IN-VITRO AND IN-VIVO ONCOGENIC POTENTIAL OF BOVINE LEUKEMIA-VIRUS G4 PROTEIN

In addition to the genes involved in the structure of the viral partic le, the bovine leukemia virus (BLV) genome contains a region called X which contains at least four genes, Among them, the tox and rex genes, respectively, are involved in transcriptional and posttranscriptional regulation of viral transcription, Two other genes, R3 and G4, were i dentified after cloning of the corresponding mRNAs from BLV-infected l ymphocytes. Although the function of the two latter genes is still unk nown, they appear to have important roles, since deletion of them rest ricts viral propagation in vivo. In order to assess the oncogenic pote ntial of the R3 and G4 proteins, we first analyzed their ability to im mortalize and/or transform primary rat embryo fibroblasts (Refs), In t his assay, the G4 but not the R3 protein cooperated with the Ha-ms onc ogene to induce tumors in nude mice, It thus appears that G4 exhibited oncogenic potential in vitro, To extend these observations in vivo, t he pathology induced by recombinant viruses with mutations in G4 and i n R3 and G4 was nest evaluated with the sheep animal model, Viral prop agation, as measured by semiquantitative PCR, appeared to be reduced w hen the R3 and G4 genes were deleted, These observations confirm and e xtend our previous data underlining the biological function of these g enes, In addition, we present the results of a clinical survey that in volves 39 sheep infected with sis different BLV recombinants. Over a p eriod of 40 months, 83% of the sheep infected with a wild-type virus d eveloped leukemias and/or lymphosarcomas. In contrast, none out of 13 sheep infected with viruses with mutations in G4 or in R3 and G4 devel oped disease, We conclude that in addition to its oncogenic potential in vitro, G4 is required for pathogenesis in vivo. These observations should help us gain insight into the process of leukemogenesis induced by the related human T-cell leukemia virus type 1.