Interferon Regulatory Factor 7 EBV Latency &Oncogenesis

Pagano, Joseph

Abstract

IRF-7, discovered in this laboratory in 1997, is now recognized as essential for interferon responses. We have established its importance in EBV latency states and shown its intimate relation with the EBV oncoprotein, LMP-1, which both induces transcription of IRF-7 and activates IRF-7 protein. Moreover IRF-7 has oncogenic properties that may potentiate LMP-1. Finally, IRF-7 affects specific immune responses by upregulating the TAP-2 gene. In the proposed work, we will study in Aim 1 how IRF-7 protein is activated by examining how it is phosphorylated and translocated to the nucleus and what factors interact with it.
In Aim 2 we will study suspected regulatory circuitry between IRF-7 and LMP- 1 at the level of their promoters, each of which contain ISREs. We will also identify other genes that participate in the modulation of IRF-7 by LMP- 1.
In Aim 3 we will characterize a newly identified EBV gene, BKRF-4, that in preliminary results inhibits IRF- 7 activity and see whether this early gene can cause switching of usage of a latency promoter (Qp) to a cytolytic cycle promoter (Fp) as well as counteract activation of the Tap 2 gene by LMP-1. Knowledge about the biological roles of IRF-7 has expanded rapidly since its discovery. Findings from this proposal will help to explain IRF-7's role in viral latency, oncogenesis and immune responses.