Reviews in Medical Virology

REVIEW

Rev. Med. Virol. 2015; 25: 187–201. Published online 1 April 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1836

Herpesviruses: interfering innate immunity by targeting viral sensing and interferon pathways Puja Kumari1, Sathish Narayanan3† and Himanshu Kumar1,2* 1

Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, India 2 Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan 3 Laboratory of Virology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, India

S U M M A RY Type I-interferon (IFN-I) induction pathway is one of the most commonly stimulated signaling pathways in response to viral infection. During viral infection this pathway is stimulated by various pattern-recognition receptors, which recognize different pathogen-associated molecular patterns. The pathways stimulated by different pattern-recognition receptors merge into common transcription factors IRF3 and IRF7, lead to the production of IFN-I. The secreted IFN-I stimulates JAK-STAT pathway leading to induction of interferon-stimulated genes (ISGs). The ISGs along with IFN-I create antiviral state to eliminate the virus from host. HHV infection enhances IFN-I-mediated innate antiviral response during both de novo infection and lytic reactivation from latency. However, HHV developed various molecular strategies to evade the sudden upsurge of the IFN-I and IFN-I-mediated antiviral response to establish a successful infection. Here, we focus on IFN-I induction and signaling pathways induced by three representative HHVs from each subfamily of HHV and strategies acquired by these HHVs to subvert the induction of IFN-I and ISGs to evade the host innate immunity. These fundamental understanding provides the clue for viral targets for pharmacological manipulation to develop potential therapeutics for broad subtypes of HHVs. Copyright © 2015 John Wiley & Sons, Ltd. Received: 22 December 2014; Revised: 3 March 2015; Accepted: 4 March 2015 *Correspondence to: Dr Himanshu Kumar, Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, India. E-mail: [email protected] † Deceased on 27 October 2014. Abbreviations used BST2, bone-marrow-stromal-cell-antigen-2; DAI, DNA-dependent activator of IRFs; HFF, human foreskin fibroblast; HUVECs, human umbilical vein endothelial cells; ICP, infectious cell protein; IFI16, IFN inducible protein 16; IPS1, interferon-β promoter stimulator 1; IRAK, interleukin-receptor associated kinase 1; IRFs, interferon regulatory factors; ISGF3, interferon stimulated gene factor 3; ISGs, interferon stimulated genes; ISRE, interferon-stimulated response element; LANA, latency-associated nuclear antigen; MDA5, melanoma differentiation association gene 5; MEF, mouse embryonic fibroblast; MIR2, modulator of immune response 2; MxA, myxovirus resistance A; ND10, nuclear domain 10; OAS, oligoadenylate synthetase; PAMPs, pathogen-associated molecular patterns; PAN RNA, polyadenylated nuclear RNA; pDCs, plasmacytoid dendritic cells; PKR, protein kinase R; PML, promyelocytic leukemia; PML-NB, PML nuclear bodies; PRRs, pattern-recognition receptors; RIG-I, retinoic acid inducible gene-I; RLR, RIG-I-like receptors; RNF, RING finger protein; RTA, replication and transcription activator; SHP2, Src-homology-region-2 domain-containing phosphatase-2; TBK, TANK-binding kinase; TBK1, TANK-binding kinase 1; TLR, toll-like receptors; Viperin, virus inhibitory protein, endoplasmic reticulum associated, interferon inducible; RING, really interesting new gene; vIRFs, viral interferon regulatory factors; vMIA, viral mitochondrial inhibitor of apoptosis.

Copyright © 2015 John Wiley & Sons, Ltd.

INTRODUCTION Among more than 100 herpesviruses discovered, only eight are capable of infecting humans, and they are named as HHV. HHVs are generally categorized into three sub-families, alpha-herpesvirinae, betaherpesvirinae, and gamma-herpesvirinae. HHVs are DNA viruses, and in the case, of HSV-1 and human cytomegalovirus (HCMV) viral genes are denoted as UL (unique long) and US (unique short), whereas in the case of Kaposi’s sarcoma-associated herpesvirus (KSHV), genes are designated as ORFs [1,2]. Viruses of each sub-family differ from each other by showing different pathogenic effects, rate of growth in culture, varied length of productive cycle, and cell-type specificity to maintain latency [2,3]. Given their prevalence in world’s population, HHV infections are a major public health issue. HHV infection leads to range of illness from simple skin or genital lesions to severe health complications such as chickenpox, mononucleosis, Burkitt’s lymphoma, Kaposi’s sarcoma, which cause a serious epidemiological burden globally [4].

