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PubMed2004

Genome sequence analysis of the avian retrovirus causing so-called fowl glioma and the promoter activity of the long terminal repeat.

So-called fowl glioma is a retroviral infectious disease caused by avian leukosis virus subgroup A (ALV-A). We determined the complete nucleotide sequence of the virus genome. The full-length sequence was consistent with a genetic organization typical of a replication-competent type C retrovirus lacking viral oncogenes. The coding sequences were well conserved with those of replication-competent viruses, but the 3' noncoding regions including LTR were most related to those of replication-defective sarcoma viruses. The U3 region of the LTR had a few deletions and several point mutations compared to that of other ALVs. The promoter activities of the LTRs of glioma-inducing ALV and ALV-A standard strain, RAV-1, were equivalent in chick embryo fibroblasts (CEF), while that of glioma-inducing ALV was significantly lower than that of RAV-1 in human astrocytic cells. These subtle differences of the promoter activity of the LTR may be related to the induction of glial neoplasm.

Alpharetrovirus↗
PubMed2004

Local definition of Ty1 target preference by long terminal repeats and clustered tRNA genes.

LTR-containing retrotransposons reverse transcribe their RNA genomes, and the resulting cDNAs are integrated into the genome by the element-encoded integrase protein. The yeast LTR retrotransposon Ty1 preferentially integrates into a target window upstream of tDNAs (tRNA genes) in the yeast genome. We investigated the nature of these insertions and the target window on a genomic scale by analyzing several hundred de novo insertions upstream of tDNAs in two different multicopy gene families. The pattern of insertion upstream of tDNAs was nonrandom and periodic, with peaks separated by approximately 80 bp. Insertions were not distributed equally throughout the genome, as certain tDNAs within a given family received higher frequencies of upstream Ty1 insertions than others. We showed that the presence and relative position of additional tDNAs and LTRs surrounding the target tDNA dramatically influenced the frequency of insertion events upstream of that target.

5' Flanking Region↗
PubMed1991

Bone marrow depletion by 89Sr complements a preleukemic defect in a long terminal repeat variant of Moloney murine leukemia virus.

We previously described a preleukemic state induced by Moloney murine leukemia virus (Mo-MuLV) characterized by hematopoietic hyperplasia in the spleen. Further experiments suggested that splenic hyperplasia results from inhibitory effects in the bone marrow, leading to compensatory extramedullary hematopoiesis. An enhancer variant of Mo-MuLV, Mo + PyF101 Mo-MuLV, fails to induce preleukemic hyperplasia and has greatly reduced leukemogenicity, indicating the importance of this state to efficient leukemogenesis. An alternative method for induction of preleukemic hyperplasia was sought. Treatment of mice with 89Sr causes specific ablation of bone marrow hematopoiesis and compensatory extramedullary hematopoiesis in spleen and nodes. NIH Swiss mice were inoculated neonatally with Mo + PyF101 Mo-MuLV and treated with 89Sr at 6 weeks of age. Approximately 85% developed lymphoid leukemia with a time course resembling that caused by wild-type Mo-MuLV. In contrast, very few animals treated with Mo + PyF101 Mo-MuLV or 89Sr alone developed disease. In approximately one-third of cases, the Mo + PyF101 Mo-MuLV proviruses were found at common sites for wild-type Mo-MuLV-induced tumors (c-myc, pvt-1, and pim-1), indicating that this virus is capable of performing insertional activation in T-lymphoid cells. These results support the proposal that splenic hyperplasia results from inhibitory effects in the bone marrow. They also indicate that Mo + PyF101 Mo-MuLV is blocked in early and not late events in leukemogenesis.

Animals↗
PubMed1993

Influence of sequences in the long terminal repeat and flanking cell DNA on polyadenylation of retroviral transcripts.

Readthrough transcripts are formed during retrovirus infection by polyadenylation of viral RNA in cellular sequences adjacent to the provirus. We have studied such transcripts in avian leukosis virus-infected cell clones containing a single provirus, either the wild type or one with an inactivating mutation in the poly(A) addition signal. All individual wild-type proviruses produced readthrough transcripts, implying that this property is not restricted to a few integration sites. The range of sizes of viral RNA in the mutant lacking a correct signal for poly(A) addition reflected both the occurrence of functional polyadenylation sites within flanking cell DNA and increased usage of cryptic sites within viral sequences.

