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At least 127 records · Page 7Linked to original sources
PubMed1997

STAT1 pathway is involved in activation of caprine arthritis-encephalitis virus long terminal repeat in monocytes.

The caprine arthritis-encephalitis virus (CAEV) long terminal repeat (LTR) is activated by gamma interferon (IFN-gamma) in promonocytic cells. We have previously shown that a 70-bp element is necessary and sufficient for the response of the CAEV LTR to this cytokine. At the 5' end, this 70-bp IFN-gamma response element contains sequence similarity to the gamma activated site (GAS). Here we demonstrate that the putative GAS element in the CAEV LTR binds specifically to a cellular factor induced by IFN-gamma in promonocytic cells. Substitution mutations in this consensus sequence eliminate binding of the inducible factor. The GAS element from the 70-bp motif is sufficient to confer responsiveness to IFN-gamma using a heterologous minimal promoter. Consistent with the binding data, the same mutations in the GAS element eliminate responsiveness to IFN-gamma in the context of both a functional CAEV LTR and a heterologous promoter. The cellular factor that binds to the GAS element is present from 5 min to 14 h after stimulation with IFN-gamma. Binding of the nuclear factor to the GAS element in the CAEV LTR is inhibited by antibody directed against STAT1 (p91/84). Thus, the GAS sequence in the CAEV LTR is essential for the response to IFN-gamma and a STAT1-like factor binds to this site. The STAT-1 signaling pathway provides at least one mechanism for activation of the CAEV LTR by IFN-gamma in monocytes. These data are the first demonstration of a role for a STAT family member in the regulation of a viral promoter.

Arthritis-Encephalitis Virus, Caprine↗
PubMed1984

Use of the mouse mammary tumor virus long terminal repeat to promote steroid-inducible expression of v-mos.

We used the mouse mammary tumor virus long terminal repeat to promote dexamethasone-regulated expression of the Moloney murine sarcoma virus (M-MSV) transforming gene, v-mos. A recombinant DNA vector containing the mouse mammary tumor virus long terminal repeat fused to the M-MSV 124 v-mos gene was cotransfected with a plasmid containing the herpes simplex virus thymidine kinase gene (tk) into 3T3TK- cells. Individual clones of cells which grew in hypoxanthine-aminopterin-thymidine medium were tested for dexamethasone-regulated expression of p37mos as well as several transformation-specific phenotypic parameters. In the absence of dexamethasone, the v-mos transfectants appeared morphologically similar to the control cells despite low basal levels of p37mos expression. Upon hormone treatment, the levels of p37mos increased 5- to 10-fold, coincident with morphological changes typical of M-MSV transformation of 3T3 cells. The ability to form foci in monolayers also correlated with p37mos induction. The extent of morphological changes varied in individual clones of cells with similar levels of induced p37mos. Although the induced levels of p37mos were comparable to those seen in stable M-MSV 124 virus-transformed NIH 3T3 cells, the transfectants were unable to grow in soft agar under conditions which support growth of the virus-transformed cells. Acute infection of the transfectants with M-MSV 124 virus, a situation which resulted in elevated levels of p37mos, allowed these cells to grow in soft agar. The results described in this paper suggest that different threshold levels of p37mos may be necessary for the expression of various parameters of the transformed phenotype and also that continued expression of p37mos is necessary for maintenance of the transformed state. However, it also appears that the sensitivity to given levels of p37mos varies among clonal cell lines.

Animals↗
PubMed1988

A repetitive DNA sequence in the salmonid fishes similar to a retroviral long terminal repeat.

We describe the characteristics of a repetitive DNA sequence from the rainbow trout and related salmonid fishes that is similar to a retroviral long terminal repeat (LTR). The repeat is 160 bp long and contains a region of homology to the LTR of the avian sarcoma virus. Two clones with this repeat from the chum salmon also have a polypurine tract and tRNA binding site, respectively, and these clones may represent the two LTRs of a retrovirus or retroviral-like repetitive element. Copies of the repeat are also adjacent to rainbow trout and chum salmon protamine genes. These repeats may be "solo" LTRs. There appears to be some polymorphism in restriction sites between individual rainbow trout and considerable differences between salmonid fish species when the repeat is used as a probe.

Amino Acid Sequence↗
PubMed1998

FMEV vectors: both retroviral long terminal repeat and leader are important for high expression in transduced hematopoietic cells.