188 In spite of these dissimilarities, all HHVs share a common microscopic structure that contains single double-stranded linear-DNA surrounded with an inner capsid, middle thick tegument followed by outer glycoprotein-rich lipid envelope layer. Herpesviruses can establish lifelong infections in their natural hosts with little or no disease symptoms. LIFE-CYCLE OF HHVS The HHVs productive infectious cycle starts as viruses release their tegumented capsid into cell cytoplasm following attachment and fusion with host cell-surface receptors and cell membrane, respectively. Tegumented capsids are then transported to the nucleus resulting into the release of the viral nucleic acid into the nucleus. Inside the nucleus, viral-DNA is replicated into many copies and de novo synthesized viral proteins are assembled with single copy of viral genome to make mature virionparticles that are transported to the cell periphery to egress. Released virion particles start a fresh cycle of infection to propagate viral infection. In response to propagated viral infection, host cells elicit innate immune response to stop further infection. The co-evolution of host and viruses enables HHVs to acquire a clever strategy called latency to escape from the immunity. During latency, virion production does not take place but the expression of limited number of latency-associated genes help viruses to sustain in the host. To maintain latent state, viral-DNA is kept as an episome attached to host chromosome, and the replication of the viral genome is coupled with the host cell replication. Lytic reactivation of the latent viral genome takes place as the immune competence of the infected individual declines. During lytic reactivation, viral DNA gets detached from the host chromosome and initiates synthesis of multiple copies of viral DNA, expression of viral genes, and synthesis of new virion particles, which on egress start a secondary recurrent infection to bring about severe health complications to the infected host [2]. INNATE SENSING AND SIGNALING PATHWAYS ACTIVATED BY HHVS Type I-interferon (IFN-I) pathway is induced as soon as these viruses interact [5] or enter [6,7] the host cell where their presence is sensed by cellsurface or endosomal TLRs, cytosolic RNA sensors, and DNA sensors. These sensors are collectively known as pattern recognition receptors (PRRs) Copyright © 2015 John Wiley & Sons, Ltd.

P. Kumari et al. [8–12]. Various components of HHVs such as DNA, RNA, structural-proteins or envelope glycoproteins can induce the production of inflammatory cytokine and IFN-I. The IFN-I in turn induces ISGs to establish appropriate antiviral state [7,13–16]. Upon sensing of HHV by TLRs, an adaptor toll-interleukin-1 receptor domain-containing adapterinducing interferon-β (TRIF) or myeloid differentiation primary response gene 88 (MyD88) is recruited, whereas sensing by RLRs recruits IPS-1 (also known as MAVS/VISA/CARDIF), and TBK1 is directly recruited to DNA sensors in the case of cytosolic DNA sensor-mediated signaling. Further, these PRRs activate cascade of signaling, which culminate to downstream kinases such as IRAK1, IRAK4, TBK1, IKKi, and ubiquitinases, such as TNF receptor-associated factor (TRAF)6 and TRAF3, resulted to the activation of IRFs. Initially, IRF3 is phosphorylated and translocated to the nucleus to make a complex with histone transacetylase CBP (CREB binding protein, CREB: cAMP response element-binding protein)/p300, which binds to the positive regulatory element positive regulatory domain (PRD)-III-I of IFNβ promoter and initiates the early phase transcription of IFNβ gene. Production of IFNβ stimulates many downstream genes called interferon stimulated genes (ISGs), which perform effector role against invading viruses. Further, the IFN-I production is amplified to greater magnitude by IFN-signaling pathway through ISGs as a result of positive feedback loop [8,17–19] (Figure 1). INTERFERRON SIGNALING PATHWAY INVOLVED IN INNATE ANTIVIRAL IMMUNITY Secreted IFN-I stimulates another cascade of signaling in an autocrine or paracrine manner by binding to heterodimeric interferon receptor (IFNAR) on the cell-surface. Further, the signaling is mediated by Janus kinases (Tyk2 and JAK1), STATs (STAT2 and STAT1) and IRF9/p48 by making a heterotrimeric complex of STAT1-STAT2-p48 called ISGF3. ISGF3 binds to an ISG promoter element called ISRE and stimulates the transcription of several ISGs such as PKR, OAS, BST2, PML, Sp100, Viperin, IFI16, DAI, MxA, ISG54, ISG56 along with IRF7 gene, and thus creates an antiviral state in the host to restrict viral replication. IRF7 then trans-activates both the IFNα and IFNβ genes for the late phase of IFN-I induction. In specialized innate immune cells such as pDCs, IRF7 is directly Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

