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

The HIV Tat protein is a potent transactivator of HIV transcription, increasing both RNA initiation and elongation. We now demonstrate that purified, full-length 86 amino acid Tat protein specifically transactivates the HIV LTR in vitro to a high level (25- to 60-fold). Tat transactivation was specifically blocked by anti-Tat serum, but not preimmune serum. Tat did not transactivate transcription from the control adenovirus major late promoter (AdMLP). HIV transcription was blocked at various functional steps during initiation and elongation complex formation. Similar to the control AdMLP, HIV basal initiation complex assembly was sensitive to the addition of 0.015% sarkosyl prior to the addition of nucleoside triphosphates. Resistance to 0.05% sarkosyl required the addition of G, C, and U, which constitute the first 13 bases of the HIV RNA transcript. The addition of Tat to the in vitro transcription relieved the 0.015% sarkosyl block. These Tat-induced complexes were sensitive to 0.05% sarkosyl, suggesting that transcriptional initiation had not occurred. Consistent with this hypothesis, the addition of G, C, and U to the Tat-induced transcription complexes allowed the rapid conversion to transcription initiation complexes. Tat also facilitated the formation of 0.015% sarkosyl-resistant complexes in a reconstituted transcription system containing partially purified transcription factors and polymerase II. Following the formation of stable initiation complexes, Tat increased the rate and efficiency of transcription elongation on the HIV but not the AdML template. Kinetic analysis of Tat transactivation suggests that approximately 30% of the Tat initiation complexes are converted to elongation complexes. We conclude that Tat, in addition to its demonstrated role in RNA elongation, facilitates transcription initiation in vitro.
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PMID:Analysis of Tat transactivation of human immunodeficiency virus transcription in vitro. 128 57

Human foamy virus (HFV) encodes the transcriptional transactivator bel1. The bel1 protein transactivates HFV long terminal repeat (LTR)-directed gene expression by recognizing a region in U3. It also transactivates human immunodeficiency virus type 1 (HIV-1) LTR-directed gene expression in transient transfection assays. To identify the specific region in HIV-1 LTR responsible for bel1 action, we examined the effect of bel1 on chloramphenicol acetyltransferase (CAT) gene expression in transfected cells with a series of mutant HIV-1 LTR/CAT plasmids. The region between -158 and -118 from the transcription initiation site, immediately upstream of the core enhancer element, was identified as responsible for the transactivation by bel1. In addition, bel1 transactivated a heterologous promoter when this region was positioned upstream of it in the sense and antisense orientations. Optimal transactivation of the HIV-1 LTR by bel1 did not require an intact TAR sequence, suggesting that the binding of tat to the TAR sequence is not a prerequisite for bel1 function in HIV-1 LTR-directed gene expression. In the region of the HIV-1 LTR that is necessary for the bel1-mediated transactivation, we have found a sequence which is conserved between HIV-1 and HFV. Our results suggest that the bel1 action on HIV-1 seems to be mediated by a specific DNA sequence which is shared by both the HIV-1 LTR and HFV LTR.
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PMID:Transactivation of human immunodeficiency virus type 1 long terminal repeat-directed gene expression by the human foamy virus bel1 protein requires a specific DNA sequence. 131 28

We have established a line of malignantly transformed human B cells by infecting purified primary B lymphocytes with human immunodeficiency virus type 1 (HIV-1). This line, termed B-HIV1, may serve as a model system for a subset of AIDS-related B-cell lymphomas in which the transformed phenotype may be initiated and/or maintained through an HIV-1 gene product. The B-HIV1 line contains both Epstein-Barr virus (EBV) and HIV-1 genomes. In addition, the c-myc gene is expressed at levels 10 to 20 times those in normal B cells. Similarly, EBV sequences, including those for the latent membrane protein (LMP), are expressed at greatly enhanced levels relative to expression in normal, EBV-immortalized B cells. The upregulation of c-myc and of EBV gene expression can both be produced by infection of susceptible B cells (not already harboring HIV) with exogenous HIV-1. The B-HIV1 line exhibits properties of malignantly transformed cells, in that it grows logarithmically in 1% serum, clones in soft agar, and produces invasive, malignant B-cell lymphomas in severe combined immunodeficient (SCID) mice. We have shown that HIV-1 has the ability to infect primary human B cells and to activate expression of EBV and c-myc. HIV activation of EBV has been documented previously in certain cell lines, here we note that such activation can occur in primary B cells and, under certain conditions, can result in outgrowth of immortalized cell lines. This phenomenon may contribute to the clinical manifestation of lymphadenopathy early after infection with HIV. In addition, we have demonstrated that HIV infection of primary B cells in vitro can result in appearance of a fully malignant phenotype. This phenotype is likely to be due, at least in part, to the activation of c-myc by HIV. Preliminary experiments indicate that Tat, the gene product of the transactivator of viral gene transcription tat, can upregulate c-myc transcription after addition to the culture media of certain B-cell lines. This raises the possibility that Tat can bind to target sequences in cellular RNA and enhance transcription as it does for HIV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human immunodeficiency virus activates c-myc and Epstein-Barr virus in human B lymphocytes. 131 11

