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At least 1,297 records · Page 72Linked to original sources
PubMed1999

Resistance to avian leukosis virus lymphomagenesis occurs subsequent to proviral c-myc integration.

Most chicken strains are highly susceptible to avian leukosis virus (ALV) induction of bursal lymphoma, involving proviral integration within the c-myc proto-oncogene, while certain strains are genetically resistant to lymphomagenesis. A nested PCR assay was developed to analyse the appearance of proviral c-myc integrations after ALV infection of lymphoma-susceptible birds, and to determine whether these integrations arise in lymphoma-resistant birds. Proviral c-myc integrations are detected in bursa and other tissues from 6 day-old lymphoma-susceptible birds infected as embryos. The abundance of bursal cells carrying these integrations increases roughly 40-fold by 35 days of age, indicating that these cells hyperproliferate within the bursal environment. Bursal cells with proviral c-myc integrations also arise soon after infection of lymphoma-resistant embryos. However, these cells expand much more slowly than cells from lymphoma-susceptible birds. Both strains show the same rate of viral infection, so that resistance to lymphomagenesis occurs at a step subsequent to proviral c-myc integration. Proviral c-erbB gene integrations arise at the same frequency in bursa and other tissues of both strains, and they do not increase in abundance during development. These findings indicate that the mechanism of resistance to lymphomagenesis involves specific inhibition of cells with proviral c-myc integrations within the bursa.

Animals↗
PubMed2004

Tumorigenesis by adenovirus type 12 in newborn Syrian hamsters.

Ad12 oncogenesis in hamsters has been studied in detail to provide the following new data in this tumor model. Cells in the Ad12-induced tumors, often thought to be of neuronal origin, actually exhibit mesenchymal and neuronal characteristics and are probably of an undifferentiated derivation. Their intraperitoneal spread upon intramuscular injection of Ad12 adds another important new aspect. Differences in the integration patterns among the tumors suggest clonal origins from individual transformation events. Ad12 gene expression in the tumors is determined, at least in part, by the patterns of DNA methylation imprinted de novo upon the integrated Ad12 genomes. Differential Ad12 gene expression patterns, which have previously not been described in tumors, are an important parameter in Ad12 oncogenesis. The availability of cellular DNA arrays has opened up unprecedented possibilities to document changes in cellular transcription patterns, particularly of cancer-specific genes. These patterns exhibit differences and similarities among the different Ad12-induced tumors. Among the cellular genes, which are expressed in the Ad12-induced tumors, many are cancer-specific. We pursue the hypothesis that these alterations in cellular transcription patterns as a consequence of viral DNA integration and expression play an essential role in Ad12 oncogenesis.

Adenoviruses, Human↗
PubMed1995

Site-specific integration of the phage phi CTX genome into the Pseudomonas aeruginosa chromosome: characterization of the functional integrase gene located close to and upstream of attP.

The site-specific integration of the phage phi CTX genome, which carries the gene for a pore-forming cytotoxin, into the Pseudomonas aeruginosa chromosome was analysed. The 1,167 bp integrase gene, int, located immediately upstream of the attachment site, attP, was characterized using plasmid constructs, harbouring the integration functions, and serving as an integration probe in both P. aeruginosa and Escherichia coli. The attP plasmids p1000/p400 in the presence of the int plasmid pIBH and attP-int plasmids pINT/pINTS can be stably integrated into the P. aeruginosa chromosome. Successful recombination between the attP plasmid p1000 and the attB plasmid p5.1, in the presence of the int plasmid pIBH in E. coli HB101 showed that the int gene is active in trans in E. coli. The int gene product was detected as a 43 kDa protein in E. coli maxicells harbouring pINT. Proposed integration arm regions downstream of attP are not necessary for the integration process. pINT and phage phi CTX could be integrated together into P. aeruginosa chromosomal DNA, yielding double integrates.

Attachment Sites, Microbiological↗
PubMed2002

In search of authentic inhibitors of HIV-1 integration.

