Lesson from Viral Interferon Regulatory Factors

Review Article

J Immun Res. 2015;2(2):1016.

Lesson from Viral Interferon Regulatory Factors

Priyanka Sivadas and Hye-Ra Lee*

Department of Molecular Microbiology and Immunology,Keck School of Medicine, University of Southern California, Harlyne J Norris Cancer Research Tower, USA

*Corresponding author: Hye-Ra Lee, Department of Molecular Microbiology and Immunology, University of Southern California, Harlyne J Norris Cancer Research Tower, Los Angeles, USA

Received: February 01, 2015; Accepted: February 16, 2015; Published: February 17, 2015

Abstract

Once virus infects cells, the host immediately turns on their immune reponse to eliminate the virus, while the virus attempts to subvert the host immune system for survival. Therefore, kaposi’s sarcoma-associated herpesvirus (KSHV), a DNA tumor virus, dedicates a large portion of its genome to harbor immunomodulatory proteins in order to sustain efficient life long persistency as well as their life cycle. This review delineates a concise overview of the molecular events of viral interferon regulatory factors (vIRFs) underlying viral immune evasion strategies during life cycle of KSHV.

Keywords: KSHV; VIRFs; Viral immune evasion; KSHV life cycle

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus family and is known to be the causative agent of several human cancers including primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and kaposi’s sarcoma (KS) [1]. As with other herpesviruses, once KSHV infected the host, KSHV displays two different life cycles; latent and lytic. During the latent life cycle, it manifests persistency as well as reversibility property. Hence, viral genome exists as a circular episome in the nucleus of host cells, rigorously expressing a handful of viral genes to allow the virus to retain lifelong persistent infection [2]. Under certain circumstances, however, it can reactivate and virtually the entire set of viral genes is expressed, leading to progeny virus production. Thereby, in order to establish their efficient life cycle, KSHV harbors numerous genes that have abilities to overcome the host immune antiviral responses. One mechanism through which KSHV evades the host immune system is by encoding viral homologs of cellular genes that augment or subvert the functions of their cellular counterparts. Among them,KSHV harbors genes with significant homology to cellular interferon regulatory factors (IRFs), aptly named viral IRFs (vIRFs) [3, 4].

Remarkably, KSHV is the only human virus known to carry vIRFs and contains four different vIRFs (vIRF1-vIRF4) within a clustered locus [5, 6]. They are all expressed during lytic reactivation, but vIRF3, also called latency-associated nuclear antigen 2 (LANA2), has been detected in latently infected PEL cells [3, 4, 6]. It is indicated that they may act independently depending on the cell type and the phase of the viral life cycle. The accumulated previous studies suggested that vIRFs have developed two main strategies: First, it inhibits the IFNmediated innate immunity. Second, it represses the p53-mediated tumor suppressor activity [3]. In addition, a recent growing body of evidence is shedding light on its function as a viral transcriptional factor to regulate cellular gene expression. The goal of this review is to delineate how KSHV vIRFs modulate host immune system for their own benefits, thereby either promoting efficient viral replication or viral persistency.

Immune Responses

IFN pathway

One of the primary responses to viral infection by cells is the expression of type I IFNs (IFN-α and IFN-β) that result in the expression of genes that cause cell growth suppression, apoptosis, antigen presentation, and modulation of several signal transduction pathways [7, 8]. These genes are upregulated by IRFs, a family of transcription factors, which are activated by IFN signaling through their cognate receptor [9]. All IRFs share homology in the C-terminal region that contains the IRF-association domain (IAD) and the N-terminal region that encodes the DNA-binding domain (DBD), which is characterized by the presence of five tryptophan repeats. Among the nine members (IRF1 to IRF9) of the IRF family identified thus far, IRF3 and IFR7 are the key regulators of the expression of the IFN-α/β genes upon viral infection [7, 9]. Viral infection activates certain host pattern recognition receptors (PRRs), resulting in the phosphorylation of cytoplasmic IRF3 and its subsequent translocation to the nucleus, wherein it interacts with the transcriptional coactivator histone acetyltransferase (HAT) CBP/p300 to induce IFN-β gene expression [10, 11]. IRF7 is highly homologous to IRF3, but unlike IRF3, IRF7 is constitutively expressed at low levels in most cells and is strongly induced by the type I-IFN-mediated signaling stemming from an IRF9-dependent pathway [12-14]. Like IRF3, IRF7 undergoes phosphorylation upon viral infection, which allows its dimerization and nuclear translocation [13, 15]. IRF7 either hetero dimerizes with IRF3 or homodimerizes, with these dimers inducing the expression of chemokines and the IFN-α/β genes [13, 15]. The large set of genes then induced by IFN-α/β ultimately form the first line of the anti-viral defenses in suppressing viral replication and propagation. In turn, viruses have evolutionally developed various strategies to subvert these pathways, to the benefit of their life cycles. As an example, KSHV expresses the vIRFs to act as dominantnegative inhibitors by targeting IRF3 and IRF7 [7, 9]. Hence, it is not surprising that KSHV IRFs have evolutionarily developed various tactics to subvert these pathways, to their advantage.

