A Rhesus Rhadinovirus Viral Interferon (IFN) Regulatory Factor Is Virion Associated and Inhibits the Early IFN Antiviral Response

Abstract

The interferon (IFN) response is the earliest host immune response dedicated to combating viral infection. As such, viruses have evolved strategies to subvert this potent antiviral response. 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 regulatory factors (IRFs), termed viral IRFs (vIRFs). Cellular IRFs are a family of transcription factors that are particularly important for the transcription of type I IFNs. Here, we demonstrate a strategy employed by RRV to ensure rapid inhibition of virus-induced type I IFN induction. We found that RRV vIRF R6, when expressed ectopically, interacts with a transcriptional coactivator, CREB-binding protein (CBP), in the nucleus. A ctivation of type I interferons (IFNs) is a fundamental component of a host's antiviral response. Type I IFNs (alpha and beta interferon [IFN-␣ and -␤]) are produced by virus-infected cells and are responsible for initiating the primary response to viral infection. IFN-␣ is produced largely by plasmacytoid dendritic cells (pDCs) (1), whereas IFN-␤ is produced by a variety of cell types, including epithelial and endothelial cells, fibroblasts, monocytes/macrophages, and B cells (2, 3). The induction of IFNs is a tightly regulated process controlled by IFN regulatory factors (IRFs). Within the broad family of IRFs, IRF3 and -7 are specifically important for the induction of type I IFNs (4, 5). IRF3 is constitutively expressed in all cell types, while IRF7 is induced by type I IFNs. As a consequence of viral infection or treatment with double-stranded RNA (dsRNA), inactive cytoplasmic IRF3 is phosphorylated, after which it forms a homodimer and is translocated to the nucleus (2, 5). Phosphorylated IRF3 (pIRF3) then interacts with the transcriptional coactivator CREB-binding protein (CBP)/p300 and binds the positive regulatory domain I (PRDI)-PRDIII element of the IFN-␤ promoter, thus inducing transcription. To effectively establish infection within a host, viruses have evolved a variety of mechanisms that specifically target cellular IRFs, induction of IFNs, and downstream signaling pathways induced by IFNs (6-8).Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) and rhesus rhadinovirus (RRV) are two closely related gamma-2 herpesviruses that are capable of inducing lymphoproliferative disorders in their respective immunocompromised hosts. Both KSHV and RRV encode multiple viral homologues to cellular proteins that play various roles in cellular processes, such as apoptosis, cellular growth and differentiation, and immune signaling. These viral proteins have the ability to manipulate the host environment in a manner that maximizes conditions for efficient viral replication. In particular, these viral homologues, namely, viral CD200 (vCD200), viral interleukin 6 (vIL-6), viral G protein-coupled re-

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

“…Additionally, KSHV deploys vIRF2 to target IRF3-driven gene expression [ 223 ]. Similar to vIRF1, also the virion-associated vIRF R6 of the gammaherpesvirus rhesus macaque rhadinovirus (RRV) inhibits IFNB1 expression by targeting CBP and competing with phosphorylated IRF3 for binding [ 224 ]. As tegument proteins, RRV R6 and also HSV-1 VP16 are released into the host cell alongside the entering virus and can directly take action to interfere with IRF3 activity before a potent type I IFN response can be mounted.…”

Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments

“…Recently, the RRV vIRF R6 has been shown to interact with the transcriptional coactivator CBP in the nucleus, similar to the KSHV vIRF1. As a result, CBP cannot form a complex with the phosphorylated IRF3, and the IFN expression is not induced (93)(94)(95). Interestingly, RRV R6 is the first vIRF for which an association with the viron could be shown.…”

“…Interestingly, RRV R6 is the first vIRF for which an association with the viron could be shown. Therefore, vIRF V6 can shut down the type I IFN response shortly after the cell was infected, rendering the cell more susceptible to infection (95). The PEDV protein nsp1 also targets CBP.…”

KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production

“…Because of this, KSHV encodes for various immunomodulatory proteins, including four vIRFs (vIRF1 to 4) that are homologous to cellular IRFs [17]. Accumulated results showed that vIRF1, vIRF2, and vIRF3 counteract IFN-mediated anti-viral activity of the host [7,18–22]. Specifically, vIRF3 suppresses IRF7-mediated IFN-α production through inhibition of the IRF7 binding to DNA [7].…”