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PubMedDate not supplied

Oligonucleotide analogue interference with the HIV-1 Tat protein-TAR RNA interaction.

The HIV-1 Tat protein interaction with its RNA recognition sequence TAR is an important drug target and model system for the development of specific RNA-protein inhibitors. 2'-O-methyl oligoribonucleotides complementary to the TAR apical stem-loop effectively block Tat binding in vitro. Substitution by 5-propynylC or 5-methylC LNA monomeric units into a 12-mer 2'-O-methyl oligoribonucleotide leads to stronger inhibition, as does a 12-mer PNA. 10-16 mer 2'-O-methyl oligoribonucleotides give sequence- and dose-dependent inhibition of Tat-dependent transcription of an HIV DNA template in HeLa cell nuclear extract. Inhibition is maintained for the substituted 12-mer analogues but is poorer for PNA and is not correlated with TAR binding strength.

Anti-HIV Agents↗
PubMed2001

A divergent simian immunodeficiency virus from sooty mangabey with an atypical Tat-TAR structure.

SIVsm, the simian immunodeficiency virus that naturally infects sooty mangabeys in West Africa, is the closest lentiviral relative of human immunodeficiency virus type 2 (HIV-2). To determine the genetic characteristics of SIVsm in its natural host, we sequenced the full-length genome of SIVsmSL92b, a primary isolate obtained from a pet sooty mangabey in Sierra Leone. SIVsmSL92b proved to be the most divergent member of the HIV-2/SIVsm lineage found thus far, having as much as 35% nucleotide divergence from other HIV-2 genomes. A phylogenetic association between SIVsmSL92b and HIV-2 PA subtype E, which had been previously revealed by the analysis of partial gag sequences, was extended to the pol gene. SIVsmSL92b showed several divergent features, including a short Tat protein of 104 residues and an atypical TAR structure. Specifically, only one of the duplicate TAR elements contained the conserved hexanucleotide loop sequence CUGGGX important for Tat-cyclin T1 binding. These features suggested that the mechanism of SIVsmSL92b Tat and TAR interaction differed from that described for HIV-2. Taken together, these findings indicated that the structural diversity within the HIV-2/SIVsm lineage was greater than previously appreciated.

Amino Acid Sequence↗
PubMed1998

Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat.

Human cyclin T1 (hCycT1), a major subunit of the essential elongation factor P-TEFb, has been proposed to act as a cofactor for human immunodeficiency virus type 1 (HIV-1) Tat. Here, we show that murine cyclin T1 (mCycT1) binds the activation domain of HIV-1 Tat but, unlike hCycT1, cannot mediate Tat function because it cannot be recruited efficiently to TAR. In fact, overexpression of mCycT1, but not hCycT1, specifically inhibits Tat-TAR function in human cells. This discordant phenotype results from a single amino acid difference between hCycT1 and mCycT1, a tyrosine in place of a cysteine at residue 261. These data indicate that the ability of Tat to recruit CycT1/P-TEFb to TAR determines the species restriction of HIV-1 Tat function in murine cells and therefore demonstrate that this recruitment is a critical function of the Tat protein.

Amino Acid Sequence↗
PubMed1991

Detailed mutational analysis of TAR RNA: critical spacing between the bulge and loop recognition domains.

Trans-activation of HIV-1 by the Tat protein is mediated through a cis-acting element (TAR) in the viral RNA. In order to obtain further insight into the molecular interactions for trans-activation, a detailed mutational analysis of TAR RNA was carried out. TAR RNA forms a hairpin structure with important sequence elements in the single-stranded bulge- and loop-domains. We found that the sequence of the base-pairs flanking the bulge is critical for Tat-mediated trans-activation. In addition, Tat-response is reduced when the bulge is forced into a base-paired configuration through the introduction of complementary nucleotides on the opposite side of the stem. Thus, the 3-nucleotide bulge and adjacent base-pairs comprise a recognition domain with both sequence- and structure-elements. Accessibility of the loop sequences is also important for Tat function, since base-pairing through the formation of a pseudoknot-like structure does inhibit Tat action. A third critical parameter that influences the magnitude of Tat response is the number of loop nucleotides. Finally, the relative spacing between the loop and the bulge is also important. We introduced additional base-pairs in the stem connecting the two domains. Such mutations progressively decreased the efficiency of Tat induction. Interestingly, activity of the HIV-2 Tat protein did markedly increase on targets with one or two additional basepairs. These results suggest that Tat interacts with a cellular loop-binding protein(s) to increase HIV gene expression.

