect of the HL mutation on the IRE emphasizes the importance of HL structure in other mRNAs, viral RNAs (e.g. HIV-TAR), and ribozymes.
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PMID:The importance of a single G in the hairpin loop of the iron responsive element (IRE) in ferritin mRNA for structure: an NMR spectroscopy study. 787 May 79

Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of acquired immune deficiency syndrome (AIDS). The Tat protein of HIV-1 is a potent activator of transcription directed by the viral long terminal repeat. It has been widely reported that this activation requires a specific interaction between Tat and a RNA target termed TAR in the 5'-leader sequence of HIV-1 mRNAs. In this report we present data and describe results which illustrate that under appropriate conditions activation of transcription by Tat occurs independent of the TAR element. The ability to mediate TAR-independent transactivation by Tat is constitutive in some central nervous system cells and requires prior activation in others such as T lymphocytes. Evidence implicating a specific transcription factor in mediating Tat activation is also presented. Studies with site-directed mutants demonstrate that the RNA-binding domain of Tat is dispensable for TAR-independent activation of HIV-1. In contrast, the requirement for specific components of the Tat activation domain suggests that common targets exist for this viral activation factor to exert its activity in TAR-independent and TAR-dependent transactivation pathways of HIV-1 transcriptional activation. A working model of TAR-independent transactivation, which we believe may be responsible for the activation of cellular genes which contribute to AIDS pathology, is presented.
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PMID:Activation of HIV-1 transcription by Tat in cells derived from the CNS: evidence for the participation of NF-kappa B--a review. 787 98

The HIV-1 promoter directs the high level production of transcripts in Xenopus oocytes. However, despite being exported to the cytoplasm, the transcripts are not translated [M. Braddock, A. M. Thorburn, A. Chambers, G. D. Elliott, G. J. Anderson, A. J. Kingsman and S. M. Kingsman (1990) Cell, 62, 1123-1133]. We have shown previously that this is a function of promoter sequences and is independent of the TAR RNA element that is normally located at the 5' end of all HIV mRNAs. We now show that a three nucleotide substitution at position -340, upstream of the RNA start site, reverses the translation inhibition. This site coincides with a sequence that can bind the haematopoietic transcription factor GATA. The inhibition of translation can also be reversed by treatment with inhibitors of casein kinase II or by injection into the nucleus of antibodies specific for the FRGY2 family of RNP proteins. We suggest that the -340 site influences the quality of the transcription complex such that transcripts are diverted to a nucleus-dependent translation inhibition pathway.
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PMID:Promoter control of translation in Xenopus oocytes. 788 36

The primary body of information on the structure of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)/gag leader genotypes has been determined from the analysis of cocultivated isolates. Functional studies of this regulatory portion of the provirus have been derived from the study of in vitro-generated mutations of laboratory-adapted molecular clones of HIV-1. We have performed a longitudinal analysis of molecular clones from the LTR/gag leader region amplified directly from the peripheral blood of four patients over three years. We have found a remarkable number of point mutations and length polymorphisms in cis- and trans-acting regulatory elements within this cohort. Most of the length polymorphisms were associated with duplications of Sp1 and TCF-1 alpha sequences. These mutations were associated with a wide range of transcriptional activities for these genotypes in a reporter gene assay. Mutations in conserved Sp1 sequences correlated with a diminished capacity of such genotypes to bind purified Sp1 protein. Although no generalized trend in transcriptional activity was seen, a single patient accumulated mutations in NF-kappa B, Sp1, and TAR elements over this period. The analysis of naturally occurring mutations of LTR genotypes provides a means to study the molecular genetic consequences of virus-host interactions and to assess the functional impact of HIV therapeutics.
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PMID:Naturally occurring genotypes of the human immunodeficiency virus type 1 long terminal repeat display a wide range of basal and Tat-induced transcriptional activities. 790 1

Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) express related Tat proteins that are encoded in two exons. Tat proteins bind directly to the TAR RNA element contained in the 5' ends of viral transcripts and thereby stimulate transcription through an as yet unidentified mechanism. We have investigated the functional significance of exon2 of the HIV-2 Tat protein by examining properties of proteins consisting of exon1 alone or exon1 + 2. In transactivation assays in vivo, exon2 modestly increased HIV-2 Tat stimulation of transcription from the HIV-2 long terminal repeat (LTR) but had no effect on transcription from the HIV-1 LTR. In HeLa cells, exon2 increased transactivation of the HIV-2 LTR by approximately three-fold, while in COS and Jurkat cells this value was less than two-fold. In binding assays in vitro, exon2 increased the binding affinity of the HIV-2 Tat protein to HIV-2 TAR RNA. Results with GAL4 fusion proteins and a synthetic promoter containing GAL4 DNA binding sites indicated that exon2 does not contribute to the HIV-2 Tat activation domain. These observations suggest that exon2 of HIV-2 Tat contributes to transactivation of the HIV-2 LTR by increasing the binding affinity to HIV-2 TAR RNA.
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PMID:Exon2 of HIV-2 Tat contributes to transactivation of the HIV-2 LTR by increasing binding affinity to HIV-2 TAR RNA. 797 Dec 71

One approach to gene therapy for AIDS is to block the replication of human immunodeficiency virus type 1 (HIV-1) by inhibiting that tat gene, whose product activates the expression of all HIV-1 genes. To accomplish this, we constructed an antitat gene expressing an RNA with dual (polymeric TAR and antisense-tat) function in an attempt to both sequester Tat protein and block its translation from mRNA. A minigene consisting of the antitat gene driven by the HIV-1 long terminal repeat was inserted into a double-copy retrovirus vector, such that antitat expression would be upregulated only in HIV-1-infected cells. After transduction of a T-lymphocytic cell line (Molt-3) the antitat gene inhibited HIV-1 replication. This inhibition was inversely correlated with the virus infections dose. Virus replication was also inhibited for 5 months in two different T-cell lines after they had been infected at a high multiplicity of infection, suggesting that the antitat gene may be effective over long periods. Importantly, antitat blocked the replication and the cytopathic effect of HIV-1 in human peripheral blood mononuclear cells and led to as much as 4,000-fold inhibition of the replication of an HIV-1 field isolate as well as HIV-1 prototypes maintained in culture. These results suggest that antitat gene therapy has potential use for blocking HIV-1 replication in infected individuals.
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PMID:An autoregulated dual-function antitat gene for human immunodeficiency virus type 1 gene therapy. 798 11


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