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At least 397 records · Page 22Linked to original sources
PubMed2006

Integration of human immunodeficiency virus type 1 in untreated infection occurs preferentially within genes.

Previous analyses of human immunodeficiency virus type 1 (HIV-1) integration sites generated in infections in vitro or in patients in whom viral replication was repressed by antiviral therapy have demonstrated a preference for integration within protein-coding genes. We analyzed integration sites in peripheral blood mononuclear cells (PBMCs), spleen, lymph node, and cerebral cortex from patients with untreated HIV-1 infections. The great majority of integration sites in each tissue were within genes. Statistical analyses of the frequencies of integration in genes in PBMCs and lymph tissue demonstrated a strong preference for integration within genes. Although the sample size for brain tissue was too small to demonstrate a clear statistical preference for integration in genes, four of the five integration sites identified in brain were within genes. Taken together, our data indicate that HIV-1 preferentially integrates within genes during untreated infection.

Cerebral Cortex↗
PubMed1988

Regional mapping to 4q32.1 by in situ hybridization of a DNA domain rearranged in human liver cancer.

Recently, a unique cellular DNA segment, representing the normal allele counterpart of hepatitis B virus integration site, has been isolated. It has allowed the identification of a cellular domain in which rearrangements occur in approximately 10% of primary liver tumours. We here report on the assignment of this probe, D4S112, by in situ hybridization to band 4q32.1.

Carcinoma, Hepatocellular↗
PubMed1987

Avian v-myc replaces chromosomal translocation in murine plasmacytomagenesis.

Deregulation of c-myc expression in association with chromosomal translocations occurs in over 95% of murine plasmacytomas, rat immunocytomas, and human Burkitt lymphomas. Infection with a murine retrovirus (J-3) containing an avian v-myc rapidly induced plasmacytomas in pristane-primed BALB/cAn mice. Only 17% of the induced plasmacytomas that were karyotyped showed the characteristic chromosomal translocations involving the c-myc locus. Instead, all of the translocation-negative tumors demonstrated characteristic J-3 virus integration sites that were actively transcribed. Thus, the high levels of v-myc expression have replaced the requirement for chromosomal translocation in plasmacytomagenesis and accelerated the process of transformation.

Animals↗
PubMed1998

Efficient transduction of hemopoietic CD34+ progenitors of human origin using an original retroviral vector derived from Fr-MuLV-FB29: in vitro assessment.

A novel retroviral vector has been designed based on a Friend-murine leukemia virus (Fr-MuLV) FB29 strain. The latter has been selected according to characteristics of pathogenicity in mice where it induces a disease of the haemopoietic system affecting all lineages. Higher infectivity has also been demonstrated as compared to other strains. In accordance with these findings, the amphotropic producer clone used in this study carrying along the neomycine resistance gene (FOCH-Neo), harbors viral titers over 10(7) cfu/ml. To investigate the potential of genetically engineering hematopoietic precursors, CD34+ progenitors were selected from cord blood, bone marrow, and peripheral blood mobilized stem cells (patients + solid tumors) and transduced with FOCH-Neo. High transduction rates were achieved using virus supernatant and minimal doses of hematopoietic growth factors during pretransduction and transduction steps. A polymerase chain reaction (PCR) assay investigating the presence of both neomycin-encoding and viral vector sequences tested positive in 45-90% of granulocyte-macrophage colony-forming units (CFU-GM) generating cells (bone marrow and peripheral blood derived cells) following transduction. An average of 35% colonies showed resistance to G418. Such levels of transduction proved reproducible using only supernatants harboring over 10(7) cfu/ml. In those experiments where long-term in vitro cultures could be maintained over 5 weeks (all cord blood and 5 among 23 PBSC), efficient transduction of long-term culture initiating cell (LTC-IC) hematopoietic progenitors was demonstrated on the basis of both resistance to G418 and virus integration. In the latter case, the PCR assay tested positive in as much as 35-60% of late unselected CFU-colonies. This novel retroviral vector harbors interesting features toward genetic modification of hematopoietic progenitors.

3T3 Cells↗
PubMed1984

Induction of brain tumors by a newly isolated JC virus (Tokyo-1 strain).

