ANTISENSE TO THE EPSTEIN-BARR-VIRUS (EBV)-ENCODED LATENT MEMBRANE-PROTEIN-1 (LMP-1) SUPPRESSES LMP-1 AND BCL-2 EXPRESSION AND PROMOTES APOPTOSIS IN EBV-IMMORTALIZED B-CELLS

The Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP-1) i s required for viral transformation and functions to protect cells fro m apoptotic cell death, in part, by induction of antiapoptotic genes, including Bcl-2 and A20. We have used antisense oligodeoxynucleotides targeted to LMP-1 as a strategy to suppress LMP-I expression and there by inhibit its functions. We have shown that levels of LMP-1 protein i n EBV-positive lymphoblastoid cell lines can be reduced by in vitro tr eatment with unmodified oligodeoxy-nucleotides targeted to the first f ive codons of the LMP-1 open-reading frame. Furthermore, suppression o f LMP-1 was associated with molecular and phenotypic effects that incl uded downregulation of the LMP-1-inducible antiapoptotic genes, Bcl-2 and Mcl-1, inhibition of proliferation, stimulation of apoptosis, and enhancement of sensitivity to the chemotherapeutic agent, etoposide. T hese effects were largely sequence-specific and observed in EBV-positi ve. but not EBV-negative cell lines. These studies suggest that loweri ng expression of LMP-1 in EBV-associated malignancy might have therape utic effects and might synergize with other antitumor agents. (C) 1998 by The American Society of Hematology.