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Figure 1. HHVs sensed by PRRs: Downstream signaling pathway is activated leading to activation of appropriate transcription factors, for example, IRF3 and IRF7, which induce transcription of IFN-I genes, which, in turn, stimulates JAK–STAT pathway for the synthesis of antiviral molecules known as ISGs such as PKR, OAS, Viperin, BST2, and components of ND10. HHVs utilize their various components such as tegument proteins, capsid proteins, and miRNA to curb the immune response initiated by all these PRRs at various steps. TLRs: TLR3 is targeted by HSV-1-US3, HCV-1-ICP4, and HCV-1-ICP34.5, whereas TLR4 is targeted by KSHV-vGPCR and KSHV-vIRF1. KSHV RTA, an E3 Ubiquitin ligase, promotes proteasomal degradation of MyD88 and TRIF. HSV-1-UL36 deubiquitinates TRAF3, and kinase activity of TBK1/IKKi is inhibited by HSV-1-ICP34.5 and KSHV-ORF45. KSHV-miR-K12-11 reduces the expression of IKKi. Many of the HSV-1 proteins target IRF3 activation. Phosphorylation, dimerization, and nuclear translocation of IRF3 are inhibited by US3, US11, UL36, ICP0, ICP4, and ICP34.5. HSV-1ICP0 also prevents recruitment of IRF3-CBP/p300 complex onto PRD-III-I element of IFN-β. HSV-1-VP16 blocks IRF3-CBP/p300 complex formation, whereas HCMV-pp65 stimulates dephosphorylation of IRF3 and prevents its nuclear accumulation. KSHV-vIRF1 physically binds with CBP and p300, whereas KSHV-LANA1 and KSHV-K-bZIP bind to PRD-III-I element of IFN-β thus inhibit the recruitment of IRF3-CBP/p300. KSHV-ORF36 inhibits the ability of IRF3 to recruit RNA polymerase II and CBP/p300 onto the PRD-III-I region. KSHV-ORF45 and KSHV-RTA inhibit phosphorylation of IRF7 and stimulate its proteasomal degradation. KSHV-vIRF3 prevents IRF7 recruitment onto IFN-I promoter. RLRs: HSV-1-US11 interacts with RIG-I and hinders interaction with its activator protein PACT. Interaction with US11 also inhibits interaction of RIG-I and IPS-1. KSHV inhibits the activity of RIG-I by deubiquitinating it through ORF64. HSV-1-US11 interaction with MDA5 prevents MDA5-IPS1 interaction. Herpesviral-mediated inhibition of TRAF3, TBK1/IKKi and IRFs active in RLR pathway occurs as mentioned above. DNA Sensor IFI16: IFI16 is utilized by HCMV-pp65 for the expression of viral major immediate early proteins, whereas HSV-1-ICP0 promotes degradation of IFI16. Herpesviral-mediated inhibtion of TBK1/IKKi and IRFs active in this pathway occurs as mentioned above. Janus kinases: Tyk2 and JAK1 phosphorylation is inhibited by KSHV-RIF. JAK1 level is brought down by HSV-1-UL41. ISGF3 complex: KSHV-RIF inhibits the phosphorylation of STAT1 and disturbs the function of STAT2 by aberrantly loading it to IFNARs in the absence of IFN-I. HSV-1-UL41 inhibits the phosphorylation of STAT1 and brings down the level of STAT2 mRNA. Phosphorylation of STAT1 is also inhibited by HSV-1-ICP27. Recruitment of ISGF3 complex on ISRE element is inhibited by HCMV-IE1 and KSHV-vIRF2 ISGs: Antiviral function of PKR is inhibited by HSV-1ICP34.5, US11 and HCMV pIRS1 and pTRS1, which makes dsRNA unavailable for PKR activation. Activity of OAS is inhibited by HSV-1ICP4 and HSV-1-US11 and HSV-1-UL126a, whereas RNaseL is inactivated by HCMV-pIRS1 and HCMV-pTRS1. Viperin is utilized by HCMV-vMIA for increased viral infection, whereas Viperin mRNA level is decreased by HSV-1-UL41. BST2 mRNA also is degraded by HSV-1-UL41, whereas HCMV-vBST2 interacts with host cell membrane BST2 for increased viral entry, and KSHV-K5 induces proteasomal degradation of host BST2. Integrity of ND10 is disturbed by HSV-1-ICP0, which stimulates proteasomal degradation of PML. HCMV-IE1 inhibits PML SUMOylation, whereas KSHV-vIRF3 increases PML SUMOylation to promote its degradation. Red-pointed end arrows show stimulation, and black-blunted end arrows show inhibition. Components of HSV-1, HCMV, and KSHV have been indicated with red, blue, and green, respectively. JAK, Janus kinase; KSHV, Kaposi’s sarcoma-associated herpesvirus; vGPCR, KSHV-encoded G-protein-coupled-receptor; MyD88, myeloid differentiation primary response gene 88; TRIF, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β; TRAF, TNF receptor-associated factor; US, unique short; UL, unique long; CBP, cAMP response element-binding protein; PRD, positive regulatory domain; pTRS1 and pIRS1, HCMV-encoded dsRNA binding proteins; HCMV, human cytomegalovirus

Copyright © 2015 John Wiley & Sons, Ltd.

Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

P. Kumari et al.

190 activated through interaction with MyD88 and induces robust amount of IFNα [17,20] (Figure 1). ANTIVIRAL RESPONSES TO HHVS Antiviral mechanism of few ISGs such as PKR, OAS, Viperin, and BST2 is well understood in immunity. HHV infection generates a pool of double-stranded RNA (dsRNA), which activates PKR and OAS. The PKRs are dimerized and autophosphorylated, which then phosphorylate the α-subunit of translation initiation factor eukaryotic initiation factor 2 (eIF2) to shut down protein synthesis machinery of host cell. Whereas, OAS enzymes upon activation, oligomerize ATP into 2′5′ oligoadenylate (2–5A), which then activates RNaseL to degrade viral and cellular RNAs to stop host as well as viral protein synthesis, which restricts viral replication [21,22]. Similarly, Viperin downregulates HHV structural proteins indispensable for viral maturation [23], and BST2 prevents the egress of HHVs [24], and thus help in reducing the number of infectious virion particles in the host. ANTIVIRAL EVASION MECHANISMS OF HHVS As IFN-I-mediated immune response is the primary barrier against any viral infection and given the magnitude of the immune responses triggered throughout the viral life cycle, HHVs acquire various components, which help in evasion or subversion of IFN-I-related signaling pathways. In this review, we focus on how IFN-I induction as well as signaling pathways are evaded or subverted by HHVs during different stage of their life cycle, that is, primary infection, latency, and following lytic reactivation. This review discusses about all three sub-families of HHVs taking one virus from each sub-family as example (Figure 1 and Tables 1–3). HHV FACTORS TARGETING INNATE SENSORS

