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At least 109 records · Page 6Linked to original sources
PubMed1999

Prenatal transmission and pathogenicity of endogenous ecotropic murine leukemia virus Akv.

OBJECTIVE: Mouse strains carrying endogenous ecotropic murine leukemia viruses (MuLV) are capable of expressing infective virus throughout life. Risk of transplacental transmission of MuLV raises concerns of embryo infection and induction of pathogenic effects, and postnatal MuLV infection may lead to tumorigenesis. METHODS: Endogenous ecotropic MuLV-negative SWR/J embryos were implanted into Akv-infected viremic SWR/J mice, into spontaneously provirus-expressing AKR/J mice, and into noninfected SWR/J control mice; virus integration and virus expression were investigated at 14 days' gestation. Tumor development was monitored over 18 months. RESULTS: Of 111 embryos, 20 (18%) recovered from Akv-infected SWR/J mice, which had developed normally, were infected. New proviruses were detected in 10 of 111 (9%) embryos from Akv-infected SWR/J mice, and in 2 of 60 (3%) embryos from AKR/J mice; none expressed viral protein. Of 127 embryos recovered from Akv-infected SWR/J mice, 16 (13%) were dead; 4 of 5 (80%) were infected and expressed viral protein. Of 71 embryos from AKR/J mice, 11 (15%) were dead, and 2 of 2 had virus integration; virus expression was not detected. Numbers of dead embryos recovered from experimentally infected, viremic SWR/J mice and from spontaneously endogenous MuLV-expressing AKR/J mice were significantly higher, compared with numbers from nonviremic SWR/J control mice, and embryo lethality was significantly associated with prenatal provirus expression. Postnatal inoculation of Akv induced lymphoblastic lymphomas in 15 of 24 (61%) SWR/J mice within mean +/- SD latency of 14 +/- 2.4 months. Only 3 of 39 (8%) control mice developed lymphomas (P < 0.005). CONCLUSION: Embryos in MuLV-viremic dams are readily infected, and inappropriate prenatal expression of leukemogenic endogenous retroviruses may play a critical role in embryo lethality and decreased breeding performance in ecotropic provirus-positive mouse strains.

AKR murine leukemia virus↗
PubMed1997

Field and vaccine strains of fowlpox virus carry integrated sequences from the avian retrovirus, reticuloendotheliosis virus.

For baculoviruses and herpesviruses, integration of transposons or retroviruses into the virus genome has been documented. We report here that field and vaccine strains of fowlpox virus (FPV) carry integrated sequences from the avian retrovirus, reticuloendotheliosis virus (REV). Using PCR and hybridization analysis we observed that vaccine and field strains of FPV carry REV sequences integrated into a previously uncharacterized region of the right 1/3 of the FPV genome. Long-range PCR, hybridization, and nucleotide sequence determination demonstrated that one vaccine strain (FPV S) and recently isolated field strains carry a near-full-length REV provirus. For another vaccine strain (FPV M) a rearranged remnant of the LTR was found at the same insertion site. By Western blotting and reverse transcriptase assays we were unable to demonstrate free REV in supernatants of FPV S cultures. The near-full-length REV provirus integrated into the FPV genome is infectious since FPV S DNA gave rise to REV upon transfection into chicken embryo fibroblasts. Upon infection of chickens with FPV S, all chickens developed high-titered antibodies to REV, and REV was isolated from the blood of half of the inoculated chickens. Our observations add to the list of targets for retrovirus integration into DNA virus genomes. The integration of a near-full-length, and apparently infectious, REV provirus into FPV provides additional transmission routes for the retrovirus by way of the infectious cycle of FPV, including the possibility of mechanical transmission by biting insects since FPV is believed to be transmitted by this route. For large DNA viruses, including the poxviruses, retrovirus integration with attendant possibilities of gene transduction may be an important mechanism for virus evolution, including the acquisition of cellular genes with the potential to modify virus virulence and pathogenicity.

