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PubMed1984

Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease.

The genome of human T-cell leukemia virus (HTLV) was surveyed in fresh tumor cells of 163 patients with lymphoma and leukemia from the southwest part of Japan where adult T-cell leukemia (ATL) is endemic. Leukemic cells of all 88 cases of ATL tested so far were found to contain the provirus genome and also found to be monoclonal with respect to the integration site of provirus genome. In most cases of ATL, leukemic cells contained one or two copies of the complete HTLV provirus genome, and it was shown that the single species of HTLV with a fully determined sequence is typical in ATL. Some cases of T-cell malignancies, diagnosed as chronic lymphocytic leukemia or non-Hodgkin lymphoma, also had the provirus genome in their tumor cells, whereas some cases with the same diagnosis did not. No cases of other types of lymphoma or leukemia contained the provirus genome in their tumor cells. Monoclonal integration of the HTLV provirus genome in all primary tumor cells of ATL not only indicates that HTLV directly interacts with target cells, which become leukemic, and that integration of the provirus genome is a prerequisite for development of ATL and possibly other related diseases but also indicates that the virus is not associated with other types of lymphoma or leukemia.

Cloning, Molecular↗
PubMed1981

Variety of endogenous proviruses in the genomes of chickens of different breeds.

We have compared endogenous proviruses in DNA of chickens of 11 breeds by means of Southern's technique. Many of the endogenous virus loci found were missing from the genomes of the extensively studied white leghorn chickens, although some of the proviruses and especially ev-1 appeared to be widely spread among different chickens. Most of the proviruses were similar to Rous-associated virus (RAV-O) as judged by the EcoRI digestion patterns. Several genetically different proviruses were found in the DNA of 28 brown leghorns. They contain neither ev-1 provirus in their genome, nor any other one common for all individuals. All four Italian partridge-coloured chickens examined appeared to be free from ALV-related sequences in their DNA showing the possibility of normal life without known endogenous proviruses. Possible causes of inter-breed differences of chicken endogenous proviruses are discussed.

Animals↗
PubMed1980

Evidence for the Asiatic origin of endogenous AKR-type murine leukemia proviruses.

A restriction endonuclease cleavage map of the genome of AKV, the endogenous, ecotropic leukemia virus of AKR mice, has been derived. By using this map and analyzing DNA from congenic mice, we have defined four DNA fragments diagnostic for AKV proviruses. Analysis of DNAs from 10 strains of American laboratory mice revealed that all strains carrying inducible, ecotropic murine leukemia viruses yielded DNAs which contained the four DNA fragments diagnostic for AKV. Virus-negative strains lacked these fragments in their DNA. Screening DNA from 23 additional mice revealed that, among these mice, only mice from Asia gave rise to the DNA fragments diagnostic of an AKV provirus. We conclude that all of the endogenous ecotropic murine leukemia proviruses in American laboratory mice are closely related since they share a common set of restriction endonuclease cleavage sites. These proviruses appear to derive from the East Asian ancestors of these mouse strains. Analysis of DNA from six selected mice with an additional restriction endonuclease showed that greater than 97% of the nucleotide sequences in each provirus are contigous and that these endogenous proviruses are indistinguishable from proviruses introduced by exogenous infection.

Animals↗
PubMed1985

Molecular and biological characterization of the endogenous ecotropic provirus of BALB/c mice.

We have isolated two identical molecular clones of the single, endogenous ecotropic provirus of BALB/c mice. The BALB/c clones are approximately 1/10 as infectious as an exogenous proviral clone derived from AKR mice, p623. Transfection of mouse cells with each BALB/c proviral clone yielded XC-negative, N-tropic, ecotropic virus. Cotransfection of subgenomic fragments of p623 and the BALB/c provirus did not increase infectivity to the level observed for p623; however, a 292-base-pair fragment of the p623 env gene was found to rescue XC-plaque formation. Sequence analysis showed that the XC-negative BALB/c provirus differed from the XC-positive AKR-derived provirus at a single nucleotide at the junction of the gp70 and p15E envelope proteins. Extensive sequence analysis of the BALB/c endogenous provirus showed that it differed from the sequence of the AKR-derived provirus at approximately 0.5% of 4,500 sequenced nucleotides. In addition, the BALB/c long terminal repeat contains a single copy of the enhancer-containing sequences that are repeated twice in p623. The limited variation between the ecotropic proviruses of BALB/c mice and AKR mice suggests that few cycles of reverse transcription separate these viral genomes.

Amino Acid Sequence↗
PubMed1985

Analysis of a deleted MC29 provirus: gag sequences are not required for fibroblast transformation.

