Role of PML nuclear body proteins for establishment of EBV latent infection

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DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is one of the most potent transforming viruses and it is found in several human cancers, including B cell lymphomas in patients with AIDS who are immunosuppressed by HIV. The long- term goal of our laboratory is to understand how EBV latent proteins mediate B cell transformation. Of particular interest are the EBNA2 and EBNA-LP transcription factors. EBNA2 functions in part through mimicry of cellular Notch signaling pathways to induce expression of viral and cellular genes. EBNA-LP is a coactivator of EBNA2, but the mechanism(s) by which it coactivates EBNA2 remains elusive. Recent observations from our laboratory indicate that EBNA-LP interacts with and displaces the promyelocytic nuclear body (PML NB) protein Sp100 from PML NBs, suggesting that Sp100 is an important cellular cofactor that mediates EBNA-LP coactivation function. In addition, we have demonstrated that EBNA2 amino acid residues 1-58 comprise an oligomerization domain that is able to act as a dominant negative inhibitor of EBNA2 transcriptional activation function. To further clarify how Sp100 mediates EBNA-LP coactivation function and to test whether the EBNA2 oligomerization domain can be harnessed to inhibit EBV-driven B cell immortalization, we have developed the following aims: 1) To determine how EBNA-LP mediates Sp100 displacement from PML NBs and if Sp100 is essential for EBNA2 coactivation, 2) To determine the mechanism by which Sp100 contributes to EBNA-LP coactivation function, and 3) To determine whether dominant negative forms of EBNA2 can inhibit EBV-induced B lymphocyte immortalization. Herpesviruses modify and/or modulate PML and PML-associated NB proteins. However, it remains unclear whether PML NBs are a collection of proteins that mediate an antiviral cellular defense mechanism that herpesviruses have evolved to counteract or if viruses co-opt factors in PML-NBs to their advantage to help facilitate virus gene expression and/or replication. Our investigations into the unique interaction between EBNA-LP and Sp100 will help to yield new insights into the relationship of herpesviruses and PML NBs. Design of EBNA2 and/or EBNA-LP inhibitors is a potential practical application that will be derived from our studies.