A newly isolated virus from a patient with progressive multifocal leukoencephalopathy (PML) (Tokyo-1 strain) was found serologically identical to JC virus (Mad-1 strain) and showed high neurooncogenicity in hamsters. Twenty-one animals inoculated intracerebrally with the virus developed brain tumors during a period that averaged 5 months. The tumors were cerebellar medulloblastoma (n = 20); plexus tumor (n = 2) occurred in 1 animal as a single tumor and in another in combination with a medulloblastoma. Thalamic gliomatosis was also present in 6 animals with medulloblastoma. Five mock-infected animals did not develop tumors. Medulloblastoma cells were shown to contain papovavirus T-antigen. In 20 animals examined the medulloblastoma showed a close resemblance to the human medulloblastoma in its histologic, immunocytochemical, and ultrastructural features. Examination of the incipient tumors indicated that the hamster medulloblastoma originated in cells in the neonatal external granular layer. Following infection the cells apparently migrated into the internal granular layer, carrying integrated virus genes and expressing phenotypical transformation. These findings confirm previous reports on the oncogenicity of virus isolates from PML (ZuRhein and Varakis, 1979), but are novel in that with this new isolate tumors could be induced with comparatively low levels of virus inocula.

Animals↗
PubMed1994

I-J revisited: is the I-J genetic restriction in downregulation due to an endogenous superantigen analogous to mammary tumour virus (Mtv)-encoded endogenous superantigen?

This article puts forward the hypothesis that the I-J genetic restriction observed between certain downregulatory (suppressor) T cells and antigen presenting cells is due to an endogenous superantigen analogous to the mouse mammary tumour virus (Mtv) products encoded by the open reading frames in the 3' long terminal repeat (LTR) of mtv's. In its weak form this hypothesis asserts that the I-J genetic restriction is due to an endogenous superantigen ligand on antigen presenting cells, which crosslinks the V beta and/or V alpha chains of certain T cell receptors (TCR) with major histocompatibility complex (MHC) class II, and that MHC together with this superantigen ligand causes positive selection of T cells bearing the appropriate I-J+ TCR in the thymus. In the periphery these T cells recognize peptide/MHC complex in the presence of the superantigen. In its strong form the hypothesis states that this superantigen ligand for TCR and MHC is encoded by integrated virus genome, e.g. Mtv. These possibilities can now be approached experimentally and their exploration may uncover one of the ways in which T cells are assigned to different functions, including downregulation.

Animals↗
PubMedDate not supplied

Viral transduction of c-myc gene in naturally occurring feline leukaemias.

Feline leukaemia virus (FeLV) is epidemiologically associated with induction of the majority of lymphoid tumours of the domestic cat. However, about one-third of these tumours are devoid of exogenous virus or show evidence of virus integration only after tumour outgrowth. To help define the genetic mechanisms of feline lymphomagenesis we have explored here the possibility that cellular oncogenes (c-onc genes) are rearranged in tumour cell DNA. Of 16 FeLV-positive T-cell tumours among 31 naturally occurring lymphomas, 2 showed evidence of recombinant FeLV proviruses containing myc oncogene sequences. One of the two produced a transmissible myc-containing FeLV. In both cases c-myc and its surrounding DNA appeared unaltered. We believe that the association of myc with FeLV may result in its activation and play a part in the development of a significant fraction of cat T-cell lymphomas. Our findings contrast with studies of experimental induction of chicken lymphoma, in which myc activation occurs by retrovirus promoter insertion near c-myc (refs 3-5), rather than by incorporation into virus.

Animals↗
PubMed2001

Characterization of retrovirus-host DNA junctions in cells deficient in nonhomologous-end joining.

Formation of stably integrated proviruses is inefficient in cells that are defective in the cellular nonhomologous end-joining (NHEJ) DNA repair pathway (R. Daniel, R. A. Katz, and A. M. Skalka, Science 284:644-647, 1999; R. Daniel, R. A. Katz, and A. M. Skalka, Mol. Cell. Biol. 21:1164-1172, 2001). However, the requirement for NHEJ function is not absolute, as 10 to 20% of infected NHEJ-deficient cells can express retrovirus- transduced reporter genes in a stable fashion. To learn more about the compensatory mechanism by which viral DNA may be incorporated into the host cell genome, we analyzed the nucleotide sequences of provirus-host DNA junctions in singly infected NHEJ-deficient cell clones. The results showed that the proviral DNA ends in all NHEJ-deficient clones had the normal 5'TG...CA3' sequence. In addition, 14 of the 19 proviruses analyzed were flanked by a 6-bp direct repeat of host sequences, as is characteristic for avian sarcoma virus integration. These results indicate that the DNA repair pathway which compensates for loss of NHEJ in these transductants does not introduce any gross abnormalities at the provirus-host DNA junctions.

Animals↗
PubMed1996

Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia.

