Molecular mechanism of Epstein-Barr virus latent infection

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Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that latently infects B-lymphocytes and causes their continuous proliferation into lymphoblastoid cell lines (LCL). EBV nuclear protein EBNA-2 and EBNA-LP are the first viral proteins expressed in lymphocytes. They cooperatively up-regulate EBV and cellular gene transcription, and are required for lymphocyte outgrowth into LCL. We have now found that EBNA-LP readily associated with EBNA2 or with the EBNA2 C-terminal activation domain (E2AD) when both components were expressed in bacteria. In lymphoblasts, EBNA-LP and EBNA2 did not stably associate. However, EBNA-LP deleted for only 10 C-terminal amino acids (aa) stably associated with EBNA2 in lympohoblasts. EBNA-LP 31 aa (dW2Y1) with 24 C-or N-terminal aa was a specific and efficient affinity matrix for EBNA2 or EBNA-LP. These biochemical interactions between EBNA-LP and EBNA2 enable coordinated transcriptional regulation of cell and viral gene expression in lymphoblasts only when the interaction is unstable ; deletion of the EBNA-LP C-terminal 10aa stabilizes association with EBNA2 and prevents co-activation. Since EBNA-LPd10 dominantly inhibited EBNA-LP co-activation with EBNA2, EBNA-LP d10 over-expression in LCLs may be useful in assessing the role of EBNA-LP co-activation in LCL growth or survival.