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PubMed1985

Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat.

Human T-cell leukemia virus type III (HTLV-III) was recently identified as the probable etiologic agent of the acquired immune deficiency syndrome (AIDS). Here it is shown that, in human T-cell lines infected with HTLV-III, gene expression directed by the long terminal repeat sequence of this virus is stimulated by more than two orders of magnitude compared to matched uninfected cells. The rate of transcription of the HTLV-III long terminal repeat is more than 1000 times that of the SV40 early promoter in one infected cell line. Thus, HTLV-III, like HTLV-I, HTLV-II, and the bovine leukemia virus, is characterized by trans-activation of transcription in infected cells. The efficiency of trans-activation in the case of HTLV-III may account, at least in part, for the virulent nature of HTLV-III infection.

Acetyltransferases↗

PubMed1994

Activation of the human immunodeficiency virus type 1 long terminal repeat by transforming mutants of human p53.

We have studied the effects of human wild-type and mutant p53s on the long terminal repeat (LTR) promoter of human immunodeficiency virus type 1 (HIV). HeLa cells were cotransfected with a wild-type or mutant p53 expression plasmid and a plasmid containing a chloramphenicol acetyltransferase reporter gene under HIV LTR promoter control. As expected, expression of wild-type p53 inhibited promoter function. Expression of a p53 mutated at any one of the four amino acid positions 175, 248, 273, and 281 correlated with a significant increase of the HIV promoter activity. The HIV LTR was also significantly activated in Saos-2 cells that do not express endogenous p53. This finding suggests a gain-of-transactivation function by mutation of the p53 gene. Cotransfection of wild-type and mutant p53-281G expression plasmids indicated that either the wild type or the mutant was dominant in inhibiting or enhancing promoter activity, respectively, when transfected in excess of the other. Transfection experiments showed transactivation even when the Sp1, NF-kappa B, and TATA sites in the LTR were individually mutated. Synthetic minimal promoter constructs containing two Sp1 sites or two NF-kappa B sites or an ATF site are also significantly activated by the mutant p53-281G. Thus, the mutant protein may activate transcription through interaction with either a general transcription factor or a common factor that bridges the basal transcription machinery and the transcription factors Sp1, NF-kappa B, and ATF.

Activating Transcription Factors↗

PubMed2003

Longitudinal monitoring of 2-long terminal repeat circles in peripheral blood mononuclear cells from patients with chronic HIV-1 infection.

OBJECTIVE: To evaluate the potential use of 2-long terminal repeats (LTR) HIV circular DNA quantification for the monitoring of ongoing virus replication in treated HIV-1-infected patients. DESIGN AND METHODS: In a longitudinal setting, where the natural course of HIV-1 infection was in most cases disrupted by continuous or discontinuous antiviral therapy, 2-LTR circles of HIV-1 DNA were quantified in serial peripheral blood mononuclear cell samples, selected in retrospect from 16 patients with chronic HIV-1 infection, using quantitative real-time PCR. We compared variations of 2-LTR circle level with concomitant variations in plasma viral RNA level and with the frequency of productively infected cells and chromosome associated proviral DNA copy numbers in patient's peripheral blood mononuclear cells. RESULTS: Antiviral treatment led to a sharp decrease in plasma viraemia and infectious cell frequency. In contrast, we found that levels of proviral DNA and 2-LTR circles were significantly lower under treatment only when groups of specimens that were homogeneous, with respect both to plasma viraemia and infectious cell frequency, were compared. Moreover, during the time of undetectable plasma viraemia, scarcely any decline in proviral DNA or 2-LTR circle levels was observed. CONCLUSIONS: The low impact of antiviral treatment on 2-LTR circle levels in vivo, when plasma viraemia and infectious cell frequency both dramatically decline lead us to conclude that 2-LTR circles should not be used for the monitoring of recent viral replication in treated patients.

Anti-HIV Agents↗

PubMed1987

The mouse mammary tumor virus long terminal repeat directs expression in epithelial and lymphoid cells of different tissues in transgenic mice.