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its activation by either chromosomal translocation or proviral insertion leads to Ewing's sarcoma in humans or erythroleukemia in mice, respectively, Fli-1 is preferentially expressed in hematopoietic and endothelial cells. This expression pattern resembled that of c-ets-1, another ets gene closely related and physically linked to Fli-1. We also generated a germ line mutation in Fli-1 by homologous recombination in embryonic stem cells. Homozygous mutant mice exhibit thymic hypocellularity which is not related to a defect in a specific subpopulation of thymocytes or to increased apoptosis, suggesting that Fli-1 is an important regulator of a prethymic T-cell progenitor. This phenotype was corrected by crossing the Fli-1 deficient mice expressing Fli-1 cDNA. Homozygous mutant mice remained susceptible to erythroleukemia induction by Friend murine leukemia virus, although the latency period was significantly increased. Surprisingly, the mutant Fli-1 allele was still a target for Friend murine leukemia virus integration, and leukemic spleens with a rearranged Fli-1 gene expressed a truncated Fli-1 protein that appears to arise from an internal translation initiation site and alternative splicing around the neo cassette used in the gene targeting. The fortuitous discovery of the mutant Fli-1 protein, revealed only as the result of the clonal expansion of leukemic cells harboring a rearranged Fli-1 gene, suggests caution in the interpretation of gene-targeting experiments that result in either no or only a subtle phenotypic alteration.

Animals↗
PubMed1992

Activation of the prolactin receptor gene by promoter insertion in a Moloney murine leukemia virus-induced rat thymoma.

The prolactin receptor (Prlr) and growth hormone receptor (Ghr) genes and the Moloney murine leukemia virus integration-2 (Mlvi-2) locus were mapped to mouse chromosome 15 and human chromosome 5 bands p12-p14. To examine the potential relationship between Mlvi-2 and the genes encoding the growth hormone receptor and the prolactin receptor, we determined the chromosomal location of all three loci in the rat, using a panel of rat-mouse somatic cell hybrids, and in the mouse, using a panel of (C57BL/6J x Mus spretus)F1 x C57BL/6J interspecific backcross mice. These analyses revealed that Ghr, Prlr, and Mlvi-2 map to chromosome 2 in the rat and to chromosome 15 in the mouse, in close proximity with each other. Pulsed-field gel electrophoresis of rat genomic DNA showed no overlaps between the gene encoding the prolactin receptor and the remaining loci. Moreover, expression of the prolactin receptor was not affected by provirus insertion in Mlvi-2. During these studies, however, we detected one T-cell lymphoma line (2779) in which the prolactin receptor gene was activated by provirus integration. Sequence analysis of polymerase chain reaction-derived cDNA clones showed that the prolactin receptor RNA message initiates at the 5' long terminal repeat and utilizes the splice donor site 5' of the gag gene to splice the viral sequences onto exon 1 of the prolactin receptor. This message is predicted to encode the intact prolactin receptor protein product. Exposure of the T-cell lymphoma line 2779 to prolactin promoted cellular proliferation.

Animals↗
PubMed2002

FHIT: from gene discovery to cancer treatment and prevention.

Chromosomal abnormalities, including homozygous deletions and loss of heterozygosity, are among the most common features of human tumours. The short arm of human chromosome 3, particularly the region 3p14.2, is a major site of such rearrangements. The 3p14.2 region spans the most active common fragile site of the human genome, encompassing a familial-kidney-cancer-associated breakpoint and a papilloma virus integration site. 6 years ago, the FHIT gene was identified in this region. Subsequent studies have shown that FHIT is commonly the target of chromosomal aberrations involving the long arm of human chromosome 3 and is thereby inactivated in most of the common human malignant diseases, including cancers of the lung, oesophagus, stomach, breast, and kidney. During the past 5 years, evidence has accumulated in support of a tumour-suppressor function for FHIT. In this review, we describe the recent findings in the molecular biology of FHIT with particular focus on the opportunities for treatment and prevention of cancer that have emerged.

Acid Anhydride Hydrolases↗
PubMed2025

Role of the CTCF binding site in Human T-Cell Leukemia Virus-1 pathogenesis.