Base Sequence↗
PubMed1993

Rotational symmetry in ribonucleotide strand requirements for binding of HIV-1 Tat protein to TAR RNA.

Transactivation of human immunodeficiency virus (HIV) gene expression requires binding of the viral Tat protein to a RNA hairpin-loop structure (TAR) which contains a two or three-nucleotide bulge. Tat binds in the vicinity of the bulge and the two adjacent duplex stems, recognising both specific sequence and structural features of TAR. Binding is mediated by an arginine-rich domain, placing Tat in the family of arginine-rich RNA binding proteins that includes other transactivators, virus capsid proteins and ribosome binding proteins. In order to determine what features of TAR allow Tat to bind efficiently to RNA but not DNA forms, we examined Tat binding to a series of RNA-DNA hybrids. We found that only one specific strand in each duplex stem region needs to be RNA, implying that interaction between Tat and a given stem may be solely or predominantly with one of the two strands. However, the essential strand is not the same one for each stem, suggesting a switch in the bound strand on opposing sides of the bulge.

Amino Acid Sequence↗
PubMed1994

Exon2 of HIV-2 Tat contributes to transactivation of the HIV-2 LTR by increasing binding affinity to HIV-2 TAR RNA.

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.

Binding Sites↗
PubMed1995

NMR analysis of the trans-activation response (TAR) RNA element of equine infectious anemia virus.

Transcription of lentiviral DNA in the host cell is regulated by an interaction between the viral TAR RNA stem-loop and the viral Tat protein. Here we present a model of the three-dimensional structure of the TAR RNA stem-loop of the equine infectious anemia virus (EIAV), derived from two- and three-dimensional NMR data. This 25 nucleotide RNA consists of an A-form helical stem capped by two U-G base pairs and a four-nucleotide loop. Two loop cytidines are stacked into the loop interior and likely form a non-Watson-Crick C-C base-pair. The two nucleotides at the top of the loop, U13 and G14, appear to be excluded from the interior of the loop and solvent exposed. It is significant that now for the EIAV TAR-Tat system, three-dimensional structures are now known for both the RNA and protein components.

Base Sequence↗
PubMed1999

Does 29-mer RNA hairpin of the HIV-1 TAR RNA sequence bind magnesium? 19F-NMR and modelling studies.

5-Fluorouridine residues have been introduced into functionally important bulge and loop regions of 29-mer HIV-1 TAR RNA hairpins I and II to study Mg2+ and Ca2+ binding using 19F-NMR spectroscopy. There was no substantial binding detected up to 20-molar excess in case of both cations, whereas association of argininamide, used as a reference ligand, could be detected at less than 1-molar excess. The deltadelta 19F value of 1.93 ppm observed for (F)U23 upon argininamide binding is in agreement with former NMR studies of TAR RNA/argininamide complex. However, obtained results do not confirm U38 x A27 x U23 base-triple formation. The unmodified HIV-1 TAR RNA hairpin resulted from 600 ps in aqua molecular dynamics simulation was subjected to a molecular mechanics modelling of Mg+ binding.

Base Sequence↗
PubMedDate not supplied

Hot tar burns: twenty-seven hospitalized cases.

Between July 1, 1984, and December 31, 1991, 27 consecutive patients required admission to the Grady Memorial Hospital Burn Unit for care of hot tar burns. This group represented 1.4% of all admissions to this burn unit. Injuries occurred at the workplace and occurred mostly during the summer. They most commonly involved the patient slipping while carrying a bucket of hot tar. Ninety-six percent were male. The mean age was 33.7 years. Mean burn size was 13.1% total body surface area. Burn topography centered on the upper extremities and hands. Forty-one percent required a surgical procedure for their burn. Mean hospitalization time for survivors was 16.6 days. The survival rate was 92.6%. Both of the patients who died had large burns and/or preexisting medical problems. Hot tar burns occur under predictable circumstances, appear to be preventable, and have accounted for only a small fraction of all admissions to this burn unit.

Accidents, Occupational↗
PubMed1996

Canventol inhibits HIV-1 replication by Tat-induced Tar-independent mechanism.