Animals↗
PubMed1996

Unique long terminal repeat U3 sequences distinguish exogenous jaagsiekte sheep retroviruses associated with ovine pulmonary carcinoma from endogenous loci in the sheep genome.

Ovine pulmonary carcinoma (OPC) is a contagious lung cancer of sheep that is presumed to be caused by an exogenous retrovirus of sheep, jaagsiekte sheep retrovirus (JSRV). The sheep genome carries 15 to 20 copies of endogenous sheep retrovirus (ESRV) loci that hybridize to JSRV DNA probes. In order to clarity the etiologic roles of ESRV and an exogenous JSRV-like retrovirus (exJSRV) in OPC, we assessed sequence differences between ESRV and JSRV. Molecular characterization of six ESRV loci revealed restriction sites specific for JSRV. Nucleotide sequences of ESRVs from sheep of different breeds were similar to those of JSRV in structural genes but divergent in U3. Therefore, primers specific for the U3 sequences of exJSRV were designed for use in the PCR. Of 13 tumor DNAs tested by PCR with these exogenous-virus U3 primers, 8 produced DNA fragments that hybridized with the JSRV gag probe, but neither lung DNAs from healthy sheep nor DNAs from nontumor tissues of diseased sheep produced similar DNA fragments. exJSRV PCR products from tumor DNAs of sheep with OPC from three continents had restriction profiles similar to each other but different from those of ESRVs upon digestion with EcoRI, HindIII, NdeI, KpnI, and ScaI. These exjSRVs could be classified into two genotypes according to U3 sequences and restriction profiles. U3 sequences of exJSRV proviruses in tumors strongly resembled those of JSRV but differed from those of ESRVs, suggesting that exJSRVs, rather than ESRVs, are primarily associated with oncogenesis in OPC.

Amino Acid Sequence↗
PubMed2002

In vivo analysis of retroviral enhancer mutations in hematopoietic cells: SP1/EGR1 and ETS/GATA motifs contribute to long terminal repeat specificity.

The objective of this work was to identify, in the context of chromosomally integrated DNA, the contribution of defined transcription factor binding motifs to the function of a complex retrovirus enhancer in hematopoietic cells in vivo. Repopulating murine hematopoietic cells were transduced with equal gene dosages of replication-incompetent retrovirus vectors encoding enhanced green fluorescent protein. Enhancer sequences were derived from mouse spleen focus-forming virus. Destruction of GC-rich sites representing overlapping targets for SP1 or EGR1 uniformly attenuated gene expression (approximately 25 to 70% of wild-type levels) in all hematopoietic lineages, as shown by multicolor flow cytometry of peripheral blood and bone marrow cells at various time points posttransplantation. In contrast, a point mutation within a dual ETS/GATA motif that abolished transactivation by ETS factors but not by GATA-1 slightly increased activity in erythroid cells and significantly attenuated enhancer function in T lymphocytes. This study shows that controlled gene transfer in transplantable hematopoietic cells allows a functional analysis of distinct cis elements within a complex retrovirus enhancer, as required for the characterization and engineering of various cellular and viral regulatory sequences in basic research and gene therapy.

Animals↗
PubMed2005

Preferential feline immunodeficiency virus (FIV) infection of CD4+ CD25+ T-regulatory cells correlates both with surface expression of CXCR4 and activation of FIV long terminal repeat binding cellular transcriptional factors.

Previously, we have characterized feline CD4+ CD25+ T-regulatory (Treg) cells with regard to their immune regulatory properties and ability to support feline immunodeficiency virus (FIV) replication in vitro and in vivo. Our studies showed that while CD4+ CD25+ cells were capable of replicating FIV in the presence of interleukin-2 (IL-2) alone, CD4+ CD25- cells harbored a latent infection that required a strong mitogenic stimulus to activate virus replication. In the present study, we investigated the mechanisms governing the preferential replication of FIV in highly purified CD4+ CD25+ Treg cells compared to their CD4+ CD25+ counterparts. Studies aimed at elucidating mechanisms regulating infection of these cells revealed that CD4+ CD25- cells were less susceptible to FIV binding and entry than CD4+ CD25+ cells, which correlated with increased surface expression of FIV coreceptor CXCR4. In addition, the number of CD4+ CD25+ cells that expressed the primary receptor CD134 was greater than for CD4+ CD25- cells. Although increased permissiveness to FIV infection of CD4+ CD25- cells following mitogenic stimulation correlated strongly with upregulation of surface CXCR4, it did not correlate with CD134 expression. Further, study of intracellular factors regulating FIV replication revealed that CD4+ CD25+ but not CD4+ CD25- T cells showed constitutive and IL-2-responsive transactivation of activating transcription factor, CAAT enhancer binding protein, and activating protein 1 transcription factors that are important for FIV replication. These factors were upregulated in CD4+ CD25- T cells following ConA stimulation, which correlated with FIV replication. This is the first report elucidating the mechanisms that allow for productive lentiviral infection of CD4+ CD25+ Treg cells.

