Varicella-Zoster Virus Immediate-Early Protein ORF61 Abrogates the IRF3-Mediated Innate Immune Response through Degradation of Activated IRF3

Abstract

Varicella-zoster virus (VZV) infection of differentiated cells within the host and establishment of latency likely requires evasion of innate immunity and limits secretion of antiviral cytokines. Here we report that its immediate-early protein ORF61 antagonizes the beta interferon (IFN-␤) pathway. VZV infection down-mod-Varicella-zoster virus (VZV) is ubiquitous in most of the population worldwide and is an alphaherpesvirus restricted to humans. Primary VZV infection begins with inoculation of the respiratory mucosa, followed by cell-associated viremia and the rash of chickenpox. During primary infection, the virus establishes latency in sensory ganglia and can subsequently reactivate to cause shingles (herpes zoster) (3). The VZV genome contains one copy of linear double-strand DNA approximately 125 kb in length and encodes about 70 unique proteins. Similar to other alphaherpesviruses, the expression of VZV genes is assorted temporally into three categories-immediate-early (IE), early (E), and late (L)-and the IE proteins usually play critical roles during VZV life cycles (29).ORF61 encodes a 62-to 66-kDa phosphoprotein (45), which is highly homologous to herpes simplex virus 1 (HSV-1) ICP0 in the RING finger domain and can partially complement the function of ICP0 in ICP0-null HSV-1 (28). Both proteins exhibit regulatory functions, but the difference between them is that ORF61 has either a transactivated or repressive function (16, 31), while ICP0 mostly shows transcriptional activation (12,14). Although ICP0 can inhibit the innate immunity pathway at many levels, such as IRF3 and PML (13,26), little is known about the function of ORF61 in interrupting the innate immunity.The innate immune system is an ancient and nonspecific system that provides the first line of defense against infection. One of the most effective innate antiviral responses is the production of alpha/beta interferon (IFN-␣/␤) and the subsequent induction of interferon-stimulated genes (ISGs) (38). Previous studies have demonstrated that VZV infection stimulates innate immune responses mainly by the production of IFN-␣ and IFN-␥ (1, 2, 27), while IFN-␤ is not detected in serum of VZV-infected patients. This might be explained by the evidence provided by one group that the production of IFN-␤ may be blocked by ORF62 during VZV infection (40).Increasing evidence has shown that ICP0 possesses various antagonistic functions against the host innate immune system

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

“…For example, HCV suppresses host antiviral response by inhibiting the dimerization and phosphorylation of IRF-3 (100). Varicella zoster virus IE protein ORF61 abrogates IRF-3-mediated innate immune response through degradation of activated IRF-3 (22). Ebola virus VP35 protein inhibits the induction of antiviral genes by blocking the activation of IRF-3 (24).…”

“…For example, viruses can bind directly to IRF-3 (17,18) or interact with CBP/p300 coactivator (19)(20)(21) to impair the type I IFN production. In general, some viruses cause the degradation of activated IRF-3 (22,23), whereas most viruses suppress the production of type I IFNs through inhibition of IRF-3 activation, including phosphorylation, dimerization, and nuclear translocation (24)(25)(26)(27)(28)(29)(30). Only a few viruses have been shown to interfere with the binding of activated IRF-3 to IFN-b promoter, resulting in the suppression of type I IFNs (31,32).…”

Human Bocavirus NP1 Inhibits IFN-β Production by Blocking Association of IFN Regulatory Factor 3 with IFNB Promoter

“…Several viral proteins were also reported to modulate the function of activated IRF-3. For instance, ICP0 of bovine herpes virus 1, ORF 61 of varicella-zoster virus, and vIRF-2 of Kaposi's sarcoma-associated herpesvirus (KSHV) cause IRF-3 degradation (39,42,44); E1A of adenovirus 5 and vIRF-1/vIRF-2 of KSHV inhibit recruitment of CBP/p300 coactivators by IRF-3, decreasing the transcription efficiency (38,40,46,49); IE1 of HSV-1 disrupts IRF-3 dimer in the nucleus (41); NSs of La Crosse encephalitis virus (a bunyavirus) targets downstream of IRF-3 by specifically inducing proteasomal degradation of RNA polymerase II subunit RPB1 293T cells were cotransfected with HA-tagged NP1 and Flag-tagged IRF-3 or deletion mutant expression plasmids for 24 h. Cells were lysed and subjected to IP using mouse anti-FLAG tag (upper panel) or mouse anti-HA tag (middle panel). Mouse IgG was used as negative control.…”

“…36,37). Only a limited number of viral proteins was reported to interfere with the function of activated IRF-3 in the nucleus (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model

“…This observation may reflect a close correlation between viral replication efficiency and host responses related to virus sensing and antiviral defense mechanisms. Given that the production of type I IFNs and the subsequent induction of IFN-stimulated genes (ISGs) is inhibited by various ORFs of VZV, such as ORF61, ORF62, and ORF47 [27][28][29], a detailed profile of dual viral and host gene expression patterns at various stages post-infection would provide a valuable insight into temporal changes in host/pathogen interaction.…”