Current strategies for the treatment of HIV infection are based on cocktails of drugs that target the viral reverse transcriptase or protease enzymes. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalysed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy, so far all research efforts have led to the identification of only one series of compounds that selectively inhibit the integration step during HIV replication, namely the diketo acids. In this review we try to address the question why it has proven so difficult to find potent and selective integrase inhibitors. We point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor, and propose new strategies and technologies for the discovery of authentic HIV integration inhibitors.

Anti-HIV Agents↗
PubMed2004

The leukemogenic risk of integrating retroviral vectors in hematopoietic stem cell gene therapy applications.

Hematopoietic stem cell gene transfer using integrating vectors has been actively investigated for more than two decades as a prospective treatment for several congenital and acquired human diseases, and retroviral vectors encoding potentially therapeutic genes have been the most rigorously pursued. Early trials in humans testing retroviral vectors in several clinical settings supported the safety of this approach, and recent studies have demonstrated remarkable efficacy in children with severe combined immunodeficiency. The anticipated success established the therapeutic potential of hematopoietic stem cell gene transfer, but the subsequent development of leukemia in two treated children has re-emphasized the risks related to gene therapy. In this review, we describe this complication, discuss the leukemogenic risk of integrating retroviral vectors, and propose strategies to decrease the likelihood of its occurrence.

Animals↗
PubMed1977

State of the viral DNA in rat cells transformed by polyma virus. II. Identification of the cells containing nonintegrated viral DNA and the effect of viral mutations.

F2408 rat cells transformed by polyoma virus contained integrated and nonintegrated viral DNA. The presence of nonintegrated viral DNA is under control of the A early viral function. Polyoma ts-a-transformed rat cells lose the free viral DNA when growth at the nonpermissive temperature (40 degrees C), but they reexpress it 1 to 3 days after they are shifted back to the permissive temperature. In contrast, rat cells transformed by a late viral mutant, ts-8, contain free viral DNA at both permissive and nonpermissive temperatures. Treatment of the transformed rat cells with mitomycin C produces a large increase in the quantity of free viral DNA and some production of infectious virus. Experiments of in situ hybridization, with 3H-labeled polyoma complementary RNA as a probe, show that only a minority (approximately 0.1%) of the transformed cells contain nonintegrated viral DNA at any given time. These results suggest that the presence of free viral DNA in polyoma-transformed rat cells is caused by a spontaneous induction of viral DNA replication, occurring with low but constant probability in the transformed cell population, and that the free viral DNA molecules originate from the integrated ones, probably through a phenomenon of excision and limited replication.

Animals↗
PubMed1998

The barrier-to-autointegration protein is a host factor for HIV type 1 integration.

In vivo, retroviral integration is mediated by a large nucleoprotein complex, termed the preintegration complex (PIC). PICs isolated from infected cells display in vitro integration activity. Here, we analyze the roles of different host cell factors in the structure and function of HIV type 1 (HIV-1) PICs. PICs purified by size exclusion after treatment with high salt lost their integration activity, and adding back an extract from uninfected cells restored this activity. In parallel, the native protein-DNA intasome structure detected at the ends of HIV-1 by Mu-mediated PCR footprinting was abolished by high salt and restored by the crude cell extract. Various purified proteins previously implicated in retroviral PIC function then were analyzed for their effects on the structure and function of salt-treated HIV-1 PICs. Whereas relatively low amounts (5-20 nM) of human barrier-to-autointegration factor (BAF) protein restored integration activity, substantially more (5-10 microM) human host factor HMG I(Y) was required. Similarly high levels (3-8 microM) of bovine RNase A, a DNA-binding protein used as a nonspecific control, also restored activity. Mu-mediated PCR footprinting revealed that of these three purified proteins, only BAF restored the native structure of the HIV-1 protein-DNA intasome. We suggest that BAF is a natural host cofactor for HIV-1 integration.

Animals↗
PubMed2005

[Molecular mechanism of the integration and lysis of mycobacteriophage].