Animals↗
PubMed2003

Hepatocellular carcinoma and hepatitis virus.

Integrated hepatitis B virus (HBV) DNA is present in many hepatocellular carcinomas (HCC), suggesting that HBV has a direct oncogenic effect through interaction with transformation-associated genes. Many genes involved in cell cycle regulation (cyclins, kinases, negative regulators, Wnt-beta-catenin) and the transcriptome profile are deregulated or altered in most HCC patients. The HBx protein, potentially oncogenic via multistep carcinogenesis, modifies apoptosis, inhibits nucleotide excision and repair of damaged cellular DNA, and modulates transcriptional activation of cellular growth regulating genes. Hepatocyte transformation may be indirectly influenced by HBV DNA integration, by the generation of mutagenic oxygen reactive species, or by acquisition of mutations in association with necroinflammatory disease. HBV replication, which may occur in HCC, affects the long-term survival of patients. Prevention of HBV infection is expected to decrease the incidence of endemic HCC.

Carcinoma, Hepatocellular↗
PubMed1987

The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma.

Nineteen DNA samples that carry integrated hepatitis B virus (HBV) DNA were isolated from seven independent human hepatomas by molecular cloning, and their structures were determined. The results, combined with reported data, were analyzed so that one can obtain insights into the mechanisms of integration of this virus DNA and possible rearrangements that occur subsequently. The distribution of DNA junctions along the virus genome suggests that there are recombination-proficient regions. Thus, about half of the integrants were the Coh type, viz., one of their virus-cell DNA junctions fell within the so-called cohesive end region that lies between two 11-bp direct repeats (DR1 and DR2) in the virus genome where transcription and replication of the genome are initiated. All the integrated virus genomes were defective at least in one site around the cohesive end region, particularly within the X gene. The recombination-proficient regions are used not only for formation of virus-cell but also of virus-virus junctions. Neither virus nor cell DNA show unique sequences at the junctions, and targets for integration lie on many different chromosomes.

Base Sequence↗
PubMed1978

Integration of Epstein-Barr virus DNA.

The application to herpesviruses of different standard methods fo measuring tumour-virus integration is discussed. The evidence for the presence of integrated virus DNA in EBV-transformed cells is summarized.

Cell Transformation, Neoplastic↗
PubMed1982

Structural and biological analysis of integrated polyoma virus DNA and its adjacent host sequences cloned from transformed rat cells.

EcoRI fragments containing integrated viral and adjacent host sequences were cloned from two polyoma virus-transformed cell lines (7axT and 7axB) which each contain a single insert of polyoma virus DNA. Cloned DNA fragments which contained a complete coding capacity for the polyoma virus middle and small T-antigens were capable of transforming rat cells in vitro. Analysis of the flanking sequences indicated that rat DNA had been reorganized or deleted at the sites of polyoma virus integration, but none of the hallmarks of retroviral integration, such as the duplication of host DNA, were apparent. There was no obvious similarity of DNA sequences in the four virus-host joins. In one case the virus-host junction sequence predicted the virus-host fusion protein which was detected in the transformed cell line. DNA homologous to the flanking sequences of three out of four of the joins was present in single copy in untransformed cells. One copy of the flanking host sequences existed in an unaltered form in the two transformed cell lines, indicating that a haploid copy of the viral transforming sequences is sufficient to maintain transformation. The flanking sequences from one cell line were further used as a probe to isolate a target site (unoccupied site) for polyoma virus integration from uninfected cellular DNA. The restriction map of this DNA was in agreement with that of the flanking sequences, but the sequence of the unoccupied site indicated that viral integration did not involve a simple recombination event between viral and cellular sequences. Instead, sequence rearrangements or alterations occurred immediately adjacent to the viral insert, possibly as a consequence of the integration of viral DNA.

Animals↗
PubMed1990

A comparison of the molecular structure of integrated hepatitis B virus genomes in hepatocellular carcinoma cells and hepatocytes derived from the same patient.

