EPSTEIN-BARR VIRUS-MEDIATED B-CELL PROLIFERATION IS DEPENDENT UPON LATENT MEMBRANE-PROTEIN-1, WHICH SIMULATES AN ACTIVATED CD40 RECEPTOR

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is essen tial for the immortalization of human B cells and is linked etiologica lly to several human tumors. LMP1 is an integral membrane protein whic h acts like a constitutively active receptor, It binds tumor necrosis factor (TNF)-receptor-associated factors (TRAFs), activates NF-kappa B and triggers the transcription factor AP-1 via the c-Jun N-terminal k inase (JNK) cascade, but its specific contribution to B-cell immortali zation has not been elucidated fully. To address the function of LMP1, we established B cell lines with a novel mini-EBV plasmid in which th e LMP1 gene can be regulated at will without affecting the expression of other latent EBV genes. We demonstrate here that continuous express ion of LMP1 is essential for the proliferation of EBV-immortalized B c ells in vitro. Re-induction of LMP1 expression or activation of the ce llular CD40 receptor both induce the JNK signaling cascade, activate t he transcription factor NF-kappa B and stimulate proliferation of thes e B cells. Our findings strongly suggest that LMP1 mimics B-cell activ ation processes which are physiologically triggered by CD30-CD40 ligan d signals. Since LMP1 acts in a ligand-independent manner, it replaces the T cell-derived activation signal to sustain indefinite B-cell pro liferation.