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The Normal Cell Cycle Activation Program Is Exploited during the Infection of Quiescent B Lymphocytes by Epstein-Barr Virus¹

Ludwig Institute for Cancer Research, St. Mary's Hospital Medical School, Norfolk Place, London W2 1PG [M. H., A. St., P. F., A. Si], and Department of Immunology, The Medical School, Vincent Drive, Birmingham B15 2TT [J. G.], England

B lymphocytes in the peripheral circulation are maintained in a non-proliferative state. Antigen recognition stimulates limited proliferation, whereas infection with Epstein-Barr virus (EBV) results in continual proliferation and the outgrowth of immortal cell lines. Because it is not clear at which point in cell cycle the peripheral B lymphocytes are arrested, we characterized the expression of several cell cycle-associated genes in quiescent and stimulated cells. We show that the expression of four cell genes, cdc-2, cyclin E, CD23, and cyclin D2, are up-regulated approximately 100-fold as a result of EBV-mediated immortalization. Because these genes play a positive role in cell proliferation, we suggest that this regulatory switch contributes to controlling entry into the cell cycle. Transient stimulation of quiescent B lymphocytes with either a cocktall of anti-CD40, anti-IgM, and IL4, or EBV results in the rapid expression of the same four genes, suggesting that, after infection, EBV exploits the normal program of B-lymphocyte cell cycle activation.

¹ This work was supported by a Leukaemia Research Fund project grant to A. S. and by grants from the Medical Research Council (United Kingdom) and the EC BIOTECH program to J. G.

² To whom requests for reprints should be addressed. Phone: 0171-724-5522, extension 210; Fax; 0171-724-8586; E-mail: ajs30@dka.sm.ic.ac.uk.

Received 8/16/95. Accepted 9/21/95.

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