Date

6-2014

Document Type

Dissertation

Degree Name

Ph.D.

Department

Department of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

Two closely related gammaherpesviruses, Kaposi’s sarcoma-associated herpesvirus (KSHV) and rhesus macaque rhadinovirus (RRV), are unique in that they express viral homologues to cellular interferon (IFN) regulatory factors (IRFs), deemed viral IRFs (vIRFs). These vIRF proteins differentially regulate transcription and IFN signaling. The IFN response is an early host immune response dedicated to combating viral infection. Here, we demonstrate a strategy employed by RRV to ensure rapid inhibition of virus-induced type I IFN production. We show that vIRF ORF R6 impedes the IFN response within the first 6 h of poly(IC)-induced stimulation. We also found that RRV vIRF R6 interacts with transcriptional coactivator, CREB-binding protein (CBP), in the nucleus. Consequently, phosphorylated IRF-3, a cellular transcriptional regulator important for the activation of IFN β transcription, fails to effectively bind to the IFNβ promoter, thus inhibiting the activation of IFN β genes and causing proteasome-dependent degradation of IRF-3. Additionally, we demonstrate via immunoelectron microscopy that R6 is packaged within RRV virion particles and furthermore that virion-associated R6 is capable of inhibiting the type I IFN response by preventing efficient binding of transcription factors to the IFN β promoter in the context of infection. The work shown in this thesis is the first example of a virion-associated vIRF in either KSHV or RRV. The presence of this immunomodulatory protein in the RRV virion provides the virus with a rapid immune evasion mechanism, thus perhaps enabling the virus to effectively establish an infection within the host.

Identifier

doi:10.6083/M4B856V8

School

School of Medicine

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