Animals↗
PubMed1994

Nucleosome-mediated disruption of transcription factor-chromatin initiation complexes at the mouse mammary tumor virus long terminal repeat in vivo.

Glucocorticoid induction of mouse mammary tumor virus (MMTV) is short lived, returning to base levels within 24 h despite the continued presence of hormone. MMTV DNA sequences assembled as chromatin require hormone for binding by nuclear factor 1 (NF1) and octamer proteins (OCT). However, in the same cells, NF1 and OCT factors are bound to transiently introduced DNA in the absence of hormone. In contrast, recruitment of the TATA-binding protein and a novel DNA-binding protein, which we have designated FDT, for factor downstream of the TATA-binding protein, is hormone dependent for both stable and transient templates. Furthermore, transient DNA templates, but not nucleosomal templates, retain these transcription factors over the course of 24 h. This finding suggests that MMTV chromatin structure contributes to activation and cessation of transcription in vivo.

Animals↗
PubMed1987

An embryonic DNA-binding protein specific for the promoter of the retrovirus long terminal repeat.

Retrovirus expression is restricted in embryonal carcinoma (EC) cells but not in many differentiated cell lines. We used a very sensitive gel retardation assay to detect sequence-specific DNA-binding proteins in crude nuclear extracts obtained from EC and differentiated cells. Four binding sites were mapped in the noncoding sequences of the amphotropic murine leukemia virus. Strong binding to the CCAAT consensus sequence located in the promoter was specifically observed with EC nuclear extract. The binding protein is called EPBF (embryonal promoter-binding factor), and it is a candidate for the repressor of retrovirus transcription.

Animals↗
PubMed1989

Purification and characterization of multiple nuclear factors that bind to the TAX-inducible enhancer within the human T-cell leukemia virus type 1 long terminal repeat.

Within the human T-cell leukemia virus type I promoter, there are three copies of a 21-base-pair repeat (hereafter called the tax-responsive element [TRE]) that both contributes to basal promoter activity and mediates induction by the viral activator TAX. We have identified and separated three nuclear proteins that interact with the TRE. The TRE-binding protein designated TREB-3 bound more avidly to a multimerized TRE than to a single-copy TRE, while the other two TRE-binding proteins, TREB-1 and TREB-2, bound equally well to either TRE. TREB-1 has been purified to near homogeneity, and binding activity was localized to a protein of 35 to 43 kilodaltons. The affinity-purified TREB-1 activated transcription from the human T-cell leukemia virus type I promoter in vitro. The purified TREB-1 fraction contained activating transcription factor binding activity and showed a cooperative interaction with the TATA-binding factor (TFIID) on the adenovirus E4 promoter.

Base Sequence↗
PubMed2001

The long terminal repeat (LTR) sequence of marY1, a retroelement from the ectomycorrhizal homobasidiomycete Tricholoma matsutake, is highly conserved in various higher fungi.

marY1 is an LTR-retroelement from the homobasidiomycete Tricholoma matsutake. Nucleotide sequences that correspond to the putative U3-R region and the R-U5 region of marY1 are highly conserved in various higher fungi. Data suggest that the LTR sequence of marY1 originated early in the evolution of higher fungi and has become widely distributed. Therefore, it may be useful for the construction of an LTR-mediated transformation system in basidiomycetes.

Base Sequence↗
PubMed2006

NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site.