TLRs Antiviral response against the viruses is mostly mounted by endosomal TLRs such as TLR3, 7, 8, and 9 depending on cell types [25–27]. During HSV-1 infection, transcription of TLR3 is targeted and inhibited by HSV-1-US3 alone or with the help of HSV-1-ICP4 [25], whereas up-regulation of TLR2 and TLR3 occurs in the MEFs when infected with HSV-1-ICP34.5 null virus [26]. Upon infection, Copyright © 2015 John Wiley & Sons, Ltd.

ICP34.5 null HSV-1 increases the expression of antiviral genes and reduces the viral titer in comparison with wild type HSV-1 infection of MEFs [26], which suggests the role of HSV-1-ICP34.5 in immune evasion. In the case of HCMV infection, none of the HCMV factors has been shown to be involved in modulation of TLRs. However, a viral homologue of IL-10 (cmvIL-10) has been shown to inhibit TLR9-induced IFN-I in pDCs through an unknown mechanism [27]. As TLR4 mounts immune response against KSHV during late infection, KSHV-encoded G-Protein-coupled receptor (vGPCR) and vIRF1 antagonize TLR4 expression [28]. Thus, HHVs hijack host innate immunity via targeting TLRs and TLRdependent antiviral responses (Figure 1 and Table 1).

RLRs The RLR-mediated IFN-I induction is inhibited when C-terminal domain of HSV-1-US11, a late protein, physically binds with the RIG-I, MDA5, and PACT, a RIG-I activator protein [18,29]. Binding of US11 with RIG-I and PACT prevents PACT-RIG-I interaction [30] and thus RIG-I-dependent responses. On other hand, MDA5 association with US11 prevents oligomerization and activation [18]. Similarly, RIG-I also interacts with Riplet/RNF135, a RIG-I activator protein through ubiquitination [31], and US11 interaction with RIG-I might prevent RIG-I-Riplet interaction, which will restrict activation of RIG-I. Interaction with US11 also prevents the formation of the RIG-I/IPS-1 or MDA-5/IPS-1 complex and thereby abolishes the activation of IRF3 [18]. HCMV infection to HFF cells induces RIG-I degradation through an unknown mechanism [32], and this strategy could help HCMV in evading RLR-mediated immune response. As ubiquitination of RIG-I is necessary for activation of downstream signaling pathway, KSHV tegument protein ORF64 deubiquitinates RIG-I to suppress RLR-mediated IFN-I induction [33]. This suggests that similar to TLR inhibiting molecules, HHVs have acquired RLR inhibiting molecules, which help them suppress the overall innate immune responses by targeting the signaling cascade (Figure 1 and Table 1).

Cytosolic DNA sensors The HHVs select different DNA sensors and their downstream adaptors for induction of IFN-I pathway in cell-specific manner [34,35]. HSV-1 infection induces the degradation of IFI16 in a RING-finger Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

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Table 1. Herpesviral components targeting TLRs, RLRs DNA sensors and their downstream IFN-I pathway Herpesviral components Signaling targets

HSV-1

HCMV

KSHV

Effect in anti-viral signaling

References

TLR-mediated IFN-I response TLR MyD88 TRIF

US3, ICP4, ? ICP34.5 ? ? ? ?

vGPCR, vIRF1 RTA RTA

Downregulation of mRNA level [25,26,28] and surface expression Proteasomal degradation of MyD88 [44] Proteasomal degradation of TRIF [44,45] Prevention of interaction with IPS-1, [18,29,30,33] deubiquitination Prevention of dimerization and [18] interaction with IPS-1 Deubiquitination [49]

RLR-mediated IFN-I response RIG-I

US11

?

ORF-64

MDA-5

US11

?

?

TRAF3

UL36

?

?

Cytosolic DNA sensors mediated IFN-I response IFI16

ICP0

pp65/ pUL83

?

