EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1: role of NF-kappaB, STAT1, and p53.

Research paper by Christophe C Le Clorennec, Ibtissam I Youlyouz-Marfak, Eric E Adriaenssens, Jean J Coll, Georg W GW Bornkamm, Jean J Feuillard

Indexed on: 01 Dec '05Published on: 01 Dec '05Published in: Blood


Epstein-Barr virus (EBV) induces CD95 expression and the CD95 gene (FAS) is regulated by NF-kappaB, STAT1, and/or p53. To understand the contribution of these factors in the regulation of CD95 by EBV in lymphoblastoid cell lines (LCLs), we cloned dominant-active IkappaBalpha, active (STAT1alpha) and inactive (STAT1beta) forms of STAT1, p53, a dominant-negative mutant of LMP1, and wild-type LMP1 into a novel double-inducible episomal vector, pRT-1. These plasmids were stably transfected either into wild-type LCLs or EREB2-5 cells, an LCL with an estrogen-regulatable EBNA2 protein. Inhibition of LMP1 signaling decreased expression of CD95, whereas overexpression of LMP1 markedly increased it. Induction of the latency III program in EREB2-5 cells correlated with activation of NF-kappaB, STAT1, and p53. CD95 expression was regulated by these 3 transcriptional systems. STAT1 and p53 activation were secondary to NF-kappaB activation. CD95 surface expression sensitized EBV-infected B cells to the induction of CD95-mediated apoptosis. In vitro inhibition of CD95-CD95 ligand interaction was found to reverse T-cell killing of EBV-infected B cells. Therefore, LMP1 activation of NF-kappaB sensitizes infected B cells to CD95-mediated apoptosis and renders EBV latency III-immortalized B cells susceptible to elimination by the immune system, contributing to the establishment of a host/virus equilibrium.