Recovered avian myelocytomatosis virus HBI is an MC29-related virus that induces lymphoid tumors in chickens rather than the predominant neoplastic disease induced by wild-type MC29 (namely, endotheliomas). An analysis of the structure of the HBI provirus(es) in the tumors demonstrated that the provirus(es) could be either full size or deleted. One tumor was found to be clonal in that it contained a single provirus which had been partially deleted; this raised a question concerning the role of this provirus in the maintenance of tumor growth. To characterize the detailed structure of this provirus and determine its biological activity, it was molecularly cloned from tumor DNA. Sequencing confirmed that the provirus contained a deletion which effectively removed the whole gag gene. However, the provirus was shown to encode a myc-specific protein, presumably initiating from within the myc gene, and to be biologically active when it was transfected onto quail embryo fibroblasts. Our results suggest that myc alone is sufficient to transform quail embryo fibroblasts and to maintain tumor growth in vivo.

Amino Acid Sequence↗
PubMed1986

Frequent partial deletion of human adult T-cell leukemia virus type I proviruses in experimental transmission: pattern and possible implication.

Human T-cell leukemia virus type I (HTLV I) propagated in human diploid fibroblast IMR90 was transmitted to human promyelocytic leukemia HL60 cells by coculture. Of 14 provirus-positive HL60 clones, five harbored only defective proviruses, five had defective proviruses in addition to full-sized HTLV I, and four had full-sized proviruses integrated in their chromosomes. The frequency of defective proviruses was unexpectedly high (41% of total proviruses). Analysis of the genomic structure of these defective proviruses revealed polarity of deletion, that is, preferred conservation of the 3' end of the proviral genome (pX and the 3' long terminal repeat). The implication of these findings are discussed with reference to the replication and pathogenesis of HTLV I.

Cell Line↗
PubMed1986

Nonecotropic murine leukemia viruses in BALB/c and NFS/N mice: characterization of the BALB/c Bxv-1 provirus and the single NFS endogenous xenotrope.

We used hybridization probes that react specifically with xenotropic and mink cell focus-forming virus envelope sequences to characterize the nonecotropic proviruses of BALB/c and NFS/N mice. Analysis of somatic cell hybrids with different BALB/c chromosomes showed that the 9 xenotropic and more than 20 MCF virus-related proviral sequences in this mouse were present on more than nine BALB/c chromosomes. Multiple copies were found on chromosomes 1, 4, 7, 12, and probably 11, and the copies found on a single chromosome were not identical by restriction enzyme mapping. We also identified and characterized the proviral sequences that give rise to infectious xenotropic virus in both BALB/c and NFS/N mice. BALB/c contains the major locus for induction of infectious virus in inbred mice, Bxv-1, which is on chromosome 1. We showed that this locus contains a single xenotropic provirus on an 18-kilobase HindIII fragment. Restriction enzyme analysis of a hybrid cell DNA that contains only the Bxv-1 xenotropic provirus showed that the Bxv-1 provirus contains restriction enzyme sites characteristic of the infectious virus induced from BALB/c fibroblasts. The Bxv-1 provirus and its flanking sequences also contain the same restriction sites as the provirus thought to contribute U3 long terminal repeat sequences to leukemogenic (class I) AKR MCF viruses. Analysis of cell hybrids made with the nonvirus-inducible strain NFS/N showed that the single xenotropic virus env gene of NFS mice, here termed Nfxv-1, is not on chromosome 1. Unlike that of Bxv-1, the restriction map of Nfxv-1 does not resemble that of any known infectious xenotropic virus including xenotropic viruses isolated from NFS mice. These data suggest that Bxv-1, but not Nfxv-1, is a full-length xenotropic provirus that can be transcribed directly to produce infectious virus.

Animals↗
PubMed1986

Varied interactions between proviruses and adjacent host chromatin.

Retroviruses integrated at unique locations in the host genome can be expressed at different levels. We have analyzed the preintegration sites of three transcriptionally competent avian endogenous proviruses (evs) to determine whether the various levels of provirus expression correlate with their location in active or inactive regions of chromatin. Our results show that in three of four cell types, the chromatin conformation (as defined by relative nuclease sensitivity) of virus preintegration sites correlates with the level of expression of the resident provirus in ev+ cells: two inactive proviruses (ev-1 and ev-2) reside in nuclease-resistant chromatin domains and one active provirus (ev-3) resides in a nuclease-sensitive domain. Nuclear runoff transcription assays reveal that the preintegration sites of the active and inactive viruses are not transcribed. However, in erythrocytes of 15-day-old chicken embryos (15d RBCs), the structure and activity of the ev-3 provirus is independent of the conformation of its preintegration site. In this cell type, the ev-3 preintegration site is organized in a nuclease-resistant conformation, while the ev-3 provirus is in a nuclease-sensitive conformation and is transcribed. In addition, the nuclease sensitivity of host sequences adjacent to ev-3 is altered in ev-3+ 15d RBCs relative to that found in 15d RBCs that lack ev-3. These data suggest that the relationship between preintegration site structure and retrovirus expression is more complex than previously described.