To elucidate critical genetic elements in the development of hepatocellular carcinoma associated with hepatitis B virus DNA integration, a single integrant in hepatocellular carcinoma cells and one species of multiple integrants in hepatocytes, both obtained from the same patient, were compared structurally using molecular cloning techniques. Both hepatitis B virus integrants showed similar inverted repeat sequences consisting of two defective virus genomes. The recombination of viral DNAs seemed to be mediated by short regions of base homology near the direct repeat 1 and at other regions of the virus genomes in both integrants. The virus component in the junction with host DNAs was the cohesive end region in each identical end of the viral integrant in hepatocellular carcinoma cells and in one end of the viral integrant in hepatocytes. The structure of the integrant in hepatocellular carcinoma cells was characterized by an inverted, duplicated conformation composed not only of integrated virus genomes but also of flanking cellular sequences. It was shown to be the so-called "alpha dimer" of satellite DNA. In contrast, the flanking, nonreiterated cellular DNA in the hepatocyte-derived clone did not show discernible rearrangement. These findings suggest that a common mechanism underlies the integration of hepatitis B virus DNA so that a similar organization of inverted repeat genomes is found in hepatocellular carcinoma cells and in hepatocytes. The unstable nature of cellular DNA where DNA integration occurs may be important in generating chromosome alterations found in hepatocellular carcinoma.

Adult↗
PubMed1975

Simian virus 40 integration sites in the genome of virus-transformed mouse cells.

To gain information on the specificity of simian virus 40 (SV40) integration in the genome of transformed cells, mouse 3T3 cells were transformed by a temperature-sensitive (ts) SV40 mutant, using high multiplicity of infection (MOI). Transformed cells were superinfected with wild-type (wt) virus at high MOI. Clones were isolated and fused with permissive BSC-1 cells to promote virus rescue. All rescued viruses were of the ts type only. When the high-MOI transformants were infected with 3H-labeled wt SV40, the amount of radioactivity associated with their nuclear fraction was found to be similar to that of 3T3 cells. 3T3 cells were then transformed by ts SV40 at low MOI and superinfected by wt virus at high MOI. Upon fusion with BSC-1 cells, most clones produced both ts and wt virus. These results suggest that the number of stable SV40 integration sites in the 3T3 genome is limited, since they can be saturated by transformation at high MOI. When the MOI is low, the sites are not saturated and a subsequent infection can lead to integration.

Cell Fusion↗
PubMed1991

Chronic myeloproliferative disease induced by site-specific integration of Abelson murine leukemia virus-infected hemopoietic stem cells.

We recently showed that hemopoietic stem cells expressing the v-abl oncogene can cause leukemia when injected into lethally irradiated recipient mice. Progenitor cells expressing v-abl did not significantly contribute to disease development, and the leukemia was monoclonal in origin. By serially transplanting v-abl-transduced hemopoietic stem cells into normal, nonirradiated syngeneic recipients, we showed that multiple stem-cell clones do exist in some recipients. These cells fluctuated as normal stem cells do and could home to normal bone marrow. Based on the time course of disease, the recipients developed either an acute or a chronic phase of disorder. All recipients with the acute disease had stem-cell clones with random Abelson murine leukemia virus integration sites. All recipients with the chronic disorder had a specific Abelson murine leukemia virus integration site. We believe this abl-specific integration site, termed ASI, is important in abl-mediated stem-cell leukemogenesis.

Abelson murine leukemia virus↗
PubMed2002

Chromosomal effects of adeno-associated virus vector integration.

Adeno-associated virus (AAV) vectors are currently being used in several clinical gene-therapy trials (see the NIH OBA Human Gene Transfer Clinical Trials Database); however, little is known about the chromosomal effects of vector integration. Here we report that integrated vector proviruses are associated with chromosomal deletions and other rearrangements and are frequently located on chromosome 19 (although not at the wildtype AAV integration site).