Tuberculosis remains one of the major threats to public health. China is one of the heavy TB burden countries. Novel drugs and vaccines are urgently needed to combat the increasingly multidrug resistant TB. Mycobacteriophage is one of the hot topic in TB novel drugs discovery and drug susceptibility test. Phages can multiply via two alternative mechanisms: the lytic cycle or the lysogenic cycle. The lytic cycle ends with the lysis and death of the host cell, whereas the host cell remains alive in the lysogenic cycle. Lysogenic mycobacteriophages were intensively studied to elucidate the integration and lysis mechanisms of mycobacteriophage. The integration of mycobacteriophage requires for attP of bacteriopahge genome, attB of Mycobacterium genome, integrase and integration host factor. Some lysogenic phage, eg. mycobacteriophage Ms6, employ lytic cycle, form new phage, lysis host by the cooperation of lysin and holin, and release phages. There is no reports as to the mycobacteriophage unique to China clinical or environmental isolates. Studies on the integration and lysis molecular mechanism of mycobacteriophage might facilitate future new anti-TB drugs development.

Bacteriolysis↗
PubMed1995

Integration of glucoamylase gene from Aspergillus niger into Saccharomyces cerevisiae genome and its stable expression.

Starch digestible delta-integrants were constructed by integrative transformation of a linear YIP plasmid carrying Aspergillus niger glucoamylase cDNA under the control of the MF alpha 1 promoter and its prepro signal and the delta sequence of the Ty element from yeast. The integration of glucoamylase cDNA into Saccharomyces cerevisiae was identified by Southern analysis. The secreted glucoamylase activity of integrants in the medium with soluble starch as a carbon source reached 2.5 u/ml. After ten times of successive transfers in a nonselective medium, the activity of secreted glucoamylase of integrant was approximately at its original level.

Aspergillus niger↗
PubMed1983

Formation of oligomeric free BK virus DNA is required for tandem integration of viral genomes into cellular DNA.

Mouse kidney cells have been transformed by linear BK virus (BKV) DNA with cohesive ends. These BKV genomes can circularize and subsequently replicate or physically join end to end yielding oligomeric viral DNA molecules. Blot hybridization analysis of transformed cells showed the presence of BKV DNA both in free circular forms and integrated into cellular DNA in a tandem head-to-tail array of full-length viral genomes. Formation of oligomers either by replication via previous circularization or by end to end joining is hindered after elimination of cohesive termini by digestion with the single-strand-specific nuclease S1. After treatment of linear BKV DNA with nuclease S1 only integrations of single viral genomes were observed in transformed cells; tandem insertions and free viral DNA were absent. These results support the hypothesis that formation of tandems of free viral DNA is a necessary prerequisite for tandem integration of viral genomes.

Animals↗
PubMed2003

Chapter 7: Human papillomavirus and cancer of the upper aerodigestive tract.

We discuss current evidence of the role of human papillomavirus (HPV) in some cancers of the upper aerodigestive tract, including the oral cavity, the pharynx, and the larynx. Cancers of the oral cavity and the pharynx are associated mainly with tobacco and alcohol exposure, but there is evidence from case series, from case-control studies, and from cohort studies that HPV plays a role in a fraction of these cancers, particularly cancer in the oropharynx and tonsil. The HPV type most commonly associated with cancers in these locations is HPV 16. Laboratory evidence indicates that the virus is integrated and that HPV oncogenes are transcriptionally active in these tumors. Many aspects of the association remain to be investigated, including the epidemiology and natural history of HPV infection in the mouth, the role of cofactors, and the potential use of HPV testing and vaccines in the prevention of these tumors. An analogous role for the virus at other anatomic sites in the upper aerodigestive tract such as the larynx is less clear. The relationship between HPV infection and laryngeal cancer is of particular interest, given that recurrent respiratory papillomatosis is clearly caused by benign proliferative growths induced by HPV 6 or 11 infection of the laryngeal epithelium. Although HPV genomic DNA has been detected in a proportion of laryngeal cancers and despite the many efforts made during the last 15 years, there is not yet compelling evidence that HPV plays a substantial role in laryngeal cancer.

Confounding Factors, Epidemiologic↗
PubMed2003

[Human endogenous retroviruses and disease?].