Animals↗
PubMed1988

Avian nephroblastomas induced by a retrovirus (MAV-2) lacking oncogene. III. Presence of defective MAV-2 proviruses in tumour DNA.

Using Southern hybridization with a series of probes derived from the MAV provirus we searched for structurally changed MAV-2 proviruses in the DNA from MAV-2-induced nephroblastomas. Anomalous fragments of MAV-2 provirus were found in all samples analysed in more detail. Comparison of the sizes of anomalous fragments detected by different probes in the same sample indicates that the fragments, at least in a majority of cases, do not represent recombinant proviruses (which might contain transduced oncogene) but deleted proviruses only. Various types of proviral deletions occur in different nephroblastoma clones, and no preferred type of deletion was found. The defects in MAV-2 sequences appear in infected chickens de novo, because defective proviruses also occur in tumours of chickens that have been infected with the plaque-purified MAV-2 preparations and, in addition, most of the proviral defects found prevent the virus from replicating and from being transmitted by infection. The regular occurrence of defective proviruses in tumour DNA supports the concept that the proviral defects are involved in oncogenesis. Hypotheses on the substance of this involvement are discussed.

Animals↗
PubMedDate not supplied

[New endogenous proviruses in the genome of brown Leghorn chickens].

Genetic differences and differences in localization of endogenous proviruses in chicken genomes were found in studies on endogenous provirus sequences in DNA of white and brown Leghorn chickens. In brown Leghorn DNA, proviruses both similar with Raus-associated virus (endogenous virus of white Leghorns) and differing from it in the pattern of hydrolysis by EcoRI restricting endonuclease were found, the latter occurring more frequently. Different sets of variously localized proviruses were found in DNA of individual chickens; none of the proviruses was found in DNA of all brown Leghorns examined. No single provirus common for chickens of the two species was found. The genetic diversity of endogenous proviruses observed in brown Leghorns indicates the possibility of coexistence in the chicken DNA of message on several significantly different endogenous viruses.

Animals↗
PubMed1996

The LTR, v-src, LTR provirus in H-19 hamster tumor cell line is integrated adjacent to the negative regulatory region.

The tumor hamster cell line H-19 harbors a single copy LTR, v-src, LTR provirus that becomes permanently transcriptionally suppressed in morphological revertants segregating at high rate from this cell line. Our previous data document that the provirus suppression is mediated by epigenetic cell-regulatory mechanisms. In this report, we concentrate on cellular sequences neighboring the integration site. The locus is unique for Syrian hamster and is not detectable in DNA of several animal species. No restriction sites that usually hint at the presence of CpG islands were found in the significantly close vicinity of the provirus. Nevertheless, the chromosomal DNA flanking the provirus is rich in GC content (57.8%). We localized a 0.5-kb region downstream from the provirus that remarkably inhibits transcription in the transient expression assay and is effective both on the homologous RSV LTR promoter/enhancer and heterologous SV40 promoter. We propose that a cellular trans-acting factor is involved in the silencing of the reporter gene. Since this activity is comparable both in transformed and revertant cells, we speculate that this down-regulatory region makes the permissive integration locus prone to provirus silencing initiated by other fluctuating stimuli.

Animals↗
PubMed1990

Nucleotide sequence analysis of a provirus derived from an individual with tropical spastic paraparesis.

Human T-cell lymphotropic virus type 1 (HTLV-1), the cause of inapparent infections and T-cell leukemias and lymphomas, has also been implicated in two chronic neurological diseases, tropical spastic paraparesis (TSP) and HTLV-1 associated myelopathy (HAM). We initiated a search for a neurotropic variant of HTLV-1 that might be responsible for these chronic progressive myelopathies by cloning and sequencing a provirus from a T-cell line from an individual with TSP. The LTRs and genes of the TSP provirus differ from HTLV-1 by 20-30 nucleotides in each region, but none of the substitutions ostensibly affect functional sites with the exception of the env gene. We document one substitution in the region encoding gp46 common to TSP and HAM proviruses and a mutation that introduces two stop codons in the region encoding gp21. The latter should delete about 100 amino acids from the transmembrane anchor, and, for this reason, the progeny of the sequenced provirus are likely to be defective viruses, maintained in the culture through coinfection of cells with wild-type non-defective HTLV-1. While defective viruses could be responsible for persistent infection of the nervous system in TSP, this cannot be generally the case as we show that HTLV-1 DNA amplified from cell lines from two other individuals with TSP lacked the stop codons. Similarly, comparisons of DNA amplified from HTLV-1 DNA in cases of ATL, HAM, and TSP did not establish a correlation between the mutation in gp46 and neurological disease. The issue of neurotropic variants in HTLV-1 associated neurological disease thus remains an open one which may be resolved in the future by examining proviruses in cells in the lesions in the nervous system; or proviruses in ATL and HAM/TSP which differ in their ability to replicate in glial or neuronal cells.