Base Sequence↗
PubMed1990

Preferential integration of the Ad5/SV40 hybrid virus at the highly recombinogenic human chromosomal site 1p36.

Human fibroblasts transformed with an adenovirus-5/simian virus 40 recombinant construct (Ad5/SV40) were analyzed to determine the chromosomal site(s) of virus integration. This was firstly done by in situ hybridization using metaphase and prometaphase chromosomes and 125I-labeled Ad5 DNA. Out of seven transformed cell lines (six of clonal origin and one uncloned), six were proven to have integrated the viral genome at the short- or the long-subtelomeric regions of autosome 1, two regions known to include chromosomal modification sites induced by acute infection with Ad12. Characterization of the integration sites was carried out by restriction analysis. Transformed cell lines with the same major chromosomal integration site were found to have the viral genome inserted in restriction fragments of different size, indicating that viral integration has occurred at different sites within a relatively small chromosomal region. Molecular studies carried out on one of the transformed cell lines (H13.1) gave an independent confirmation of the viral integration at the subterminal region of autosome 1 short arm. Nucleotide sequencing at this cellular-viral junction has shown that the virus has integrated within tandemly repeated Alu-like elements and that the cellular flanking sequences have several homologies with variable number of tandem repeats core sequences. Many possible open reading frames were identified in the DNA segment adjacent to the Alu-like elements.

Adenoviruses, Human↗
PubMed1992

Stimulation of polydnavirus replication by 20-hydroxyecdysone.

During oviposition the endoparasitic wasp Campoletis sonorensis, introduces a polydnavirus into parasitized insects where viral gene expression is required for endoparasite survival. The polydnavirus is integrated into wasp chromosomal DNA and replicates only in the ovary. Ecdysteroids regulate the developmental expression of many insect genes and may regulate polydnavirus replication. Direct verification of viral replication was performed by dot blot hybridization and by amplifying DNA sequences containing the viral integration site; this 'junction' fragment cannot be amplified from integrated virus. Thoracic ligations and in vitro ecdysteroid treatments of wasp ovaries support the hypothesis that polydnavirus DNA replication is regulated by ecdysteroid during parasite development.

Animals↗
PubMed2001

A quantitative assay for HIV DNA integration in vivo.

Early steps of infection by HIV-1 involve entry of the viral core into cells, reverse transcription to form the linear viral DNA, and integration of that DNA into a chromosome of the host. The unintegrated DNA can also follow non-productive pathways, in which it is circularized by recombination between DNA long-terminal repeats (LTRs), circularized by ligation of the DNA ends or degraded. Here we report quantitative methods that monitor formation of reverse transcription products, two-LTR circles and integrated proviruses. The integration assay employs a novel quantitative form of Alu-PCR that should be generally applicable to studies of integrating viruses and gene transfer vectors.

Anti-HIV Agents↗
PubMed1989

[Hepatitis B virus: DNA integration and hepatocellular carcinoma].

Hepatitis B Virus DNA integrates into host cell DNA upon infection. Analyses of early integrants have revealed that the origin of DNA synthesis in the viral genome plays a major role in the integration process. In liver cancers many of the integrants are found in different structures, suggesting that the primary integrants must have undergone secondary rearrangements. Such rearrangements include large deletions, translocations, inversions, and local amplifications. The mechanism that leads to these rearrangements are inferred, and their role in development of hepatocellular carcinomas is discussed.

Animals↗
PubMed2003

Detection of specific reticuloendotheliosis virus sequence and protein from REV-integrated fowlpox virus strains.

