Despite the widespread use of HAART therapy to treat HIV infected individuals in the United States, the incidence of Epstein-Barr virus (EBV) associated non-Hodgkin's lymphomas has not decreased. Viral reactivation is a key component of the EBV life cycle and is intimately associated with spread of the virus. Uncovering the mechanisms governing this fundamental aspect of the viral life cycle is important for developing an understanding of how EBV contributes to malignancies in immunosuppressed individuals. Reactivation in herpesviruses is intimately linked to the cell cycle. Agents that trigger EBV lytic replication, such as anti-lg, TGF-beta, butyrate, TPA, IDU, etc. are known to induce cell growth arrest. In the oral epithelium, reactivation is associated with the upper most differentiated layers. Further, in the absence of exogenous inducing agents, the immediate early lytic transactivator, Zta, can induce a GO/G1 growth arrest in EBV positive and EBV negative cells. Therefore, there appears to be a strong preference for EBV lytic replication to proceed in a growth arrested environment and this may limit competition for nucleotide pools during viral DNA replication. Zta mediated transactivation occurs in part through its association with the transcriptional co-activators, p300 and CBP; p300 and CBP play an important role in a number of different terminal differentiation and growth arrest signaling models and disruption of p300/CBP function is required for the transforming and cell cycle promoting properties of the viral oncogenes, SV40 TAg and adenovirus E1 A. We have postulated that if growth arrest is important for efficient viral replication, there may be checkpoints in place to ensure that lytic replication is initiated only in the case where certain growth arrest signaling events have been accomplished. Our preliminary results indicate that the one such checkpoint is regulation of Zta mediated transcriptional activation. In this application we propose to address the role of the cell cycle promoting factors, c-Myc and E2F1, in modulating reactivation through inhibition of p300/CBP mediated transactivation. Overall significance to public health: EBV is associated with a number of human cancers including nasopharyngeal carcinoma, Hodgkin's disease, Burkitt's lymphoma as well as a number of B-cell lymphomas in AIDS patients. More recently, EBV has also become recognized as a significant contributing factor to idiopathic pulmonary fibrosis which is in part due to lytic reactivation. Understanding the mechanisms governing the transition between latency and reactivation will contribute to the understanding of EBV's role in these and other EBV associated diseases. ? ? ?
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