Discordance between Bovine Leukemia Virus Tax Immortalization In Vitro and Oncogenicity In Vivo

Twizere, Jean-Claude; Kerkhofs, Pierre; Burny, Arsène; Portetelle, Daniel; Kettmann, Richard; Willems, Lucas

doi:10.1128/jvi.74.21.9895-9902.2000

Cited by 18 publications

(14 citation statements)

References 76 publications

(55 reference statements)

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“…Tax and Rex are essential proteins required for transcriptional and post-transcriptional activation of viral expression. The R3 and G4 proteins are dispensable for infectivity but are involved in the maintenance of high viral loads (23)(24)(25). G4 harbors oncogenic potential and interacts with farnesyl pyrophosphate synthetase, an enzyme involved in prenylation of Ras.…”

Section: Introductionmentioning

confidence: 99%

Cell dynamics and immune response to BLV infection: a unifying model

Florins¹

2007

Front Biosci

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Section: Introductionmentioning

confidence: 99%

Cell dynamics and immune response to BLV infection: a unifying model

Florins¹

2007

Front Biosci

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“…The only data describing an impact on cell growth resulted from studies in nonlymphoid rat cells (Willems et al, 1990). Moreover, a recent study emphasized the discrepancies between this in vitro rat model and in vivo observations in sheep (Twizere et al, 2000). Although the reasons for these conflicting results are unknown, it is likely that B-cell-specific factors are required for the full appreciation of Tax-associated cellular transformation.…”

Section: Introductionmentioning

confidence: 99%

Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-κB

Szynal

Cleuter

Beskorwayne³

et al. 2003

Oncogene

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“…In fact, we have previously used the reverse genetics approach in order to assess the role of viral proteins in the leukemogenesis process. We identified three categories of mutations: (i) those that completely abolish infectivity (10,31,33,35), (ii) those that are apparently silent and do not affect replication (10,19,26,33), and (iii) intermediates that do not completely abolish infectivity but reduce proviral loads (10,15,19,31,34). Sheep 245 and 277 described here were infected with recombinant viruses belonging to the third category (15).…”

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confidence: 99%

Even Attenuated Bovine Leukemia Virus Proviruses Can Be Pathogenic in Sheep

Florins

Gillet

Boxus

et al. 2007

J Virol

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Based on a reverse genetics approach, we previously reported that bovine leukemia virus (BLV) mutants harboring deletions in the accessory R3 and G4 genes persist at very low proviral loads and are unable to induce leukemia or lymphoma in sheep, indicating that these R3 and G4 gene sequences are required for pathogenesis. We now show that lymphoma can occur, albeit infrequently (1 case of 20) and after extended periods of latency (7 years). Direct sequencing and reinfection experiments demonstrated that lymphomagenesis was not due to the reversion of the mutant to the wild type. Similar observations with another type of attenuated mutant impaired in the transmembrane protein (TM) YXXL signaling motifs were made. We conclude that the R3 and G4 genes and the TM YXXL motifs are not strictly required for pathogenesis but that their integrity contributes to disease frequency and latency.Viral persistence results from a dynamic interplay between the host immune defense and the replicative capacity of the virus. Bovine leukemia virus (BLV) replication occurs via two main processes: the infection of new cellular targets and the mitosis of the host cell (recently reviewed in references 7 and 11). Although these two mechanisms can theoretically occur simultaneously, the former operates mainly in the early stages of infection, i.e., the seroconversion period. In contrast, viral spread by mitotic cell division accounts for most of the proviral loads during the asymptomatic and leukemic phases (20). Amazingly, the leukemic clone that generates the tumor originates from a cell that was infected soon after seroconversion. It seems, therefore, that the premalignant cell clone and/or its progeny persist throughout the long latency period. However, the molecular mechanisms that govern viral persistence and spread are still largely unknown.In an attempt to define the viral determinants required for transformation, we first established a model system based on the infection of sheep with a cloned BLV provirus (36). Among a series of proviruses, the 344 strain recapitulated all aspects associated with a lymphoproliferative disease followed by the onset of leukemia, lymphoma, or lymphosarcoma. In order to discover the role of viral genes in the leukemogenesis process (which includes all events leading to leukemia, lymphoma, or lymphosarcoma), we used reverse genetics by introducing directed deletions, insertions, and point mutations into the 344 proviral clone (35). By this approach, we previously demonstrated that the R3 and G4 accessory genes are dispensable for infection but are required for the maintenance of high proviral loads (34). Furthermore, the G4 protein, but not R3, exhibits transforming potential in primary rat embryo fibroblasts when coexpressed with the Ha-ras oncogene (15). Indeed, the G4-and Ha-ras-double-positive cells form transformed foci in cell cultures and induce tumors in nude mice. Mechanistically, G4

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Discordance between Bovine Leukemia Virus Tax Immortalization In Vitro and Oncogenicity In Vivo

Cited by 18 publications

References 76 publications

Cell dynamics and immune response to BLV infection: a unifying model

Cell dynamics and immune response to BLV infection: a unifying model

Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-κB

Even Attenuated Bovine Leukemia Virus Proviruses Can Be Pathogenic in Sheep

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