The detection is described of reticuloendotheliosis virus (REV) protein in tissue culture of chicken embryonated cells (CEFs) infected with field isolates of fowl poxvirus (FPV). By the polymerase chain reaction (PCR), five out of the six field isolates, but two out of the seven vaccine strains of FPV, were found to have had a 291 bp repeat sequence of REV-LTR integrated in their genomic DNA. An immunofluorescence (IF) method was employed using a monoclonal antibody (MAb) known to specify strain common envelope proteins for REV and allowed to detect the presence of a specific REV protein. The IF results indicate the localization of REV proteins in boundaries defined precisely within cells infected with these field strains of FPV carrying REV (FPV-REV). Furthermore, by immunoblotting (IB) using a chemiluminescent detection kit, the REV protein reacted specifically with the MAb and had a relative molecular mass (RMM) of 62 kDa. The data have the potential to advance substantially the current understanding of the integrated REV in FPV strains; and the identification of a unique protein associated with variant forms of FPV will also offer great potential for identification of novel vaccine candidates for use in poultry against variant forms of FPV.

Animals↗
PubMed2005

Radiation leukemia virus common integration at the Kis2 locus: simultaneous overexpression of a novel noncoding RNA and of the proximal Phf6 gene.

Retroviral tagging has been used extensively and successfully to identify genes implicated in cancer pathways. In order to find oncogenes implicated in T-cell leukemia, we used the highly leukemogenic radiation leukemia retrovirus VL3 (RadLV/VL3). We applied the inverted PCR technique to isolate and analyze sequences flanking proviral integrations in RadLV/VL3-induced T lymphomas. We found retroviral integrations in c-myc and Pim1 as already reported but we also identified for the first time Notch1 as a RadLV common integration site. More interestingly, we found a new RadLV common integration site that is situated on mouse chromosome X (XA4 region, bp 45091000). This site has also been reported as an SL3-3 and Moloney murine leukemia virus integration site, which strengthens its implication in murine leukemia virus-induced T lymphomas. This locus, named Kis2 (Kaplan Integration Site 2), was found rearranged in 11% of the tumors analyzed. In this article, we report not only the alteration of the Kis2 gene located nearby in response to RadLV integration but also the induction of the expression of Phf6, situated about 250 kbp from the integration site. The Kis2 gene encodes five different alternatively spliced noncoding RNAs and the Phf6 gene codes for a 365-amino-acid protein which contains two plant homology domain fingers, recently implicated in the Börjeson-Forssman-Lehmann syndrome in humans. With the recent release of the mouse genome sequence, high-throughput retroviral tagging emerges as a powerful tool in the quest for oncogenes. It also allows the analysis of large DNA regions surrounding the integration locus.

Amino Acid Sequence↗
PubMed1971

Simian virus 40 integration site in an adenovirus 7-simian virus 40 hybrid DNA molecule.

The E46(+) strain of Adenovirus 7 is a mixed-virus population containing defective Adenoviurs 7-SV40 hybrid particles and helper, nonhybrid Adenovirus 7 particles. We have applied electron microscopic mapping techniques to obtain a physical map of the genome of the hybrid particles present in E46(+)PL1, a substrain of E46(+) derived from a single two-hit plaque. DNA molecules extracted from purified E46(+)Pl1 virions were found to be linear duplexes, with a mean lenght of 10.9 mum. When these molecules were denatured and renatured, a unique heteroduplex was formed that presumably derived one of its strands from an Adenovirus 7-SV40 hybrid molecule and the other from a nonhybrid Adenovirus 7 molecule. This heteroduplex was double-stranded, except for a short region near one end where the two strands were not paired. On the basis of measurements of the lengths of the single-and double-stranded regions in the heteroduplex, the structure of the Adenovirus 7-SV40 hybrid genome can be reconstructed as follows: The hybrid genome contains 16% less Adenovirus 7 DNA than the nonhybrid Adenovirus 7 genome. This deletion consists of the segment of DNA that maps between 0.05 and 0.21 molecular lenghts in the nonhybrid Adenovirus 7 DNA molecule. The deleted DNA has been partially replaced by an amount of heterologous DNA equivalent to 75% of the complete SV40 genome. A model for the generation of the hybrid genome is presented.

Adenoviridae↗