Inhibition Of Histone Deacetylases Induces Bovine Leukemia Virus Expression In Vitro And In Vivo

in Journal of Virology (2002), 76(10),

Cell turnover in BLV-infected sheep

in Aids Research and Human Retroviruses": 10th International Conference on Human Retrovirology: HTLV and Related Viruses, (2001, June)

Cd5 Is Dissociated From The B-Cell Receptor In B Cells From Bovine Leukemia Virus-Infected, Persistently Lymphocytotic Cattle: Consequences To B-Cell Receptor-Mediated Apoptosis

in Journal of Virology (2001), 75(4),

Suboptimal Enhancer Sequences Are Required For Efficient Bovine Leukemia Virus Propagation In Vivo: Implications For Viral Latency

in Journal of Virology (2001), 75(15),

Discordance between Bovine Leukemia Virus Tax immortalization in vitro and oncogenicity in vivo: generation of a rare CD8-positive B-lymphocyte leukemia by the TAX phosphorylation mutant.

Poster (2000, May 26)

Discordance between bovine leukemia virus tax immortalization in vitro and oncogenicity in vivo.

in Journal of Virology (2000), 74(21), 9895-902

Bovine leukemia virus (BLV) Tax protein, a transcriptional activator of viral expression, is essential for viral replication in vivo. Tax is believed to be involved in leukemogenesis because of its second ... [more ▼]

Bovine leukemia virus (BLV) Tax protein, a transcriptional activator of viral expression, is essential for viral replication in vivo. Tax is believed to be involved in leukemogenesis because of its second function, immortalization of primary cells in vitro. These activities of Tax can be dissociated on the basis of point mutations within specific regions of the protein. For example, mutation of the phosphorylation sites at serines 106 and 293 abrogates immortalization potential in vitro but maintains transcriptional activity. This type of mutant is thus particularly useful for unraveling the role of Tax immortalization activity during leukemogenesis independently of viral replication. In this report, we describe the biological properties of BLV recombinant proviruses mutated in the Tax phosphorylation sites (BLVTax106+293). Titration of the proviral loads by semiquantitative PCR revealed that the BLV mutants propagated at wild-type levels in vivo. Furthermore, two animals (sheep 480 and 296) infected with BLVTax106+293 developed leukemia or lymphosarcoma after 16 and 36 months, respectively. These periods of time are within the normal range of latencies preceding the onset of pathogenesis induced by wild-type viruses. The phenotype of the mutant-infected cells was characteristic of a B lymphocyte (immunoglobulin M positive) expressing CD11b and CD5 (except at the final stage for the latter marker), a pattern that is typical of wild-type virus-infected target cells. Interestingly, the transformed B lymphocytes from sheep 480 also coexpressed the CD8 marker, a phenotype rarely observed in tumor biopsies from chronic lymphocytic leukemia patients. Finally, direct sequencing of the tax gene demonstrated that the leukemic cells did not harbor revertant proviruses. We conclude that viruses expressing a Tax mutant unable to transform primary cells in culture are still pathogenic in the sheep animal model. Our data thus provide a clear example of the discordant conclusions that can be drawn from in vitro immortalization assays and in vivo experiments. These observations could be of interest for other systems, such as the related human T-cell leukemia virus type 1, which currently lack animal models allowing the study of the leukemogenic process. [less ▲]

Long-Term Protection Against Bovine Leukaemia Virus Replication In Cattle And Sheep

in Journal of General Virology (2000), 81

Bovine leukemia virus as a model for human T-cell leukemia virus

in Current Topics in Virology (1999)

Transcriptional Regulation Of The Mn/Ca 9 Gene Coding For The Tumor-Associated Carbonic Anhydrase Ix - Identification And Characterization Of A Proximal Silencer Element

in Journal of Biological Chemistry (1999), 274(46),

The MN/CA 9 (MN) gene encodes a tumor-associated isoenzyme of the carbonic anhydrase family. Functional characterization of the 3. 5-kilobase pair MN 5' upstream region by deletion analysis led to the ... [more ▼]

The MN/CA 9 (MN) gene encodes a tumor-associated isoenzyme of the carbonic anhydrase family. Functional characterization of the 3. 5-kilobase pair MN 5' upstream region by deletion analysis led to the identification of the -173 to +31 fragment as the MN promoter. In vitro DNase I footprinting revealed the presence of five protected regions (PRs) within the MN promoter. Detailed deletion analysis of the promoter identified PR1 and PR2 (numbered from the transcription start) as the most critical for transcriptional activity. PR4 negatively affected transcription, since its deletion led to increased promoter activity and was confirmed to function as a promoter-, position-, and orientation-independent silencer element. Mutational analysis indicated that the direct repeat AGGGCacAGGGC is required for efficient repressor binding. Two components of the repressor complex (35 and 42 kDa) were found to be in direct contact with PR4 by UV cross-linking. Increased cell density, known to induce MN expression, did not affect levels of PR4 binding in HeLa cells. Significantly reduced repressor level seems to be responsible for MN up-regulation in the case of tumorigenic CGL3 as compared with nontumorigenic CGL1 HeLa x normal fibroblast hybrid cells. [less ▲]

In Vitro And In Vivo Oncogenic Potential Of Bovine Leukemia Virus G4 Protein

in Journal of Virology (1998), 72(3),