To replicate, HIV-1 capitalizes on endogenous cellular activation pathways resulting in recruitment of key host transcription factors to its viral enhancer. RNA interference has been a powerful tool for blocking key checkpoints in HIV-1 entry into cells. Here we apply RNA interference to HIV-1 transcription in primary macrophages, a major reservoir of the virus, and specifically target the transcription factor NFAT5 (nuclear factor of activated T cells 5), which is the most evolutionarily divergent NFAT protein. By molecularly cloning and sequencing isolates from multiple viral subtypes, and performing DNase I footprinting, electrophoretic mobility shift, and promoter mutagenesis transfection assays, we demonstrate that NFAT5 functionally interacts with a specific enhancer binding site conserved in HIV-1, HIV-2, and multiple simian immunodeficiency viruses. Using small interfering RNA to ablate expression of endogenous NFAT5 protein, we show that the replication of three major HIV-1 viral subtypes (B, C, and E) is dependent upon NFAT5 in human primary differentiated macrophages. Our results define a novel host factor-viral enhancer interaction that reveals a new regulatory role for NFAT5 and defines a functional DNA motif conserved across HIV-1 subtypes and representative simian immunodeficiency viruses. Inhibition of the NFAT5-LTR interaction may thus present a novel therapeutic target to suppress HIV-1 replication and progression of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Biochemical analysis of long terminal repeat retrotransposons.

A brief survey of the retrotransposition cycle is given with emphasis on intermediary steps and their identification by biochemical analysis. References include some older key publications that may not be easily accessible via electronic databases. Methods for enrichment of viruslike particles from plant material and from yeast are described.

DNA, Fungal↗
PubMed2003

Activation of HTLV-I long terminal repeat by apoptosis inducing agents: mechanism and implications for HTLV-I pathogenicity (review).

HTLV-I is the etiological agent of adult T-cell leukemia (ATL), tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM) and certain other clinical disorders. After infection in human the virus enters into a latent state, in which very low viral gene expression can be detected. On the other hand several major characteristics of ATL and TSP/HAM indicate that their genesis requires activation of the dormant virus. TSP/HAM is characterized by high virus expression, which accounts for most of its immunopathological manifestations, whereas the process leading to ATL is believed to be initiated by the viral Tax protein, implying that it requires, at least, a temporary activation of the latent virus. Data from our and other laboratories suggest that this activation may likely be induced by environmental or/and intrinsic apoptosis-inducing factors. Moreover, we have demonstrated a mechanistic linkage between the activation of the viral promoter and the early stage of the apoptotic cascade. However, we have also shown that Tax rescues virus-expressing T-cells from apoptotic death. This suggests that Tax protein, emerging after activation of the latent virus, can rescue the host cells of the activated virus from the ultimate apoptotic death. Since the development of both TSP/HAM and ATL seems to depend on the viral Tax protein, we describe a possible system for anti Tax gene-therapy approach based on a negative transdominant mutant Tax gene.

Adult↗
PubMed2002

[Long terminal repeats of retroposons in Candida albicans].

25 Candida albicans strains have been analysed on Southern hybridization patterns with alpha, beta, gamma, kappa probes. The alpha, beta, gamma, kappa, elements can be used to distinguish the differences and relations between C. albicans strains. Chromosomal localization analysis indicated that the alpha, beta, gamma, kappa, elements were located on several different chromosomes in Candida albicans strains. Northern hybridization showed that alpha, beta, gamma were transcribed actively and regulated by different stimuli. The kappa was inactive. Our results indicated that in Candida albicans there were many kinds of retroposons whose numbers and distribution were different. These retroposons could be used to identify Candida albicans strains as moleculer markers.

Blotting, Northern↗
PubMed1991

ras oncogene activates the intracisternal A particle long terminal repeat promoter through a c-AMP response element.

To understand the mechanism responsible for the high expression of Intracisternal A Particles (IAP) in murine cells transformed by the Kirsten Mouse Sarcoma Virus (Ki-MSV), we have investigated the effect of p21ras on IAP transcription. By transient cotransfections of IAP LTR-CAT plasmids with v-Ki-ras and c-Ki-ras expression vectors, we have found that p21v-Ki-ras, and the p21c-Ki-ras to a lesser extent, stimulate the promoter activity of the 5' IAP LTR. We constructed several plasmids containing the CAT gene under control of IAP LTRs deleted in different regions. CAT assays demonstrate that the ras responsive sequence is a 16 bp oligonucleotide containing an effective c-AMP Response Element (CRE) TGACGTCA, which is located in the U3 region, 20 bp upstream of the CAAT box.

Animals↗