Amino Acid Sequence↗
PubMed2000

Retroviruses in foreign species and the problem of provirus silencing.

Retroviruses are known to integrate in the host cell genome as proviruses, and therefore they are prone to cell-mediated control at the transcriptional and posttranscriptional levels. This plays an important role especially after retrovirus heterotransmission to foreign species, but also to differentiated cells. In addition to host cell-mediated blocks in provirus expression, also so far undefined host specificities, deciding upon the pathogenic manifestation of retrovirus heterotransmission, are in play. In this respect, we discuss especially the occurrence of wasting disease and immunodeficiency syndrome, which we established also in avian species using avian leukosis virus subgroup C (ALV-C) inoculated in mid-embryogenesis in duck or chicken embryos. The problem of provirus downregulation in foreign species or in differentiated cells has been in the recent years approached experimentally. From a series of observations it became apparent that provirus downregulation is mediated by its methylation, especially in the region of proviral enhancer-promoter located in long terminal repeats (LTR). Several strategies have been devised in order to protect the provirus from methylation using LTR modification and/or introducing in the LTR sequence motifs acting as antimethylation tags. In such a way the expression of retroviruses and vectors in foreign species, as well as in differentiated cells, has been significantly improved. The complexity of the mechanisms involved in provirus downregulation and further possibilities to modulate it are discussed.

Animals↗
PubMed1988

Even transcriptionally competent proviruses are silent in bovine leukemia virus-induced sheep tumor cells.

To investigate the role of proviral integration and expression in cellular transformation induced by bovine leukemia virus (BLV), three BLV-induced tumors harboring a single proviral copy were selected upon restriction and hybridization analysis. Tumors 344 and 395 were shown to contain a full-size proviral copy, whereas in tumor 1345 the provirus appeared to be heavily deleted. RNA gel blot hybridization with an antisense RNA probe showed no transcription of the viral sequences in the fresh tumors or in sheep tumor cells growing in vitro. The proviruses were cloned and transfected in mammalian cell lines. Transient-expression experiments revealed that the complete proviruses were still able to express the trans-activating protein (Tat) as well as structural proteins, demonstrating that the nonexpression of a provirus in a tumor cell does not necessarily imply a structural alteration of the viral information. In contrast, sequence analysis of the provirus with a large deletion and transient-expression assays proved that this truncated provirus, isolated from a tumor, was unable to code for viral proteins. These data indicate that expression of viral genes, including tat, is not required for the maintenance of the transformed state.

Animals↗
PubMed1988

Construction of a clonable, infectious, and tumorigenic mouse mammary tumor virus provirus and a derivative genetic vector.

Molecular genetic studies of mouse mammary tumor virus (MMTV) have been hampered by the difficulty of cloning proviruses of milk-borne strains because of inhibitory sequences located in the gag gene. To surmount this barrier we have constructed a hybrid MMTV provirus composed of clonable 5' sequences (encompassing gag) from an endogenous MMTV provirus of C3H mice (Mtv-1) and 3' sequences from the milk-borne strain of MMTV in C3H mice, MMTV(C3H). Virions produced from XC cells transfected with this hybrid provirus are infectious in cell culture and tumorigenic in BALB/cJ mice. A vector derived from this provirus, containing the neomycin phosphotransferase gene (neo) and origins of replication from simian virus 40 and pBR322, is capable of transferring G418 resistance by virus infection in cell culture when supplied with viral proteins from either MMTV(C3H) or the hybrid MMTV. Expression of both hybrid and vector proviruses is inducible by dexamethasone in infected cells.

Animals↗
PubMed1991

Inhibition by interferon of herpes simplex virus type 1-activated transcription of tat-defective provirus.