Common signaling molecules to all three sensors TBK1/IKKi ICP34.5 ? ORF45, miR-K12-11 IRF3-CBP/p300 US3, US11, pp65/ vIRF1, UL36, pUL83 vIRF2, ICP0, K-bZIP, ICP4, LANA1, ICP34.5, ORF36 VP16 IRF5 ? ? vIRF3 IRF7 ? ? vIRF3/ LANA2, RTA, ORF45

Proteasomal degradation of IFI16, [37–40] enhanced expression of viral major immediate early protein Prevention of kinase activation, substrate mimicry Inhibition of phosphorylation, dimerization, nuclear translocation, formation of IRF-CBP/p300 complex, recruitment of IRF3-CBP/ p300 complex on PRD-III-I element and proteasomal degradation Inhibition of promoter binding Inhibition of phosphorylation, nuclear accumulation and promoter binding proteasomal degradation

[51–54] [18,25,49,56– 64,66,69–73]

[67,68] [53,65,74,75]

HCMV, human cytomegalovirus; KSHV, Kaposi’s sarcoma-associated herpesvirus; US, unique short; vGPCR, KSHVencoded G-protein-coupled-receptor; MyD88, myeloid differentiation primary response gene 88; TRIF, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β; IPS1, interferon-β promoter stimulator 1; TRAF, TNF receptor-associated factor; UL, unique long; K-bZIP, KSHV-encoded basic leucine zipper protein; CBP, cAMP response element-binding protein; VP16, herpes simplex virus protein vmw65; PRD, positive regulatory domain.

and proteasome-dependent manner [34,36] with the help of an E3 ubiquitin ligase HSV-1-ICP0 [37,38]. Interestingly, ICP0-mediated degradation of IFI16 is prevented by another DNA sensor, DAI, which reduces ICP0 expression and inactivates its E3 ligase activity by binding to it [34]. In the case of HCMV infection, IFI16 inhibits viral Copyright © 2015 John Wiley & Sons, Ltd.

replication by inhibiting the expression from viral early (UL44, DNA polymerase UL54) and late gene promoters [39]. However, HCMV cleverly utilizes the presence of IFI16 wherein HCMV tegument protein pp65 (pUL83) recruits it to the promoter of viral major immediate early protein (MIEP), thus, prevents antiviral response by enhancing the Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

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Table 2. Herpesviral components targeting Interferon Signaling Pathway Herpesviral components Signaling targets HSV-1 IFNAR

?

JAK1/Tyk2

UL41, ICP27 UL41, ICP27 ?

STAT1/ STAT2 p48/IRF9

HCMV

KSHV

Effect in anti-viral signaling

?

RIF/ Engagement of IFNARs with RIF ORF10 ? ? Inhibition of phosphorylation, reduction in protein level IE1 RIF/ Inhibition of phosphorylation, ORF10 reduction in protein level Early gene (?) ? Reduction in IRF9 protein level

References [79] [76] [76,79,81–83,86,87] [78,85]

HCMV, human cytomegalovirus; KSHV, Kaposi’s sarcoma-associated herpesvirus; US, unique short; UL, unique long; JAK1/Tyk2, Janus kinases; IFNAR, heterodimeric interferon receptor.

Table 3. Herpesviral components targeting ISG-encoded proteins Herpesviral components Signaling targets

HSV-1

HCMV

KSHV

PKR

ICP34.5, US11

pTRS1, pIRS1

vIRF2, vIRF3

OAS/RNaseL

ICP4, US11 pTRS1, pIRS1 ICP0

ORF94/ UL126a,

PAN RNA

IE1

vIRF3

UL41

vMIA/ pUL37

?

UL41

vBST2

K5/ MIR2

ND10 (PML and Sp100) Viperin

BST2

Effect in anti-viral signaling

References

Dephosphorylation of eIF2α, substrate [88–95] mimicry, prevents autophosphorylation and dimerization of PKR, prevents phosphorylation of eIF2α and nuclear localization of PKR Unavailability of dsRNA, inhibition of [96,98,99] OAS expression and catalytic activity, reduction in RNaseL transcription Interference with SUMOylation status of [107,110–119] ND10, proteasomal degradation mRNA degradation, trafficking Viperin [121,122] from endoplasmic reticulum to mitochondria mRNA degradation, enhancement in [123–125] viral

HCMV, human cytomegalovirus; KSHV, Kaposi’s sarcoma-associated herpesvirus; US, unique short; pTRS1 and pIRS1, HCMV-encoded dsRNA binding proteins; eIFα, eukaryotic initiation factor 2-alpha; UL, unique long.

expression of MIEPs [39,40]. This indicates that HHVs are not always inhibited by the cytosolic DNA sensors but also benefited by their presence. To date, none of the KSHV molecules has been shown to interfere with the function of DNA sensors, however, studying the role of KSHV molecules in evasion of DNA sensor-mediated IFN-I response would help in the better understanding of antiviral evasion mechanism (Figure 1 and Table 1). Copyright © 2015 John Wiley & Sons, Ltd.