Endogenous retroviruses represent sequences descended from ancient virus infections integrated in the host genome. They participate in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. It has been suggested in recent years that human endogenous retroviruses may play a role in certain types of cancer and autoimmune diseases. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases like systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple sclerosis is specifically associated with expression of human endogenous retroviruses as virions. It is not yet known if the human endogenous retroviruses also represent causal factors, but several pathogenic mechanisms are possible.

Arthritis, Rheumatoid↗
PubMed2002

Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat.

Repression of human immunodeficiency virus type 1 (HIV-1) transcription may contribute to the establishment or maintenance of proviral quiescence in infected CD4(+) cells. The host factors YY1 and LSF cooperatively recruit histone deacetylase 1 (HDAC1) to the HIV-1 long terminal repeat (LTR) and inhibit transcription. We demonstrate here regulation of occupancy of HDAC1 at a positioned nucleosome (nuc 1) near the transcription start site of integrated LTR. We find that expression of YY1 increases occupancy by HDAC1, decreases acetylation at nuc 1, and downregulates LTR expression. HDAC1 recruitment and histone hypoacetylation were also seen when Tat activation was inhibited by the overexpression of YY1. A YY1 mutant without an HDAC1 interaction domain and incompetent to inhibit LTR activation fails to recruit HDAC1 to LTR or decrease nuc 1 acetylation. Further, expression of a dominant-negative mutant of LSF (dnLSF), which inhibits LSF occupancy and LTR repression, results in acetylation and decreased HDAC1 occupancy at nuc 1. Conversely, exposure of cells to the histone deacetylase inhibitor trichostatin A or activation of LTR expression by HIV-1 Tat results in the displacement of HDAC1 from nuc 1, in association with increased acetylation of histone H4. Recruitment of HDAC1 to the LTR nuc 1 can counteract Tat activation and repress LTR expression. Significantly, when repression is overcome, LTR activation is associated with decreased HDAC1 occupancy. Since the persistence of integrated HIV-1 genomes despite potent suppression of viral replication is a major obstacle for current antiretroviral therapy, strategies to selectively disrupt the quiescence of chromosomal provirus may play a role in the future treatment of AIDS.

Acetylation↗
PubMed1999

Integration of banana streak badnavirus into the Musa genome: molecular and cytogenetic evidence.

Breeding and tissue culture of certain cultivars of bananas (Musa) have led to high levels of banana streak badnavirus (BSV) infection in progeny from symptomless parents. BSV DNA hybridized to genomic DNA of one such parent, Obino l'Ewai, suggesting integration of viral sequences. Sequencing of clones of Obino l'Ewai genomic DNA revealed an interface between BSV and Musa sequences and a complex BSV integrant. In situ hybridization revealed two different BSV sequence locations in Obino l'Ewai chromosomes and a complex arrangement of BSV and Musa sequences was shown by probing stretched DNA fibers. This is the first report of integrated sequences that possibly lead to a plant pararetrovirus episomal infection by a mechanism differing markedly from animal retroviral systems.

Badnavirus↗
PubMed2002

Integration site selection by lentiviruses: biology and possible control.

Retroviruses integrate into naked DNA in a generally sequence nonspecific fashion, but closer study reveals a variety of forces that influence target site selection. Primary sequence of the target plays a small but detectable role. Proteins bound to target DNA can inhibit integration by blocking access of integration complexes or stimulate integration by distorting DNA. An important example of the latter is DNA distortion in nucleosomal DNA. In vivo integration has not yet been convincingly shown to be biased in favor of any identifiable sequence features, though this could still change in future studies. Many applications of retroviral vectors could be facilitated by targeting integration in vivo to predetermined sites. Towards this end, several groups have studied the properties of fusions of integrase proteins to sequence-specific DNA-binding domains. To date such studies establish that targeting can work well in reactions in vitro, but a variety of obstacles complicate applications in vivo. However, naturally occurring retrotransposons do carry out highly targeted integration using retrovirus-like integrase proteins, fueling long-term hopes for targeting with retroviral integrases as well.

DNA, Viral↗