FMEV retroviral vectors combine the long terminal repeat of Friend mink cell focus-forming viruses with the 5' untranslated leader region of the murine embryonic stem cells virus. These modules were connected to achieve high transgene expression in hematopoietic progenitor and stem cells. Here, we report the cloning of safety-improved and versatile FMEV vectors allowing module-wise exchange of crucial elements for comparative studies. By transfer and expression of four different marker genes (neomycin phosphotransferase, lacZ, enhanced green fluorescent protein and truncated low affinity nerve growth factor receptor), we formally demonstrate that both the long terminal repeat and the leader contribute to the high expression of FMEV in transduced hematopoietic cells. Most prominent are the data recorded in the absence of selection in myelo-erythroid progenitor cells. Here, FMEV vectors mediate up to two orders of magnitude increased transgene expression levels when compared with vectors based on the Moloney murine leukemia virus.

5' Untranslated Regions↗
PubMed1997

Long terminal repeat and nef gene variants of human immunodeficiency virus type 1 in perinatally infected long-term survivors and rapid progressors.

HIV-1 sequences from perinatally infected children were analyzed in the long terminal repeat (LTR) region and nef in order to investigate associations of viral variation and disease progression. Four long-term survivors who reached 10 years of age or older, and four rapid progressors who survived less than 2 years, participated in this study. LTR sequences of multiple independent viral variants from each individual were compared. No sequence pattern within the LTR consistently distinguished long-term survivors from rapid progressors or vice versa. Deletions and insertions within transcription factor binding sites of the LTR and nef ranging from 8 to 341 bp were found in viral variants from the eldest long-term survivor (LTS047). These deletions and duplications may be associated with the survival of LTS047 via an unknown mechanism. Among all children in this study, the sites in the untranslated region (NF-kappaB, SP1, and TATA box) were more conserved than the sites in the nef/LTR overlap region (NFAT, purine-rich region, USF, TCF1alpha), reflecting the importance of the sites in the untranslated region for viral replication. A mutation in the E box motif within the USF site among the sequences from a long-term survivor (LTS113) is predicted to disrupt protein binding and may be associated with slow disease progression. Mutations of the SP1-III site in a rapid progressor (RP056) indicate that this site is not necessary for rapid disease progression.

Amino Acid Sequence↗
PubMed1994

Identification of a novel cell-type and context specific enhancer within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat.

One segment of the negative regulatory region of the human immunodeficiency virus long terminal repeat (HIV-LTR), nucleotides -273 to -255, is homologous to positive response elements for interleukin-2 and glucocorticoids. We demonstrate that this sequence, referred to as purine-rich response element (PRRE), acts as a classic enhancer in the context of a heterologous promoter, but serves as a functional repressor in the intact provirus, binding (a) cellular factor(s). These data suggest that certain DNA response elements in the HIV LTR serve as negative regulators only in the context of the intact LTR, presumably through interactions with other transcriptional factors, a phenomenon that might be exploited to interfere with viral gene transcription.

Base Sequence↗
PubMedDate not supplied

Transcriptional activation of the human immunodeficiency virus long terminal repeat sequences by tumor necrosis factor.

The recombinant plasmid pBHIV-1 carrying the long terminal repeat (LTR) of the human immunodeficiency virus 1 (HIV-1), linked to the reported chloramphenicol acetyl transferase (CAT) gene, was introduced into human and rat fibroblasts. Stable transfectants were obtained which were resistant to genetecin and expressed CAT-activity from the HIV-1 LTR. The response to TNF alpha was studied. It was found that, at the optimum concentration of 100 IU/ml in human and 1000 IU/ml in rat fibroblasts, the expression of CAT was stimulated by 2.1 and 2.5-fold respectively. Our findings suggest that TNF-alpha in physiological concentrations can transcriptionally activate the HIV-1 LTR sequences and this may play an important role in the pathogenesis of HIV infection.

Animals↗
PubMed1992

Natural variants of the HIV-1 long terminal repeat: analysis of promoters with duplicated DNA regulatory motifs.

Sequence variation in the long terminal repeat (LTR) region of HIV-1 was analyzed in viral isolates of 17 infected individuals. Two classes of LTR size variants were found. One HIV-1 variant was detected containing an additional binding site for the transcription factor Sp1. Another LTR size variation was observed in four patients in a region just upstream of the NF-kappa B enhancer. This variation was the result of a duplication of a short DNA sequence (CTG-motif). Cell culture experiments demonstrated that the natural variant with four Sp1 sites had a slightly higher promoter activity and viral replication rate than the isogenic control LTR with three Sp1 sites. No positive effect of the duplicated CTG-motif could be detected. In order to measure small differences in virus production more accurately, equal amounts of a size variant and the wild-type plasmid were cotransfected into T-cells. The virus with four Sp1 sites did outgrow the three Sp1 virus in 35 days of culture and CTG-monomer virus outcompeted the CTG-dimer virus in 42 days. Based on these results we estimate a 5-10% difference in virus production of the LTR variants when compared to that of wild-type.