During HTLV-1 infection, the virus integrates into the host cell genome as a provirus with a single CCCTC binding protein (CTCF) binding site (vCTCF-BS), which acts as an insulator between transcriptionally active and inactive regions. Previous studies have shown that the vCTCF-BS is important for maintenance of chromatin structure, regulation of viral expression, and DNA and histone methylation. Here, we show that the vCTCF-BS also regulates viral infection and pathogenesis in vivo in a humanized (Hu) mouse model of adult T-cell leukemia/lymphoma. Three cell lines were used to initiate infection of the Hu-mice, i) HTLV-1-WT which carries an intact HTLV-1 provirus genome, ii) HTLV-1-CTCF, which contains a provirus with a mutated vCTCF-BS which abolishes CTCF binding, and a stop codon immediately upstream of the mutated vCTCF-BS which deletes the last 23 amino acids of the p12 gene, and iii) HTLV-1-p12stop that contains the intact vCTCF-BS, but retains the same stop codon in p12 as in the HTLV-1-CTCF cell line. Hu-mice were infected with mitomycin-treated or irradiated HTLV-1 producing cell lines. There was a delay in pathogenicity when Hu-mice were infected with the HTLV-1-CTCF virus compared to mice infected with either HTLV-1-p12 stop or HTLV-1-WT virus. Proviral load (PVL), spleen weights, and CD4 T cell counts were significantly lower in HTLV-1-CTCF infected mice compared to HTLV-1-p12stop infected mice. Furthermore, we found a direct correlation between the PVL in peripheral blood and death of HTLV-1-CTCF infected mice. In cell lines, we found that the vCTCF-BS regulates Tax expression in a time-dependent manner. The scRNAseq analysis of splenocytes from infected mice suggests that the vCTCF-BS plays an important role in activation and expansion of T lymphocytes in vivo. Overall, these findings indicate that the vCTCF-BS regulates Tax expression, proviral load, and HTLV pathogenicity in vivo.

Human T-lymphotropic virus 1↗
PubMed1978

Surface-specific iodination of membrane proteins of viruses and eucaryotic cells using 1,3,4,6-tetrachloro-3alpha,6alpha-diphenylglycoluril.

The use of the iodinating reagent 1,3,4,6-tetrachloro-3alpha,6alpha-diphenylglycouril (chloroglycoluril) to selectively label membrane surface proteins was investigated with the following systems: enveloped viruses (Sendai and Newcastle disease viruses), human erythrocytes, and nucleated cells propagated both in suspension (EL-4) and in monolayer culture (BHK-21). Conditions are described for specifically iodinating surface proteins while maintaining full virus integrity or cell viability. Comparison of the chloroglycoluril method with the lactoperoxidase and chloramine-T methods for labeling surface membrane proteins shows that the chloroglycoluril method has a number of advantages: It routinely produces a 3- to 17-fold greater specific radioactivity without sacrificing viral or cellular integrity, it is technically simpler to use, it does not require the addition of extraneous protein to initiate the reaction nor a strong reducing reagent to terminate it. Chloroglycoluril also proved to be an effective substitute for chloramine-T in the nonvectorial labeling of viral and cellular proteins. Membrane protein samples were solubilized with the detergent sodium dodecyl sulfate before iodination or labeled in the presence of high iodide concentrations without prior solubilization. The resulting specific radioactivities generated by the use of chloroglycoluril were equal to or greater than those generated by the chloramine-T method. The effectiveness, simplicity of use, and versatility of chloroglycoluril recommend it as an iodinating reagent for both surface-specific and nonvectorial labeling of membrane systems.

Cell Line↗
PubMed2006

Adeno-associated virus interactions with B23/Nucleophosmin: identification of sub-nucleolar virion regions.

Adeno-associated virus (AAV) is a human parvovirus that normally requires a helper virus such as adenovirus (Ad) for replication. The four replication proteins (Rep78, 68, 52 and 40) encoded by AAV are pleiotropic effectors of virus integration, replication, transcription and virion assembly. Using Rep68 column chromatography and mass spectrometry, we have identified the nucleolar, B23/Nucleophosmin (NPM) protein as an Rep-interacting partner. Rep-NPM interactions were verified by co-immunofluorescence and chemical cross-linking studies. We have found that there is demonstrable, but limited co-localization between Rep and NPM in co-infected cells. In contrast, there was significant co-localization between NPM and AAV Cap proteins. In vitro experiments using purified MBPRep78 and NPM show that NPM stimulates MBPRep78 interactions with the AAV ITR as well as endonuclease activity. These studies suggest that NPM plays a role in AAV amplification affecting Rep function and virion assembly.

Cell Nucleolus↗
PubMed1992

Characterization of a stable eukaryotic cell line expressing the Rous sarcoma virus integrase.