HHV FACTORS TARGETING ADAPTORS

Myeloid differentiation primary response gene 88/toll-interleukin-1 receptor domaincontaining adapter-inducing interferon-β/IPS-1 Very few of the HHV factors are evident to directly regulate these adaptor molecules to affect IFN-I production. Interestingly, HSV-1 and HCMV infection regulates MyD88 function to consequently Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

Immune evasion strategies of Herpesvirus regulate NF-κB-dependent inflammatory cytokines [41–43], whereas KSHV-RTA, an E3 ubiquitin ligase, promotes proteasomal degradation of MyD88 in HUVECs to downregulate NF-κB activity as well as IFN-I production during de novo infection and lytic reactivation [44]. Interestingly, KSHVRTA regulates TRIF in cell-specific manner [44,45]. HHVs have not been evidenced with any direct modulator of IPS-1, however, absence of IPS-1 increases KSHV production [46], which gives a clue that KSHV must have IPS-1 modulating factor for unrestricted viral gene transcription and progeny generation (Figure 1 and Table 1). HHV FACTORS TARGETING UBIQUITINASES AND KINASES

TNF receptor-associated factor 6/TNF receptor-associated factor 3 While none of the components of HCMV and KSHV has been evidenced to interfere with TRAF6 and TRAF3 function leading to IFN-I activation, HSV-1-ICP0 and US3-mediated deubiquitination of TRAF6 has been shown in HSV-1-inactivated NF-κB-mediated cytokine response [47,48]. Similarly, HSV-1-UL36 deubiquitinates TRAF3 and restricts TBK1 recruitment on TRAF3, which interferes with IFN-β transcription [49]. Although, similar to HSV-1-UL36, HCMV, and KSHV both have deubiquitinating enzymes but their role in inhibition of TRAFs has not been established (Figure 1 and Table 1).

TBK1/IKKi-IRAK1/IRAK4 Upon activation, both ubiquitin-like and kinase domain of TBK1 interact with each other to facilitate the phosphorylation of IRF3/IRF7 that induces IFN-I expression [50]. HSV-1 tegument protein ICP34.5 binds with TBK1 to prevent its interaction with IRF3 and recruitment to the signaling scaffold by signaling adaptor proteins [51,52]. ICP34.5TBK1 interaction prevents the interaction between ubiquitin-like domain and kinase domain of TBK1 thus prevents kinase activation [51,52]. This in turn inhibits the phosphorylation and nuclear translocation of IRF3 [51,52]. While none of the HCMV components has been shown to directly inhibit IKK-related-kinases, KSHV-ORF45 inhibits the function of TBK1 and IKKi by having itself phosphorylated as an alternative substrate of these kinases Copyright © 2015 John Wiley & Sons, Ltd.

193 instead of IRF7, and thus blocks activation of IFN-I pathway [53]. Also, KSHV miR-K12-11, required for maintaining latency, reduces the expression of IKKi during the infection [54]. None of the HHV factor has yet been identified, which interferes with the function of IRAKs involved in IFN-production but KSHV-miR-K9, downregulates IRAK1 for decreased production of inflammatory cytokines [43]. Thus, by inhibiting the activation of signaling kinases or by encoding substrate mimics of kinases, HHVs interfere with the production of IFN-I, which ultimately help them to evade the IFN-I-mediated antiviral response (Figure 1 and Table 1). HHV FACTORS TARGETING TRANSCRIPTION FACTORS

IRF3, IRF5, and IRF7 During early infection, HSV-1 inhibits IRF3 and IRF7-mediated production of IFN and ISGs [55,56]. Inactivation of IRF3 is brought about by an array of HSV-1 tegument proteins such as US3, US11, UL36, ICP0, ICP4, ICP34.5, and herpes simplex virus protein vmw65 (VP16) in a cell-specific manner [18,25,49,56–59]. ICP0 also prevents circumstantially formed IRF3-CPB/p300 complex from recruitment on IFN-β promoter and accelerates IRF3 degradation in a proteasome-dependent manner [56,57,60]. Although, VP16 interacts with both, IRF3 and CBP, it does not interfere with IRF3 activation and its DNA binding activity, however, it blocks IRF3-CBP/p300 complex formation [59]. While in the case of HSV-1 infection, more than one protein have been discovered, which inactivate IRFs-mediated IFN-I induction; there is only one protein, pp65, of HCMV known to date, which interferes with the function of IRF3 through hypophosphorylating and preventing its nuclear localization during early infection [61] (Figure 1 and Table 1). For immune evasion, KSHV genome encodes for few specific proteins and a family of four viral IRFs (vIRF1–4) as homologues of cellular IRFs [62,63], which interfere with the DNA binding activity of cellular IRFs especially of IRF3, IRF5, and IRF7 [64–68]. Transactivation activity of IRF3, formation of IRF3-CBP/p300 complex and its recruitment on PRD-III-I region of IFNβ promoter is blocked by vIRF1 [64,69], vIRF2/LANA [66,69], KSHV-encoded basic leucine zipper protein (K-bZIP) [70], LANA1 [71], and a KSHV kinase ORF36 [72]. vIRF2 also Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

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194 induces the degradation of IRF3 with the help of a proteolytic enzyme caspase-3 [73]. Interestingly, in contrast to vIRF1 and vIRF2, vIRF3/LANA2 does not target IRF3 but mainly targets cellular IRF7 [65] and IRF5 [67,68] by physically binding to both the IRFs and inhibiting their promoter binding activity and hence reducing IFN-I production. At the very early stage of KSHV infection, function of IRF7 is inhibited by a major tegument protein ORF45 [53,74]. Later on, KSHV-RTA facilitates extensive proteasomal degradation of IRF7 by bilaterally binding to IRF7 and cellular HECT domain of Ubiquitin E3 ligase protein [75] (Figure 1 and Table 1). HHV FACTORS TARGETING JAK–STAT PATHWAY