A series of transgenic mice was developed that contained the simian virus 40 early region genes under the transcriptional control of the mouse mammary tumor virus long terminal repeat, including the promoter and glucocorticoid response elements. These mice all expressed the transgene in the epithelial cells of a number of different organs, such as lungs, kidneys, and prostate, salivary, and mammary glands, and in Leydig and lymphoid cells. Transcription of the chimeric gene was inducible by glucocorticoids, either after transfection into tissue culture cells or in cells cultured from animals carrying the transgene. Many, but not all, tissues which expressed the simian virus 40 sequences, as determined immunologically and by RNA analysis, developed into tumors, although they showed premalignant features. Since the mouse mammary tumor virus long terminal repeat is expressed in a number of different cell types when inherited through the germ line, the lactating mammary gland-specific transcription of endogenous proviruses must require other factors or sequences to achieve this specificity.

Animals↗

PubMed1984

Bovine leukemia virus: unique structural features of its long terminal repeats and its evolutionary relationship to human T-cell leukemia virus.

The nucleotide sequence of the long terminal repeat (LTR) of bovine leukemia virus, a unique oncogenic retrovirus of cattle, was determined. The LTR consisted of 530 base pairs (bp) with an inverted repeat of 6 bp at its 5' and 3' ends, flanked by a direct repeat of 6 bp of host cell origin. A tRNAPro binding site for minus-strand DNA synthesis followed the 5' LTR. The U3 region contained putative transcriptional promoters, "CAT" box and "TATA" box, but they had peculiar sequences (C-C-A-A-C-T and G-A-T-A-A-A-T). The U3 region also contained a potential enhancer element, whose sequence partially resembled those of other viral and cellular, especially of immunoglobulin, enhancers. The most striking structural feature of the LTR was an exceptionally long R region (228 bp), which separated a poly(A) addition signal (A-A-T-A-A-A) from a poly(A) site as far apart as 260 bp. The long R region was suggested to form a large stable hairpin structure on a nascent RNA chain, making the two transcription termination signals close together and thus ensuring normal termination of the chain. This structural feature of the bovine leukemia virus LTR was analogous to that of human T-cell leukemia virus LTR and, in fact, slight sequence homology (at most 50%) was observed between the R regions of these two retroviruses, indicating their evolutionary relationship. The unique structural feature of bovine leukemia virus and human T-cell leukemia virus LTRs may thus bear some relation to the biological features commonly shared by these retroviruses.

Base Sequence↗

PubMed1991

Efficient polyadenylation within the human immunodeficiency virus type 1 long terminal repeat requires flanking U3-specific sequences.

During transcription of the human immunodeficiency virus type 1 provirus, polyadenylation signals present in the 5' long terminal repeat (LTR) are disregarded while the identical polyadenylation signals present in the 3' LTR are utilized efficiently. As both transcribed LTR sequences contain all signals known to be required for efficient polyadenylation, the basis for this differential utilization has been unclear. Here, we describe experiments that suggest that transcribed sequences present within the human immunodeficiency virus type 1 LTR U3 region act in cis to enhance polyadenylation within the 3' LTR.

Base Sequence↗

PubMed1992

Differentiation-dependent human immunodeficiency virus long terminal repeat regulatory elements active in human teratocarcinoma cells.

We have examined the transcriptional utilization of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) under differentiating conditions by using the embryonal carcinoma cell line NTERA-2. NTERA-2 cells undergo two distinct pathways of terminal differentiation, to a neuronal phenotype in response to retinoic acid and to a nonneuronal phenotype in response to hexamethylene bisacetamide. To identify LTR regulatory elements active in each cell type we used a set of HIV LTR linker substitution mutants, which contain mutations that progressively replace adjacent 18-bp segments across the U3 region and into the R region (between nucleotides -453 and +15 relative to the transcription start site). Although each differentiating cell type showed utilization of expected key elements (e.g., NF-kappa B, SP1, TATA) in the 3' portion of the LTR (+1 to -112), the data indicated differentiation-dependent differences in the utilization of these elements. In addition, regions showing dramatic differentiation-dependent effects were detected in the 5' portion of the LTR (-112 to -453), in positions where transcription control elements have not been described previously. The marked differences in the sets of LTR regulatory elements required by each cell type indicate that the LTR can function under a variety of differentiation conditions. Together with previous findings, the data suggest that the complexity of the HIV LTR for transcriptional control is much greater than was previously thought and that the LTR maintains elements which facilitate transcription in many cell types.