SUMMARY: Canventol (2-isopropyl-4-isopropyldencyclohex-2-ene-l-ol), a blocker of tumor necrosis factor alpha (TNF-alpha) release, inhibits human immunodeficiency virus type (HIV-1) production in chronically and acutely infected cells. This effect of Canventol on virus replication could be correlated with its inhibitory influence on necrosis factor (NF)-kappa B activation and HIV-1 long terminal repeat (LTR)-driven reporter gene expression in Jurkat cells and these could be overcome by the administration of TNF-alpha. Canventol inhibits activation of the promoter by the viral protein Tat through a TAR-independent mechanism. The HIV-1 promoter is synergistically upregulated when both the TAR-independent and the TAR-dependent modes of Tat action are in operation. Tat-induced downstream events, such as the production of cytokines like TNF-alpha and NF-kappa B activation, are central for this upregulation. Inhibitors of the respective modes of action of Tat downregulate HIV-1 LTR activation and virus replication.

Antiviral Agents↗
PubMed2003

A functional genetic approach suggests a novel interaction between the human immunodeficiency virus type 1 (HIV-1) Tat protein and HIV-1 TAR RNA in vivo.

Human immunodeficiency virus type 1 (HIV-1) Tat and human Cyclin T1 form a complex and together recognize the viral TAR RNA element with specificity. Using HIV-1/equine infectious anaemia virus TAR chimeras, we show that in addition to the well-characterized interaction with the bulge, Tat recognizes the distal stem and the loop of TAR. These data support previously proposed, but unproven, molecular models.

Animals↗
PubMed1995

Measurement of a photon penumbra-generating kernel for a convolution-adapted ratio-TAR algorithm for 3D treatment planning.

A method has been developed to measure a photon penumbra-generating kernel using dosimetry equipment available in most radiation therapy departments. The kernel is used in a convolution-adapted ratio-TAR algorithm in our three-dimensional treatment planning system. The kernel is assumed to be invariant with respect to off-axis position, axially symmetric, and is divided into short- and long-range components, with a different measurement technique for each. The data required to obtain the short-range component are measured by scanning across a split-field geometry incident on a water phantom. The derivative of the measured profile is proportional to one-dimensional projections across the kernel. Because the kernel is axially symmetric, only one profile measurement is required for each depth. A CT reconstruction technique is used to extract the radial dependence of the kernel from the strip integrals. Electronic noise in the acquisition system yields significant uncertainties in the kernel shape for distances beyond 3 cm. The long-range portion of the kernel is obtained by examining tissue-air ratios (TARs). The derivative of the TAR at the center of a circular field is proportional to the kernel value at the distance corresponding to the radius of the field. The kernel measurement method was tested by comparing measured and calculated square-field profiles at a variety of depths. Agreement was within 1% within the field boundary and 3% outside the field boundary for all depths.

Algorithms↗
PubMed1991

Characterization of a human TAR RNA-binding protein that activates the HIV-1 LTR.

Human immunodeficiency virus type 1 (HIV-1) gene expression is activated by Tat, a virally encoded protein. Tat trans-activation requires viral (trans-activation--responsive; TAR) RNA sequences located in the R region of the long terminal repeat (LTR). Existing evidence suggests that Tat probably cooperates with cellular factors that bind to TAR RNA in the overall trans-activation process. A HeLa complementary DNA was isolated and characterized that encodes a TAR RNA-binding protein (TRBP). TRBP activated the HIV-1 LTR and was synergistic with Tat function.

Amino Acid Sequence↗
PubMed1995

Solution structure of a bovine immunodeficiency virus Tat-TAR peptide-RNA complex.

The Tat protein of bovine immunodeficiency virus (BIV) binds to its target RNA, TAR, and activates transcription. A 14-amino acid arginine-rich peptide corresponding to the RNA-binding domain of BIV Tat binds specifically to BIV TAR, and biochemical and in vivo experiments have identified the amino acids and nucleotides required for binding. The solution structure of the RNA-peptide complex has now been determined by nuclear magnetic resonance spectroscopy. TAR forms a virtually continuous A-form helix with two unstacked bulged nucleotides. The peptide adopts a beta-turn conformation and sits in the major groove of the RNA. Specific contacts are apparent between critical amino acids in the peptide and bases and phosphates in the RNA. The structure is consistent with all biochemical data and demonstrates ways in which proteins can recognize the major groove of RNA.

Amino Acid Sequence↗
PubMed1996

Signaling by the Escherichia coli aspartate chemoreceptor Tar with a single cytoplasmic domain per dimer.

Many transmembrane receptors are oligomeric proteins. Binding of a ligand may alter the oligomeric state of the receptor, induce structural changes within the oligomer, or both. The bacterial aspartate chemoreceptor Tar forms a homodimer in the presence or absence of ligands. Tar mediates attractant and repellent responses by modulating the activity of the cytoplasmic kinase CheA. In vivo intersubunit suppression was used to show that certain combinations of full-length and truncated mutant Tar proteins complemented each other to restore attractant responses to aspartate. These results suggest that heterodimers with only one intact cytoplasmic domain are functional. The signaling mechanism may require interactions between dimers or conformational changes within a single cytoplasmic domain.