The Rous sarcoma virus integration protein (IN) is required for efficient integration of viral DNA into the host genome. IN was expressed in mouse C127 cells using a bovine papillomavirus vector. This system utilizes the mouse metallothionein promoter and the SV40 late polyadenylation signal for efficient expression of IN. A stable cell line derived from a single hygromycin-resistant colony was characterized. The expression of IN increased significantly upon Zn2+ induction of the metallothionein promoter, but did not respond to "superinduction" protocols. Full-length nonphosphorylated IN was the major product of expression. A minor product resulting from initiation of translation at an internal Met codon was also produced. The expressed IN did not exhibit the polypeptide heterogeneity at its COOH-terminus nor phosphorylation as is seen when IN is immunoprecipitated from virions. Using subcellular fractionation and indirect immunofluorescence, IN was primarily localized to nuclei and in some cells appeared to concentrate at discrete loci within the nuclei.

Animals↗
PubMed1994

Thymic repertoire selection by superantigens: presentation by human and mouse MHC molecules.

The initial report of T cell receptor (TCR) V beta-specific thymic selection in mice showed association with expression of H-2E molecules and affected V beta 17a T cells which were present in CD4+8+ double positive thymocytes but deleted from the CD4+ and CD8+ single positive populations. Similar deletions were subsequently reported for V beta 8.1+ and V beta 6+ T cells in Mls-1a mouse strains and for V beta 3+ T cells in Mls-2a/3a strains. The 'Mls antigens' are most effectively presented by H-2E molecules but certain alleles of H-2A molecules can also present these endogenous superantigens. Expression of Mls antigens can cause both V beta-specific thymic deletion and stimulation of peripheral T cells from Mls-negative strains. Another category of 'Mls-like' antigens cause only V beta-specific thymic deletion in H-2E+ strains, affecting V beta 5+ and V beta 11+ T cells. The non-MHC ligands responsible for each of these effects are superantigens analogous to the exogenous bacterial superantigens, which also show TCR V beta-specific stimulatory effects when presented by MHC class II positive antigen-presenting cells. The genes encoding endogenous superantigens in mice were shown to co-segregate with mouse mammary tumour virus integrations (Mtv) and to be the Mtv-LTR orf genes. In vitro translation of Mtv-LTR orf genes identified their products as type II integral membrane glycoproteins with the polymorphic C terminus outside the cell. These polymorphisms correlate with specificity for the different TCR V beta chains. Virtually all TCR V beta-specific negative selection in the mouse thymus can be accounted for by the expression of Mtv or MMTV (the infectious counterparts of Mtv proviral integrants) LTR-orf proteins, presented with H-2E or certain H-2A alleles. It is unlikely that TCR V beta-specific positive selection is due to endogenous superantigens since it does not segregate with Mtv genomes. In humans, HLA-DR molecules appear to be homologous with H-2E in mice whereas HLA-DQ are the homologues of H-2A. H-2E negative mice transgenic for HLA-DR alpha chain express a mouse/human heterodimeric molecule which presents Mtv superantigens causing TCR V beta-specific deletion. Such trans-species class II molecules are also effective in TCR V beta-specific positive selection of V beta 2+, V beta 6+ and V beta 10+ T cells. Taken together, these results show that human MHC class II molecules can interact with the murine T cell repertoire.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Ethidium bromide inhibits appearance of closed circular viral DNA and integration of virus-specific DNA in duck cells infected by avian sarcoma virus.

The DNA of avian sarcoma virus assumes a closed circular configuration before integration into the host cell chromosomal DNA. Ethidium bromide reduces the formation of superhelical viral DNA and concurrently blocks integration of the viral genome. Inhibition of integration of viral DNA results in the inhibition of virus replication.

Alpharetrovirus↗
PubMed2006

Y chromosome loss and other genomic alterations in hepatocellular carcinoma cell lines analyzed by CGH and CGH array.

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignant tumors worldwide. The incidence of HCC is much higher in males than in females. In order to clarify the molecular basis of the male predominance in HCC, we have characterized the detailed genomic alterations in 5 hepatitis B virus integrated Korean HCC cell lines using G-banding, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), PCR, and CGH array. The commonest alterations were observed in chromosome 7 and Y, as well as chromosomal regions 1q, 8q, 4q, and 16q. The most frequent aberration of genomic material was gain of 1q and loss of chromosome Y. Significant loss of DNA copy number of the cancer related genes that are located on chromosome Y was detected by CGH array. By investigating the karyotypes of the previously reported 21 male HCC cell lines, we found 18 HCC cell lines with Y chromosome loss, indicating that this loss is a significant feature of HCC cell lines. We propose that Y chromosome loss in HCC cell lines may be responsible for the preponderance of males in HCC and its significance may lead to further studies for better understanding of carcinogenesis in HCC.

Carcinoma, Hepatocellular↗