Base Sequence↗
PubMed2002

Chromatin disruption and histone acetylation in regulation of the human immunodeficiency virus type 1 long terminal repeat by thyroid hormone receptor.

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) controls the expression of HIV-1 viral genes and thus viral propagation and pathology. Numerous host factors participate in the regulation of the LTR promoter, including thyroid hormone (T(3)) receptor (TR). In vitro, TR can bind to the promoter region containing the NF-kappa B and Sp1 binding sites. Using the frog oocyte as a model system for chromatin assembly mimicking that in somatic cells, we demonstrated that TR alone and TR/RXR (9-cis retinoic acid receptor) can bind to the LTR in vivo independently of T(3). Consistent with their ability to bind the LTR, both TR and TR/RXR can regulate LTR activity in vivo. In addition, our analysis of the plasmid minichromosome shows that T(3)-bound TR disrupts the normal nucleosomal array structure. Chromatin immunoprecipitation assays with anti-acetylated-histone antibodies revealed that unliganded TR and TR/RXR reduce the local histone acetylation levels at the HIV-1 LTR while T(3) treatment reverses this reduction. We further demonstrated that unliganded TR recruits corepressors and at least one histone deacetylase. These results suggest that chromatin remodeling, including histone acetylation and chromatin disruption, is important for T(3) regulation of the HIV-1 LTR in vivo.

Acetylation↗
PubMed1999

Stimulation of Tat-associated kinase-independent transcriptional elongation from the human immunodeficiency virus type-1 long terminal repeat by a cellular enhancer.

The human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR) initiates transcription efficiently but produces only short transcripts in the absence of the trans-activator protein, Tat. To determine whether a cellular enhancer could provide the signals required to recruit an elongation-competent polymerase to the HIV-1 LTR, the B cell-specific immunoglobulin heavy chain gene enhancer (IgHE) was inserted upstream of the LTR. The enhancer increased transcription in the absence of Tat between 6- and 7-fold in transfected B cells, but the full-length transcripts remained at basal levels in HeLa cells, where the enhancer is inactive. RNase-protection studies showed that initiation levels in the presence and absence of the enhancer were constant, but the enhancer significantly increased the elongation capacity of the polymerases. Tat-stimulated elongation is strongly inhibited by the nucleoside analogue 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), which inhibits the Tat-associated kinase, TAK (CDK9). However, polymerases initiating transcription from LTRs carrying the enhancer were able to efficiently elongate in the presence of DRB. Specific repression of TAK by expression in trans of the CDK9 kinase also inhibited Tat-stimulated elongation but did not inhibit enhancer-dependent transcription significantly. Thus, the activation of polymerase processivity by the IgHE involves a unique mechanism which is independent of TAK.

B-Lymphocytes↗
PubMed2001

Characterisation of the long terminal repeat regions of South African human immunodeficiency virus type 1 isolates.

The 5' long terminal repeat (LTR) region of the integrated proviral human immunodeficiency virus type I (HIV-1) template encodes cis-acting sequences for cellular proteins that are responsible for initiating viral transcription. The objective of this study was to analyse the LTR regions of isolates from a broad spectrum of South African HIV-1 infected individuals to (i) determine if sequence diversity was sufficient to allow for subtyping on the basis of this region, and (ii) to note any specific or unusual alterations in promoter binding motifs that may be common to this group of isolates or specific HIV-1 subtypes within this group. A total of 60 isolates were subtyped by heteroduplex mobility assay (HMA) and by phylogenetic analysis, using both the env and gag regions. Phylogenetic relatedness within the LTR region demonstrated the suitability of this region for use in HIV-1 subtype designation. The presence of additional NF-kappaB binding elements as well as altered USF binding sites were features common to subtype C HIV-1 isolates. Although the biological relevance of these alterations within the HIV-1 LTR with respect to viral replicative capacity and patient disease progression is unknown, there is strong support to suggest that in the presence of these features, there is increased gene transcription in subtype C isolates, and that this would be further increased in the presence of secondary infection.

Base Sequence↗
PubMed1984

Involvement of retrovirus reverse transcriptase-associated RNase H in the initiation of strong-stop (+) DNA synthesis and the generation of the long terminal repeat.