vIRF1 (K9): vIRF1 has been identified as the first vIRF found to effectively repress cellular IFN responses [16, 17]. vIRF1 suppresses type I and type II IFN response and one of the known mechanisms is through inhibition of IRF1 transactivation without competing with IRF1 for DNA binding [16]. Alternatively, vIRF1 binds to transcriptional cofactor p300 and interferes with CBP/p300-IRF3 complex formation along with p300 histone acetyltransferase (HAT) activity, thus preventing IRF3-mediated transcriptional activation [18, 19]. Recently, it was shown that vIRF1, vIRF2, vIRF3 have different capability to block Toll-like receptor 3 (TLR3)-mediated IFN induction [20]. First, vIRF1 and vIRF2 inhibit transcription and translational level of IFN- upon TLR3 activation [20]. Second, only vIRF1 but not vIRF2 or vIRF3 reduced phosphorylation and nuclear translocation of IRF3 upon TLR3 activation [20]. Overall, it implies that vIRFs might possess selectivity for a specific TLR owing to inhibition of TLR-mediated IFN production.

vIRF2 (K11/K11.1): Full-length vIRF2, which is translated from exons K11.1 and K11, repressed IRF3 mediated IFN-β transcriptional activity via stimulation of IRF3 degradation and inhibition of IRF3 transactivation [21]. vIRF2 inhibits IFN-α/β driven signaling as well as signaling induced by IFN-γ [22]. The underlying mechanism, however, is yet to be defined. In addition, vIRF2 reduced the activation of the IFN-induced interferon-response element (ISRE) promoter through the deregulation of IFN-stimulated gene factor-3 (ISGF-3) [23]. It is suggested that vIRF2 possesses pleiotropic activity of inhibiting early type I IFN (IFN enhancesome-dependent) and delayed type I IFN (ISGF-dependent) responses. Furthermore, previous studies have shown that the first exon of vIRF2 (K11.1) prevents dsRNA-activated protein kinase (PKR) kinase activity [24], reducing protein synthesis and blocking IFN-α/β signaling to decrease the ability of cells to respond to viral infections [25, 26]. In binding assay, this short form of K11.1 interacts with cellular IRF1, IRF2, IRF8, RelA, and p300, but not IRF3.

vIRF3 (K10.5): vIRF3 interaction with cellular IRF7, suppresses IRF7 DNA binding activity and, therefore, inhibits IFN-mediated immunity through the inhibition of IFN-α production [27]. Remarkably, a putative double α-helix motif of vIRF3 (residues 240- 280) that has been shown to be responsible for the interaction of vIRF3 with IRF7 is also sufficient to bind to IRF5 [28]. As a result of this interaction, vIRF3 inhibits IRF5-mediatd ISRE and IFN-β promoter activity [28]. It was recently shown that vIRF3 is required for the survival of PEL cells. RNA interference (RNAi) knockdown of vIRF3 in PEL cells reduced cell proliferation by releasing IRF5 from p21 promoter transcription complexes. Moreover, vIRF3 inhibits the function of the IFN-induced PKR. PKR inhibits viral mRNA translation by phosphorylating eIF-2 and regulates host defense by controlling transcription [29].

In summary, the downregulation of the IFN regulatory pathway is a common characteristic of the three vIRFs whose functions have been well studied, as IRF3 and IRF7 are the initial key factors of the host immune surveillance program against viral infections (Table 1). While it remains to be discovered whether vIRF4, the most recently identified member of the vIRF family, affects IFN-mediated innate immunity, the down-regulation of the IFN regulatory pathway is a common characteristic of vIRFs, as IRF3 and IRF7 are key initiation factors of the host immune surveillance program against viral infection.

Citation: Sivadas P and Hye-Ra Lee. Lesson from Viral Interferon Regulatory Factors. J Immun Res. 2015;2(2): 1016. ISSN:2471-0261