The herpes simplex virus type 1 (HSV-1)-mediated transactivation of human immunodeficiency virus type 1 (HIV-1) provirus was studied in cell lines containing either integrated tat-defective HIV-1 provirus (HNHIVdt4 cells) or the tat-defective HIV-1 provirus, and a plasmid in which the expression of human alpha 2 interferon (HuIFN-alpha 2) was under the control of the HIV-1 long terminal repeat (LTR) (HNHIV alpha 1 cells). In both cell lines, transcription of the HIV-1 provirus was below the limits of detection, but it could be induced effectively by transfection with a HIV-1 tat-expression plasmid. In HNHIV alpha 1 cells, HuIFN-alpha 2 was induced concomitantly with HIV-1 provirus, although these cells synthesized only low levels of IFN constitutively. In contrast, infections with HSV-1 activated transcription of HIV-1 provirus only in HNHIVdt4 cells but not in HNHIV alpha 1 cells. Similarly in a transient expression assay, HSV-1 up-regulated expression of a HIV LTR-CAT (chloramphenicol acetyltransferase gene) plasmid in HNHIVdt4 but not in HNHIV alpha 1 cells. No major differences could be detected in the expression of HSV-1 immediate-early (IE) genes IE175 and IE110 (which are essential for the activation of HIV-1 LTR) in HNHIVdt4 and HNHIV alpha 1 cells to account for the inability of HSV-1 to induce HIV-1 in HNHIV alpha 1 cells. However, major differences were observed in the binding pattern of NF-kappa B-specific nuclear proteins to the enhancer region of the HIV-1 LTR: whereas binding of the 45-kDa NF-kappa B-specific nuclear protein was detected in nuclear extracts from HNHIVdt4 cells, no protein binding was seen in extracts from HNHIV alpha 1 cells. These results suggest an alternate mechanism by which IFN may alter the expression of cellular and viral genes.

Cells, Cultured↗
PubMed1990

Activation of multiple genes by provirus integration in the Mlvi-4 locus in T-cell lymphomas induced by Moloney murine leukemia virus.

Moloney murine leukemia virus-induced rat T-cell lymphomas harbor proviruses integrated near c-myc and near Mlvi-1/Mis-1/Pvt-1, another locus of common integration which maps 270 kilobases 3' of c-myc. In this report, we present the characterization of a new locus of common integration in Moloney murine leukemia virus-induced T-cell lymphomas (Mlvi-4) which maps 30 kilobases 3' of c-myc, between c-myc and Mlvi-1. The Mlvi-4 locus, whose chromosomal map location is conserved in rats, mice, and humans, is also the target of chromosomal rearrangements in a variety of animal and human tumors. Evidence presented elsewhere shows that provirus integration in Mlvi-4 enhances the expression of c-myc and Mlvi-1 by cis-acting mechanisms operating over long distances of genomic DNA. In this manuscript, we show that provirus integration in the Mlvi-4 locus activates, by promoter insertion, one additional gene which maps immediately 3' to the cluster of the Mlvi-4 proviruses and which is transcribed in the same orientation as c-myc, giving rise to 3- and 10-kilobase mRNA transcripts. The Mlvi-4 gene is also expressed in normal thymus and spleen at very low levels, giving rise to 3- and 5.5-kilobase messages. Although Mlvi-4 is expressed in normal thymus, it is not expressed in Moloney murine leukemia virus-induced T-cell lymphomas corresponding to several stages of T-cell differentiation, but lacking a provirus in this locus. This suggests that Mlvi-4 may be expressed only in a subpopulation of T cells. We conclude that provirus insertion in Mlvi-4 activates c-myc and two additional genes, Mlvi-1 and Mlvi-4, whose expression is restricted to, and may be developmentally regulated in, T cells. Since Mlvi-4 is the target of genetic changes in a great variety of human and animal neoplasms, these results are critical for our understanding of oncogenesis.

Animals↗
PubMed1993

Long-range mapping of Mis-2, a common provirus integration site identified in murine leukemia virus-induced thymomas and located 160 kilobase pairs downstream of Myb.

The nondefective Moloney murine leukemia virus (MuLV) induces clonal or oligoclonal T-cell tumors in mice or rats. The proviruses of these nondefective MuLVs have been shown to act as insertion mutagens most frequently activating an adjacent cellular gene involved in cell growth control. Mutations by provirus insertions, recognized as common provirus integration sites, have been instrumental in identifying novel cellular genes involved in tumor formation. We have searched for new common provirus integration sites in Moloney MuLV-induced thymomas. Using cellular sequences flanking a provirus cloned from one of these tumors, we found one region, designated Mis-2, which was the target of provirus integration in a low (3%) percentage of these tumors. Mis-2 was mapped on mouse chromosome 10, approximately 160 kbp downstream of myb. The Mis-2 region may contain a novel gene involved in tumor development.

Animals↗