Ro 5-3335, 7-chloro-5-(2-pyrryl)-3H-1,4-benzo-diazepin-2-(H)-one, has been shown to inhibit gene expression controlled by the human immunodeficiency virus-1 (HIV-1) LTR promoter. The inhibition was specific for the viral transcriptional transactivator Tat. The compound did not inhibit the basal activity of the HIV-1 LTR or the activity of promoters not responsive to Tat. Consistent with its mode of action, Ro 5-3335 inhibited HIV-1 replication (IC50 = 0.1-1 microM) by reducing viral RNA synthesis in acutely, as well as chronically, infected cells in vitro. The compound was active against HIV-1 and HIV-2, and AZT-resistant clinical isolates.
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PMID:Discovery and characterization of an HIV-1 Tat antagonist. 139 54

The Epstein-Barr virus latent membrane protein (LMP) is an integral membrane protein that is expressed in cells latently infected with the virus. LMP is believed to play an important role in Epstein-Barr virus transformation and has been shown to induce expression of several cellular proteins. We performed a series of experiments that demonstrated that LMP is an efficient transactivator of expression from the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR). Mutation or deletion of the NF-kappa B elements in the LTR abolished the transactivation, indicating that the LMP effect on HIV expression was due to induction of NF-kappa B activity. Experiments in which the HIV-1 Tat protein was coexpressed in cells together with LMP showed that Tat was able to potentiate the transactivation. Surprisingly, a synergistic effect of the two proteins was observed even in the absence of the recognized target region for Tat (TAR) in the HIV-1 LTR.
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PMID:Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. 140

The Rev transactivator protein of human immunodeficiency virus type 1 (HIV-1) is required for protein expression from the HIV-1 RNAs which contain a binding site for the Rev protein, termed the Rev-responsive element (RRE). This transactivator acts both at the level of splicing/transport of nuclear RNAs and at the level of translation of cytoplasmic RNAs. We used a monoclonal antibody specific for the HIV-1 Rev protein to immunoprecipitate cellular extracts from HIV-1-infected and -transfected cells. High levels of specific binding of wild-type Rev to the RRE-containing RNAs were found in cytoplasmic, but not nuclear, extracts from these cells. A Rev mutant which lacked both nuclear and cytoplasmic Rev function but retained RNA binding in vivo was generated. This binding was detectable with both nuclear and cytoplasmic extracts. These results verify the existence of direct binding of Rev to HIV-1 RNAs in vivo and conclusively prove that binding of Rev is not sufficient for nuclear or cytoplasmic Rev function. The results also support a direct role for Rev in the nuclear export and translation of HIV-1 RNAs.
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PMID:In vivo binding of wild-type and mutant human immunodeficiency virus type 1 Rev proteins: implications for function. 150 Dec 91

Levels of trans activation of the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) by the virally encoded transactivator Tat show marked species-specific differences. For example, levels of transactivation observed in Chinese hamster ovary (CHO) rodent cells are 10-fold lower than those in human cells or in CHO cells that contain the human chromosome 12. Thus, the human chromosome 12 codes for a protein or proteins that are required for optimal Tat activity. Here, the function of these cellular proteins was analyzed by using a number of modified HIV-1 LTRs and Tats. Neither DNA-binding proteins that bind to the HIV-1 LTR nor proteins that interact with the activation domain of Tat could be implicated in this defect. However, since species-specific differences were no longer observed with hybrid proteins that contain the activation domain of Tat fused to heterologous RNA-binding proteins, optimal interactions between Tat and the trans-acting responsive RNA (TAR) must depend on this factor(s).
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PMID:Human chromosome 12 is required for optimal interactions between Tat and TAR of human immunodeficiency virus type 1 in rodent cells. 160 63

