Control of human B-lymphocyte replication. II. Transforming Epstein-Barr virus exploits three distinct viral signals to undermine three separate control points in B-cell growth.

Highly purified resting (Go) B lymphocytes were monitored for their response to transforming Epstein-Barr virus (B95-8 strain), to a non-transforming mutant (P3HR-1) containing a deletion in the EBNA-2 coding region, and to inactivated virus of either type. All preparations induced an early appearance of two activation antigens, which included the CD23,p45 ("Blast-2') antigen. Thus, virus binding was sufficient for an initial activation step. Further change required an active viral genome. Infection with the P3HR-1 strain prompted the exit of cells out of Go but led to an arrest in the early G1 phase of the cycle. While initially showing sequels to activation indistinguishable from those observed with P3HR-1 virus, cells infected with B95-8 virus continued through G1 to express late activation antigens, enter S-phase and complete the replicative cycle. The addition of the phorbol ester TPA was found to compensate for the abortive cell cycle entry achieved with the P3HR-1 mutant, but could not supplement the minimal activation observed with inactivated virus. These findings demonstrate that the Epstein-Barr virus undermines three separate control points in the growth cycle of human B lymphocytes, and exploits three distinct viral signals to achieve this end.