EXPRESSION OF THE EPSTEIN-BARR-VIRUS (EBV) LATENT MEMBRANE-PROTEIN IS TIGHTLY REGULATED, INDEPENDENTLY OF EB NUCLEAR ANTIGEN-2 AND OF EBV INTEGRATION OR COPY NUMBER

In vivo, Epstein-Barr virus (EBV) is associated with human tumours and with lymphoproliferations in immunosuppressed patients. In vitro, EBV induces unlimited growth of normal B-lymphocytes, a phenomenon known as immortalization. A limited number of viral genes is expressed during this phenomenon and their relative role concerning the deregulation of cellular proliferation is still unclear. At present, the nuclear antigen EBNA2 and the membrane protein LMP are the two EBV proteins considered to be implicated in the immortalization process. Moreover, many data support the hypothesis that EBNA2 is the major inducer of LMP expression by transactivation; however, in some instances, expression of the two proteins is not correlated, suggesting the existence of complex interactions between EBV and its host-cell that influence viral gene regulation. In an attempt to study thoroughly these EBNA2/LMP interactions, it is important to evaluate whether EBNA2 is or is not a major inducer of LMP expression, and which other parameters can influence LMP expression. By analysing two sets of B-lymphoma lines either infected in vitro with EBV or stably transfected with EBNA2, we have demonstrated that (1) LMP expression can be absolutely independent of EBNA2 expression, (2) the level of LMP expression is very tightly regulated, and is independent of EBV genome status (integrated or episomal) and copy number. Our findings provide compelling evidence that LMP expression has to be related to that of cellular factors that remain to be identified.