Published in: The EMBO Journal, vol. 21, no. 5, pp. 954-965, (March 1, 2002):
http://emboj.oupjournals.org/cgi/content/abstract/21/5/954
"Epstein–Barr Virus RNA Confers Resistance to Interferon-a-Induced Apoptosis in Burkitt’s Lymphoma".

Asuka Nanbo, Kaori Inoue, Kumi Adachi-Takasawa and Kenzo Takada1

Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan
1Corresponding author e-mail: kentaka@med.hokudai.ac.jp


Abstract:
We investigated whether Epstein–Barr virus (EBV) infection could counteract the antitumor effect of interferon (IFN)-a. EBV-negative subclones isolated from EBV-positive Burkitt’s lymphoma (BL) cell lines Akata, Daudi and Mutu were found to fall into apoptosis after IFN-a treatment. On the other hand, EBV-positive counterparts exhibited striking resistance against IFN-a-induced apoptosis. Transfection of an individual EBV latent gene into EBV-negative BL cells revealed that EBV-encoded poly(A)– RNAs (EBERs) were responsible for IFN resistance. EBERs bound double-stranded (ds) RNA-activated protein kinase (PKR), a key mediator of the antiviral effect of IFN-a, and inhibited its phosphorylation. Transfection of dominant-negative PKR, which was catalytically inactive and could block phosphorylation of endogenous PKR, made EBV-negative BL cells resistant to IFN-a-induced apoptosis. Furthermore, EBERs did not bind mutant PKR, which was catalytically active but lacked dsRNA-binding activity, nor did they inhibit its phosphorylation. These results indicate that EBERs confer resistance to IFN-a-induced apoptosis via binding to PKR and inhibition of its phosphorylation. This is the first report that the virus counteracts IFN-induced apoptosis in virus-associated tumors.

Additional References:

1. Maruo S, Nanbo A, and Takada K, "Replacement of the Epstein-Barr Virus Plasmid with the EBER Plasmid in Burkitt's Lymphoma Cells", J. Virol. vol. 75, no. 20, pp. 9977-9982 (October, 2001).

2. Frenster JH, "Activation of DNA Transcription within Repressed Chromatin", 14th John Innes Symposium, September 5-8, 2001.

3. Frenster JH, "Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA", AACR, April 6-10, 2002.


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