Aspartic Acid↗
PubMed1990

Role of threonine residue 154 in ligand recognition of the tar chemoreceptor in Escherichia coli.

The Tar chemoreceptor of Escherichia coli mediates attractant responses to aspartate, maltose, and phenol, repellent responses to Ni2+ and Co2+, and thermoresponses. To understand the role of threonine residue 154, which is located in the ligand-binding domain of Tar, we replaced the residue with serine, isoleucine, and proline by site-directed mutagenesis. The replacements caused reductions in aspartate sensing but had only a small effect on maltose sensing and almost no effect on phenol sensing, repellent sensing, and thermosensing. These results indicate that Thr-154 of Tar is rather specifically involved in aspartate sensing. The reductions in the response threshold for aspartate by the replacements with serine, isoleucine, and proline were less than 1, about 2, and more than 5 orders of magnitude, respectively. When the corresponding threonine residue in the Tsr chemoreceptor was replaced with the same amino acids, roughly similar reductions in the response threshold for serine resulted. Thus, these threonine residues seem to have a common role in detecting the aspartate and serine attractant families. A mechanism by which these chemoreceptors detect the amino acid attractants is discussed.

Aspartic Acid↗
PubMed1994

The human immunodeficiency virus type 1 Tat protein transactivates tumor necrosis factor beta gene expression through a TAR-like structure.

We have previously shown that the Tat protein of human immunodeficiency virus type 1 (HIV-1) transactivates tumor necrosis factor alpha and beta (TNF alpha and TNF beta) gene expression in HIV-1-infected and in tat-transfected T-lymphocytic and monocytic cell lines. The product encoded by the first exon of the tat gene (amino acids 1 to 72) is sufficient for this transactivation. Here we show that (i) the NF-kappa B and Sp1 binding sites of the TNF beta promoter are required for Tat-mediated transactivation and (ii) a predicted stem-loop structure in the TNF beta mRNA leader region, which resembles the Tat-responsive element of the HIV-1 long terminal repeat (TAR) and which is therefore termed TAR-like, is essential for TNF beta transactivation by Tat. These data suggest that similar promoter regulatory elements are necessary for Tat-mediated transactivation of both TNF beta and HIV-1 gene expression. This represents the first demonstration of a cellular gene with a regulatory element downstream of the transcriptional initiation site that, like TAR, may function as an RNA element.

Base Sequence↗
PubMed1996

Cooperation between herpes simplex virus type 1-encoded ICP0 and Tat to support transcription of human immunodeficiency virus type 1 long terminal repeat in vivo can occur in the absence of the TAR binding site.

Expression of human immunodeficiency virus type 1 (HIV-1) provirus can be stimulated by herpes simplex virus type 1 (HSV-1) infection; the stimulation occurs at the level of transcriptional activation of the HIV long terminal repeat (LTR) and is mediated by both cellular and HSV-1-encoded transactivators. We have shown in this study that HSV-1 immediate-early gene ICP0 cooperates effectively with the HIV-1-encoded transactivator, Tat, in the stimulation of HIV-1 LTR-directed transcription. The cooperation between ICP0 and Tat is specific for the HIV-1 LTR and was not observed with other promoters (e.g., ICP0) that can be transactivated by ICP0 but not by Tat. Analyses of HIV-1 LTR deletion mutants have shown that ICP0 not only transactivates an HIV-1 LTR mutant that is unresponsive to NF-kappaB and Tat-mediated transactivation, such as the HIV-1 LTR with the enhancer deleted (-83 LTR) and TAR deleted (+20 to +81), but also restores responsiveness to Tat. ICP0 also showed cooperation with Gal4-Tat fusion protein-mediated transactivation of Gal4-HIV-1 LTR with TAR deleted. Enhancement of the transcriptional activation of ICP0 by Tat requires both the cysteine-rich and core domains of Tat and is inhibited by RO5-3335. ICP0 stimulates transcription of not only the HIV-1 LTR but also the TAR-defective HIV-1 provirus. We suggest that ICP0 can (i) recruit Tat to the vicinity of the HIV-1 promoter, thereby providing an alternative binding site for Tat, and (ii) substitute for the enhancer-binding proteins that are required for efficient Tat transactivation in T cells.

Binding Sites↗