Base Sequence↗

PubMed1994

Elements in the long terminal repeat of HIV-1 that interact with nuclear extracts from Jurkat cells persistently infected with vaccinia virus.

Previous reports showed transactivation of the long terminal repeat (LTR) of HIV-1 in Jurkat cells persistently infected with vaccinia virus. In this communication, electrophoretic mobility shift assays were used to characterize the elements in HIV-1 LTR which might be responsible for the mechanism of transactivation. The results indicated that two elements, those for binding NF-kB and NFAT-1, were able to interact with nuclear extracts derived from Jurkat cells persistently infected with vaccinia virus, suggesting that they may play a role in the transactivation of HIV-1 LTR.

Base Sequence↗

PubMed1995

Recombinant mink cell focus-inducing virus and long terminal repeat alterations accompany the increased leukemogenicity of the Mo+PyF101 variant of Moloney murine leukemia virus after intraperitoneal inoculation.

We recently showed that different routes of inoculation affect the leukemogenicity of the Mo+PyF101 variant of Moloney murine leukemia virus (M-MuLV). Intraperitoneal (i.p.) inoculation of neonatal mice with Mo+PyF101 M-MuLV greatly enhanced its leukemogenicity compared with subcutaneous (s.c.) inoculation. We previously also suggested that the leukemogenicity defect of Mo+PyF101 M-MuLV when inoculated s.c. may result from the inability of this virus to form env gene recombinant (mink cell focus-inducing [MCF]) virus. In this study, virus present in end-stage tumors and in preleukemic animals inoculated i.p. by Mo+PyF101 M-MuLV was characterized. In contrast to s.c. inoculation, all tumors from i.p.-inoculated mice contained high levels of recombinant MCF virus. Furthermore, Southern blot analyses demonstrated that the majority of the tumors contained altered Mo+PyF101 M-MuLV long terminal repeats. The U3 regions from several tumors with altered long terminal repeats were cloned by PCR amplification. Sequence analyses indicated that the M-MuLV 75-bp tandem repeat in the enhancer region was triplicated. This amplification was also previously observed in mice infected s.c. with a pseudotypic mixture of Mo+PyF101 M-MuLV and Mo+PyF101 MCF virus. The enhancer triplication was an early event, and it occurred within 2 weeks postinfection. Recombinant MCF viruses were not detected by Southern blot analyses until 4 weeks postinfection. Thus, the M-MuLV enhancer triplication event was initially important for efficient propagation of ecotropic Mo+PyF101 M-MuLV. The increased leukemogenicity following i.p. inoculation could be explained if the triplication enhances Mo+PyF101 M-MuLV replication in the bone marrow and bone marrow infection is required for recombinant MCF virus formation.

3T3 Cells↗

PubMed1998

Amino acid analogs activate NF-kappaB through redox-dependent IkappaB-alpha degradation by the proteasome without apparent IkappaB-alpha phosphorylation. Consequence on HIV-1 long terminal repeat activation.

We report here that amino acid analogs, which activate hsp70 promoter, are powerful transcriptional activators of human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR), an activation which was impaired when the two kappaB sites present in the LTR were mutated or deleted. Amino acid analogs also stimulated the transcription of a kappaB-controlled reporter gene. Upon treatment with amino acid analogs, the two NF-kappaB subunits (p65 and p50), which are characterized by a relatively long half-life, redistributed into the nucleus where they bound to kappaB elements. This phenomenon, which began to be detectable after 1 h of treatment, was concomitant with the degradation of the short lived inhibitory subunit IkappaB-alpha by the proteasome. However, contrasting with other NF-kappaB inducers that trigger IkappaB-alpha degradation through a phosphorylation step, amino acid analogs did not change IkappaB-alpha isoform composition. Antioxidant conditions inhibited amino acid analog stimulatory action toward NF-kappaB. This suggests that aberrant protein conformation probably generates a pro-oxidant state that is necessary for IkappaB-alpha proteolysis by the proteasome. Moreover, this activation of NF-kappaB appeared different from that mediated by endoplasmic reticulum overload as it was not inhibited by calcium chelation.

Amino Acids↗

PubMed1999

Lactobacilli and vaginal host defense: activation of the human immunodeficiency virus type 1 long terminal repeat, cytokine production, and NF-kappaB.