Reconstructed enzymatic reactions containing purified reverse transcriptase and defined analog substrates which mimic those purported to be natural substances for reverse transcription in vivo were employed to delineate the mechanism of strong-stop (+) DNA synthesis. Our analysis of this system has indicated that strong-stop (+) DNA synthesis is initiated after the introduction of a nick in the viral RNA genome between a polypurine sequence and an inverted repeat that represents the end of the long terminal repeat. Since inhibitors of the reverse transcriptase-associated RNase H activity prevent the introduction of the nick and the synthesis of strong-stop (+) DNA synthesis, it appears that this particular reverse transcriptase-associated enzymatic activity is responsible for the initiation of strong-stop (+) DNA. Our data also indicated that the RNase H activity creates a second nick in the viral RNA genome 11 nucleotides upstream from the strong-stop (+) DNA initiation site since the strong-stop (+) DNA synthesized in these reactions is covalently linked to an oligoribonucleotide 11 residues in length. Nucleotide sequence analysis of the oligoribonucleotide primer molecule indicated that a single homogenous oligomer was associated with strong-stop (+) DNA exhibiting the sequence rArGrGrGrArGrGrGrGrGrA. The oligoribonucleotide primer can be removed from strong-stop (+) DNA by the purified reverse transcriptase, which creates a nick at the junction between the primer and strong-stop (+) DNA. These data demonstrate that the initiation of strong-stop (+) DNA synthesis is mediated by RNase H and that the site of initiation is exactly at the end of the long terminal repeat, providing evidence for yet another function of this reverse transcriptase-associated enzymatic activity in the synthesis of retrovirus DNA.

Animals↗
PubMed1994

In vitro study of functional involvement of Sp1, NF-kappa B/Rel, and AP1 in phorbol 12-myristate 13-acetate-mediated HIV-1 long terminal repeat activation.

We examined the cooperative activity between the Sp1 and NF-kappa B/Rel sites of the human immunodeficiency virus type 1 long terminal repeat in response to phorbol 12-myristate 13-acetate (PMA) stimulation in an in vitro transcription assay. Sp1 sites alone do not account for the activation induced by PMA. When mutations in Sp1 sites were combined with mutations in the NF-kappa B/Rel sites, a dramatic reduction in PMA-induced transcriptional activity was observed. This reduction was much greater than the reduction associated with mutations involving only the NF-kappa B/Rel sites. This finding suggests that there is functional cooperation between Sp1 and NF-kappa B/Rel and that this is one possible mechanism for transcription activation by NF-kappa B/Rel. The three AP1 sites in the negative regulatory region of the long terminal repeat, however, seem to be uninvolved in the earliest moments of transcriptional activation by PMA.

Base Sequence↗
PubMed1989

Hepatitis B virus X gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1.

The role of the hepatitis B virus (HBV) X gene during virus infection has not been defined. We previously showed that expression of the HBV X gene in the human hepatocellular carcinoma cell line HepG2 trans-activates chloramphenicol acetyltransferase gene expression under control of the human immunodeficiency virus 1 (HIV-1) long terminal repeat and we have now identified a specific sequence in the HIV-1 long terminal repeat that is responsive to the HBV X gene. Plasmid constructs with the chloramphenicol acetyltransferase gene regulated by an isolated and twice-repeated 12-base-pair HIV-1 enhancer sequence homologous to the nucleotide sequence that binds the nuclear transcription factor NF-kappa B (the HIV-1 kappa B-like sequence) were trans-activated by the HBV X gene in HepG2 cells, indicating that the kappa B-like enhancer sequence in the HIV-1 long terminal repeat is responsive to the X gene. When eight copies of the HIV-1 kappa B-like sequence were used to regulate beta-globin gene expression, transcription of this gene was activated by the HBV X gene in HepG2 cells and no beta-globin gene transcription was detected in the absence of the HBV X gene. beta-globin gene expression regulated by the activator protein 2 (AP-2) binding sequence was not activated by the HBV X gene. Treatment of HepG2 cells with phorbol ester resulted in modest activation of the HIV-1 kappa B-like enhancer sequence suggesting that an NF-kappa B-like factor was induced in these cells as it is in T lymphocytes by phorbol ester; however, phorbol ester did not demonstrably enhance the activation of the HIV-1 enhancer observed with the HBV X gene. These experiments indicate that the HIV-1 kappa B-like transcriptional enhancer sequence is activated by the HBV X gene and suggest that the HBV X gene might play a role in regulating transcription of a gene under control of a kappa B-like enhancer during HBV infection. Since such a sequence has not been found in the HBV genome and HBV gene expression appears not to be regulated by the HBV X gene, a cellular gene that plays a role in HBV replication could be the target of the X gene during HBV infection.