Human immunodeficiency virus type 2 (HIV-2) gene expression is downmodulated by sequence elements downstream of the transcriptional initiation site, corresponding to the U5 region of the long terminal repeat (LTR) and further downstream. This repression appeared to be related more to the length of the sequence intervening the transcriptional initiation site and the coding region than to a particular sequence content. The repressive effect of the downstream segment was not affected by HIV-2 and HIV-1 TAT or by the cytomegalovirus transactivator IE-2 gene. Nor was it affected by T-cell activation signals or by such cytokines as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN gamma), and interferon-alpha (IFN alpha). In contrast to HIV-1, HIV-2 LTR-directed gene expression was not modulated by TNF-alpha. A specific sequence element, located downstream of the TAR element in the R region, seemed to participate in modulation of gene expression. This element interacted with a nuclear protein with a mobility of about 26 kD. The repressive effect of the downstream sequence was to a certain extent cell type dependent, suggesting the involvement of cell type-specific factors. It was more effective in human lymphocytic CEM cells than in Jurkat cells. This may be relevant to the HIV-2 cell tropism (replication), latency, and virulence.
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PMID:Human immunodeficiency virus type 2 (HIV-2) gene expression: downmodulation by sequence elements downstream of the transcriptional initiation site. 181 41

It is hypothesized that the immediate-early (IE) gene products of human cytomegalovirus (CMV) and the transactivator (TAT) of human immunodeficiency virus type 1 (HIV-1) regulate HIV-1 gene expression through mechanisms involving host cell factors. By using transient transfection assays with the gene for chloramphenicol acetyltransferase (CAT) under the transcriptional control of the HIV-1 long terminal repeat (LTR), we examined transactivation of the LTR by plasmids that express either the HIV-1 gene for TAT or human CMV IE. The ratio of the level of transactivation by CMV IE to the level of transactivation by TAT varied up to 1,000-fold between cell types. The difference in the activities of these transactivators in various cell types was not a consequence of differential expression of the transactivator gene. Analysis of RNA species initiated in the HIV-1 LTR supports the conclusion that cellular factors regulate the level of elongation of the transcription complex on the LTR. Furthermore, evidence that in some cell types the predominant mechanism of transactivation by HIV-1 TAT involves posttranscriptional processes is presented.
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PMID:Cellular factors regulate transactivation of human immunodeficiency virus type 1. 199 49

The Tat protein coded by HIV-1 is a unique eukaryotic transactivator. It activates gene expression from the viral LTR by its interaction with a nascent RNA element (TAR) located at the 5' end of all HIV-1 transcripts. Tat appears to bind to its target RNA structure in a highly sequence-specific manner. The TAR-binding activity of Tat has been localized in an Arg-rich basic domain located between residues 49 and 57 of the Tat protein. We have carried out domain substitution studies with heterologous basic domains which are also implicated in RNA binding. Here, we report that a 19 or a 12 amino acid region from the N-terminus of HTLV-I Rex can functionally substitute for the Tat basic domain. In contrast, the Arg-rich domains of the N gene products of bacteriophages lambda and 21 do not functionally substitute for the Tat basic domain. The positive and negative effects of various domain substitution mutants have facilitated identification of a consensus sequence (Arg/Lys-X-X-Arg-Arg-X-Arg-Arg) in the basic domain required for Tat activity. Conversion of the functionally inactive basic domain of the lambda N protein to the consensus motif restored the transactivation function of the Tat-N chimeric protein. Similarly, the Rex basic domain containing scrambled sequences unrelated or partially related to the consensus motif were either totally defective in transactivation or exhibited reduced activity. Our results further suggest that the activity of the core Arg motif may be enhanced by the presence of Gln or Asn within the basic domain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heterologous basic domain substitutions in the HIV-1 Tat protein reveal an arginine-rich motif required for transactivation. 206 67


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