Lactobacilli, a component of the normal vaginal flora, can activate the human immunodeficiency virus (HIV)-1 long terminal repeat (LTR) in the Jurkat T lymphocyte and THP-1 macrophage cell lines. Activation of the LTR in Jurkat cells was strongly enhanced by vanadate and inhibited by catalase, implicating H2O2. In contrast, activation in THP-1 cells occurred in the absence of vanadate and was unaffected by catalase. The active material partitioned into the phenol layer on hot aqueous phenol extraction. Lactobacilli also increased tumor necrosis factor-alphaand interleukin-1betaproduction and activated NF-kappaB in THP-1 cells and increased tumor necrosis factor-alphaproduction by human monocytes. Human vaginal fluid specimens had comparable properties, which correlated with their bacterial content. These findings suggest the presence in vaginal fluid of agent(s) derived from indigenous bacteria that can activate the HIV-1 LTR, cytokine production, and NF-kappaB in cells of macrophage lineage, with possible influence on vaginal physiology and host defense.

Catalase↗

PubMed1986

Androgen regulation by the long terminal repeat of mouse mammary tumor virus.

Mouse mammary tumor virus (MMTV) has long been implicated in mouse mammary carcinogenesis, and it is now well established that the long terminal repeat (LTR) contains regulatory sequences responsible for glucocorticoid-mediated induction of viral RNA. However, we have demonstrated previously that androgens as well as glucocorticoids can regulate MMTV RNA in the S115 mouse mammary tumor cell line. To determine if androgens act directly on the LTR in these cells, plasmids were constructed with the MMTV LTR joined to the coding sequences of genes not normally expressed in the cells. Following transfection of these chimeric genes into S115 cells, we show that the expression of the genes is regulated by both androgens and glucocorticoids. Furthermore, hormonal regulation is also conferred by the LTR on the neighboring guanine phosphoribosyltransferase (gpt) gene. Thus, androgens can act on the LTR of MMTV when the appropriate receptors are present in the cells, and this interaction can influence the expression of additional adjacent genes.

Androgens↗

PubMed1983

The high leukemogenic potential of Gross passage A murine leukemia virus maps in the region of the genome corresponding to the long terminal repeat and to the 3' end of env.

The Gross passage A murine leukemia virus (MuLV) is a highly leukemogenic, ecotropic fibrotropic retrovirus. Its genome is similar to that of other nonleukemogenic ecotropic fibrotropic MuLVs but differs at the 3' end and in the long terminal repeat. To determine whether these modifications were related to its leukemogenic potential, we constructed a viral DNA recombinant in vitro with cloned infectious DNA from this highly leukemogenic Gross passage A MuLV and from a weakly leukemogenic endogenous BALB/c B-tropic MuLV. Infectious viruses, recovered after microinjection of murine cells with recombinant DNA, were injected into newborn mice. We show here that the Gross passage A 1.35-kilobase-pair KpnI fragment (harboring part of gp70, all of p15E, and the long terminal repeat) is sufficient to confer a high leukemogenic potential to this recombinant.

AKR murine leukemia virus↗

PubMed1989

Functional mapping of the activity of the R region in the human T-cell leukemia virus type I long terminal repeat to increase gene expression.

We previously demonstrated the activity of the R fragment in the long terminal repeat of human T-cell leukemia virus type I for elevation of the level of gene expression. In this study, the fragment was deleted with BAL31 nuclease to determine its functional domain. Series of the shortened R fragments were linked to the simian virus 40 promoter unit, which regulated expression of a reporter gene. Examination with the R fragments deleted from the 5' and 3' ends showed that borders of the functional domain were mapped within nucleotide positions 458 to 473 for the 5' end and nucleotide positions 559 to 594 for the 3' end, respectively. Thus we conclude that a 136-base-pair fragment corresponding to the second half of the R region was sufficient to allow elevation of the level of gene expression.

Base Sequence↗

PubMed1989

Mutational analysis of sodium butyrate inducible elements in the human immunodeficiency virus type I long terminal repeat.