Base Sequence↗
PubMed1993

Inducible transcriptional activation of the human immunodeficiency virus long terminal repeat by protein kinase inhibitors.

The protein kinase inhibitor 2-aminopurine (2-AP) greatly stimulated expression in human promonocytes-macrophages of plasmid constructs carrying various reporter genes (chloramphenicol acetyltransferase, lacZ, firefly luciferase [luc], and Salmonella typhimurium histidinol dehydrogenase [his]) driven by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat. Adenine, adenosine, and caffeine were also effective inducers, but other purine or pyrimidine derivatives were ineffective. Experiments with mutant derivatives of the HIV-1 long terminal repeat revealed no specific eukaryotic promoter elements necessary for 2-AP induction but indicated the need for some minimum combination of such elements. Induction of HIV-1-directed gene expression appeared not to require action of the transcription factor NF-kappa B. The mechanism of induction was investigated by using the luc and his genes linked to the HIV-1 long terminal repeat. 2-AP induced marked, steady rises in mRNA accumulation from both transfected and chromosomally integrated HIV-1 constructs but no increases from an endogenous gene encoding gamma-actin or glucose 6-phosphate dehydrogenase. Thus, induction is selective and not an artifact induced by transfecting DNA into cells. In run-on transcription experiments, the rates of transcription initiation of both transfected and integrated copies of the his gene increased about sixfold in cells treated with 2-AP. Thus, while increased initiation accounted for a portion of 2-AP induction, it could not cause the far greater increase in steady-state mRNA levels. 2-AP induction did not change mRNA decay rates and differed from the phorbol ester (phorbol myristate acetate)-induced activation of the protein kinase C-NF-kappa B pathway in its time course and in its requirement for new protein synthesis. Gel retardation assays showed that unlike phorbol myristate acetate induction, 2-AP induction is enhancer independent. Whereas many previous studies have implicated the activation of various protein kinases in gene induction, we here describe a mechanism of gene activation that appears to involve protein kinase inhibition as a component of the induction response.

2-Aminopurine↗
PubMed1983

Nucleotide sequence of the long terminal repeat and flanking cellular sequences of avian endogenous retrovirus ev-2: variation in Rous-associated virus-0 expression cannot be explained by differences in primary sequence.

A fragment of chicken DNA containing the left long terminal repeat of endogenous retrovirus ev-2 and flanking cellular sequences has been molecularly cloned and analyzed. Comparison with sequence data from the analogous regions of ev-1 and Rous-associated virus-0 viral DNA reveals similarities among flanking regions of the integrated proviruses and among all three long terminal repeats. From the latter finding, we conclude that the difference in level of expression of ev-2 and its progeny Rous-associated virus-0 provirus cannot be due to sequence differences in their upstream long terminal repeats.

Animals↗
PubMed2002

Dasheng and RIRE2. A nonautonomous long terminal repeat element and its putative autonomous partner in the rice genome.

Dasheng is one of the highest copy number long terminal repeat elements and one of the most recent elements to amplify in the rice (Oryza sativa) genome. However, the absence of any significant coding capacity for retroviral proteins, including gag and pol, suggests that Dasheng is a nonautonomous element. Here, we have exploited the availability of 360 Mb of rice genomic sequence to identify a candidate autonomous element. RIRE2 is a previously described gypsy-like long terminal repeat retrotransposon with significant sequence similarity to Dasheng in the regions where putative cis factors for retrotransposition are thought to be located. Dasheng and RIRE2 elements have similar chromosomal distribution patterns and similar target site sequences, suggesting that they use the same transposition machinery. In addition, the presence of several RIRE2-Dasheng element chimeras in the genome is consistent with the copackaging of element mRNAs in the same virus-like particle. Finally, both families have recently amplified members, suggesting that they could have been co-expressed, a necessary prerequisite for RIRE2 to serve as the source of transposition machinery for Dasheng. Consistent with this hypothesis, transcripts from both elements were found in the same expressed sequence tag library.

Base Sequence↗
PubMed1990

A novel T-cell protein which recognizes a palindromic sequence in the negative regulatory element of the human immunodeficiency virus long terminal repeat.

Two major protein-binding sites within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat have been identified. One (site B) contained a palindromic sequence with homology to steroid/thyroid hormone response elements but was distinct from previously described binding sites of this class. A novel T-cell protein recognized the palindromic sequence within site B and also bound estrogen- or thyroid hormone-response elements with lower affinity. A 7-base-pair mutation in the site B palindrome, which destroyed protein binding, resulted in increased expression from the human immunodeficiency virus type 1 long terminal repeat in T cells.

Base Sequence↗