Interferon receptor Herpesvirus-mediated interference in IFN-I signaling at the level of interferon receptor has not been evidenced much but with few exceptions. During late infection of HSV-1, decrease in IFNAR level is evident, which correlates with the decrease in IFNAR-associated JAK1 level by HSV-1 tegument protein UL41/vhs during early infection [76]. As Tyk2 prevents IFNAR from endocytosis [77], reduced level of JAK1 because of HSV-1-UL41 might interfere with Tyk2 function and hence might cause reduction in IFNAR level. Similarly, HCMV infection inhibits IFNAR1 phosphorylation [78] through the unknown mechanism. While none of the components of HSV-1 and HCMV has been found to block IFN-I signaling directly through IFNARs, KSHV-ORF10/RIF, a delayed–early protein, engages IFN-I receptors (IFNAR1/IFNAR2) and blocks the downstream signaling [79]. In a microarray data, it was revealed that infection with ORF45 mutant KSHV increases the transcription of IFNAR1 and IFNAR2 in comparison with wild type KSHV [80], which suggests a role of ORF45 in IFNAR inhibition (Figure 1 and Table 2).

level of STAT1 [81–83], UL41 alone brings down the level of JAK1 and STAT2 [76], whereas ICP27/UL54 inhibits nuclear accumulation of STAT1, which cumulatively prevents ISGF3 formation [76,81]. Inhibition of JAK/STAT signaling with HSV-1 infection possibly occurs at or before JAK1 activation [83] (Figure 1 and Table 2). The HCMV infection to fibroblasts or endothelial cells stimulates a proteasome-dependent degradation of JAK1 [78] and decreases tyrosine phosphorylation of IFNAR1, Janus kinases [78], and STATs [78,85] by an unknown mechanism. Although HCMV-IE1 physically interacts with STAT2 and also weakly interacts with STAT1, it does not interfere with the phosphorylation of both the STATs and the nuclear translocation of ISGF3 but prevents the interaction of ISGF3 with its cognate ISG promoters thus reduces transcription of several ISGs [86,87]. Moreover, HCMV-mediated downregulation of STAT2 is viral strain-dependent wherein early genes but not the IE or late genes of HCMV get involved [78,85,87]. One study shows that HCMV-pUL27, a homologue of MCMV-pM27 known to mediate the proteolysis of STAT2, does not downregulate STAT2 [85]. HCMV infection to fibroblasts [78,85] and endothelial cells [78] also brings down the level of p48/IRF9 protein [78,85] without affecting the level of IRF9 mRNA [78] (Figure 1 and Table 2). During KSHV infection, KSHV-RIF/ORF10, which shows delayed–early kinetics, aberrantly recruits STAT2 to IFNAR1 in the absence of IFN followed by inhibition of phosphorylation of both the Janus kinases and STATs, which prevents ISGF3 formation and nuclear accumulation [79]. Similarly, vIRF2, present in viral latency and lytic phase inhibits the expression of ISGs regulated by ISGF3 [66]. This suggests that by solely inhibiting JAKSTAT pathway HHVs can evade innate immune response and subsequent development of HHVspecific adaptive immunity (Figure 1 and Table 2). HHV FACTORS TARGETING ISGS: THE EFFECTORS OF IFN-I PATHWAY

Janus kinases, STATs, and ISGF3 complex Inhibition of JAK/STAT pathway by HHVs is the key step to stop ISGs production and further amplification of IFN-I. During early HSV-1 infection, phosphorylation of Janus kinases (Tyk2 and JAK1) and STATs is inhibited [81–84]. While UL41 and ICP27/UL54 commonly lower the phosphorylation Copyright © 2015 John Wiley & Sons, Ltd.

PKR Infection of MEF with HSV-1-ICP34.5-null virus upregulates PKR [26], which suggests the role of ICP34.5 in PKR inactivation. ICP34.5 bilaterally interacts with eukaryotic initiation factor 2-alpha (eIF2α) and host protein-phosphatase-1 (PP1) to Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

Immune evasion strategies of Herpesvirus dephosphorylate eIF2α and prevent host translational arrest induced by PKR [88,89]. Unlike ICP34.5, US11 binds to PKR in an RNA-dependent manner to competitively inhibit PKR-mediated phosphorylation of eIF2α by itself getting phosphorylated at its PKR substrate domain [90]. Thus, US11 compensates for ICP34.5 deficiency in ICP34.5 null HSV-1-infected cells if present before activation of PKR [91,92]. Binding of US11 to PKR might interfere with self-dimerization and interaction of PKR with other members of the PKR family. Similarly, HCMV-encoded dsRNA binding proteins pTRS1 and pIRS1 interfere with activation of PKR by translocating it in the nucleus so that PKR becomes away from its activating environment, that is, cytosolic dsRNA and its substrate eIF2α [93]. Similar to HSV-1-US11 [91], HCMV-pIRS1 can restore the function of HSV-1-ICP34.5 in an ICP34.5-deleted chimeric HSV-1, by inhibiting the PKR activity [58]. KSHV prevents PKR-mediated host protein shut off by utilizing its vIRFs wherein vIRF2 physically interacts with PKR to prevent its activation [94], and vIRF3 prevents PKR-mediated phosphorylation of eIF2α [95]. Thus, by encoding proteins similar to host antiviral proteins such as dsRNA binding PKR, HHVs competitively inhibit the function of PKR and escape the immune response mounted by the host (Figure 1 and Table 3).