Sodium butyrate induces gene expression directed by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in HeLa cells. Inducible regions of the HIV-1 LTR were elucidated by using 5' and 3' LTR deletion mutants and LTR site-directed mutants within the Sp1 binding sites and the trans-activation responsive (TAR) region. Two LTR regions inducible by sodium butyrate were located: one at -117 to -103 (distal site) and one at -65 to -17 (proximal site). In HeLa cells trans-fected with pZ6neo, a biologically active HIV-1 proviral clone, sodium butyrate stimulated virus production following a 3-day treatment. Inducibility of HIV-1 gene expression by sodium butyrate was unrestricted in many human cell types, including CD4+ lymphoid cells and non-CD+ brain cells and fibroblasts. Additionally, sodium butyrate transiently induced HIV-2 LTR-directed gene expression in HeLa cells. Using the HIV-1SF-2 tat gene cotransfected with pLTR-CAT site-directed TAR mutants in HeLa cells, the boundaries of tat-trans-activation were delineated more precisely. These results suggest that the induction of HIV-1 gene expression is mediated by the interaction of sodium butyrate with cellular transcription factors that bind to the HIV-LTR.

Base Sequence↗

PubMed1996

Regulatory properties of the integrated long terminal repeat of the feline immunodeficiency virus.

To examine the regulatory properties of feline immunodeficiency virus (FIV) long terminal repeat (LTR) integrated into host chromatin, Crandell feline kidney cells were stably transfected with the FIV LTR that directs the bacterial chloramphenicol acetyltransferase (CAT) gene. Using these cells, we examined the effects of treatment with several chemical agents, infection with feline viruses, or transfection with effector plasmids expressing FIV gene products on FIV LTR-directed gene expression. Among them, treatment with the phorbol ester (a strong activator of protein kinase C), forskolin (an inducer of cyclic-AMP), 5-azacytidine (a DNA methylation antagonist), or infection with feline herpesvirus type 1 (FHV-1), resulted in induction of CAT activity in the cells. These results suggest that the integrated FIV LTR is stimulated by cellular transcriptional factors induced by phorbol ester, forskolin and FHV-1, and is also inactivated by DNA methylation. Furthermore, this permanent cell line can be used as a screening system of activators of the FIV LTR.

Animals↗

PubMed1982

Encapsidation sequences for spleen necrosis virus, an avian retrovirus, are between the 5' long terminal repeat and the start of the gag gene.

The minimal cis-acting sequences outside the long terminal repeat (LTR) required for formation of an infectious retrovirus cloning vector were determined with recombinants of spleen necrosis virus (SNV) DNA and herpes simplex virus type 1 thymidine kinase gene. The 3' end of SNV DNA was removed to within 40 base pairs (bp) from the 3' LTR with only a 2-fold effect on the recovery of infectious recombinant virus. However, when the 5' end of SNV DNA was removed to within 100 bp from the 5' LTR, infectious recombinant virus was not recovered. Deletion mutants constructed around this latter region showed that nucleotides between 100 and 285 bp from the 5' LTR are necessary for encapsidation of genomic viral RNA. We call this region required for encapsidation E.

Animals↗

PubMed2001

Upstream stimulatory factors binding to an E box motif in the R region of the bovine leukemia virus long terminal repeat stimulates viral gene expression.

The bovine leukemia virus (BLV) promoter is located in its 5'-long terminal repeat and is composed of the U3, R, and U5 regions. BLV transcription is regulated by cis-acting elements located in the U3 region, including three 21-bp enhancers required for transactivation of the BLV promoter by the virus-encoded transactivator Tax(BLV). In addition to the U3 cis-acting elements, both the R and U5 regions contain stimulatory sequences. To date, no transcription factor-binding site has been identified in the R region. Here sequence analysis of this region revealed the presence of a potential E box motif (5'-CACGTG-3'). By competition and supershift gel shift assays, we demonstrated that the basic helix-loop-helix transcription factors USF1 and USF2 specifically interacted with this R region E box motif. Mutations abolishing upstream stimulatory factor (USF) binding caused a reproducible decrease in basal or Tax-activated BLV promoter-driven gene expression in transient transfection assays of B-lymphoid cell lines. Cotransfection experiments showed that the USF1 and USF2a transactivators were able to act through the BLV R region E box. Taken together, these results physically and functionally characterize a USF-binding site in the R region of BLV. This E box motif located downstream of the transcription start site constitutes a new positive regulatory element involved in the transcriptional activity of the BLV promoter and could play an important role in virus replication.

Animals↗