OAS/RNaseL

Infection of mouse embryonic fibroblast with HSV1-ICP34.5 null virus upregulates OAS-1B and OAS1C [26] expressions. During the late phase of productive life cycle, two of the HSV-1 proteins, ICP4 and US11, lead to inactivation of OAS without affecting its transcription in IFN-I-treated primary human cells [96]. US11 tends to inhibit OAS activity [96] similar to PKR [97] by making dsRNA unavailable for OAS. Not always but in few cases of HCMV infection, pTRS1 and pIRS1 inactivates RNaseL through an unknown mechanism [98], whereas HCMV-UL126a inhibits OAS1 expression and catalytic activity during productive infection [99]. Although less is known about the HCMVencoded direct inhibitors of OAS/RNaseL, screening for HCMV homologues of HSV-1-US11 and other US22 gene family members for their activity in OAS/RNaseL inhibition would help understand antiviral evasion of this pathway well. During lytic infection, KSHV-encoded non-coding PAN RNA decreases the transcription of IFNα-16 and RNaseL Copyright © 2015 John Wiley & Sons, Ltd.

195 through an unknown mechanism [100]. As activation of OAS and PKR takes place in a similar manner, HHVs also utilize more or less same proteins to inhibit both the host proteins for evasion of antiviral response mounted by OAS and PKR (Figure 1 and Table 3).

ND10/PML-NB A subnuclear structure nuclear domain 10 (ND10) acts as replication and transcription hub for genomes of several viruses [101]. At the same time, viruses evolve strategies to degrade ND10 for their benefit as ND10 plays a role in host antiviral immunity [102]. The ND10 components PML, hDaxx, and Sp100 maintain the integrity of ND10 complex [103,104] by making a small ubiquitin-like modifier (SUMO) bridge [105,106] and depletion or deSUMOylation of anyone of them would lead to disruption of ND10. During early infection, HSV-1-ICP0 colocalizes with ND10 and inhibits SUMOylation of PML and Sp100 [107] whereas during lyticreactivation, ICP0 recruits E2-ubiquitin-conjugating enzyme UbcH5a on ND10 [37,108,109] for proteasomal degradation of PML and Sp100 [110–112]. Since, PML and ICP0 both contain RING finger domain which is essential for PML SUMOylation [106], interference in PML SUMOylation by ICP0 appears as competitive inhibition. Similar to HSV1-ICP0, HCMV-IE1 disrupts ND10 [107,113–115] either by inhibiting PML SUMOylation, or by deSUMOylating PML [107,113,116] and Sp100 [107,117]. Unlike HSV-1-ICP0 and HCMV-IE1, KSHV-vIRF3 disrupts ND10 by increasing PML SUMOylation, which helps in vIRF3–ND10 interaction through SUMO bridge and degradation of ND10 by proteasome [118,119]. This shows that HHVs are capable of hijacking host SUMO machinery for modulating antiviral responses of the host (Figure 1 and Table 3).

Viperin Viperin is an interferon-inducible antiviral protein, activity of which ranges from blocking viralreplication, protein synthesis to blocking viral egress [120]. To evade the antiviral activity of viperin, HSV-1 reduces the accumulation of viperin mRNA in the infected cell with the help of UL41 [121]. Similarly, HCMV infection redistributes cellular viperin from the endoplasmic reticulum to mitochondria and finally to HCMV assembly Rev. Med. Virol. 2015; 25: 187–201. DOI: 10.1002/rmv

P. Kumari et al.

196 compartment. Trafficking of ER-localized viperin to mitochondria of HCMV infected cells is mediated through interaction of vMIA with viperin. In the mitochondria, viperin interacts with proteins involved in ATP synthesis and reduces ATP generation, and hence results into actin cytoskeleton disruption and enhancement of viral infection [122]. Thus, acting as an antiviral protein, viperin is induced by HCMV for its own benefit than for benefit of the host. There is no study that shows KSHV components, directly or indirectly inhibiting the function of viperin (Figure 1 and Table 3).

BST2/Tetherin During primary infection and upon lytic reactivation HSV-1 and KSHV evade the anti-egress and antiviral activity of BST2 by reducing its level in the infected cell [123,124]. While HSV-1 utilizes its endoribonuclease UL41 to stimulate BST2 mRNA degradation [123], KSHV induces its ubiquitinmediated proteasomal degradation by KSHV-K5/ MIR2, an E3 ubiquitin ligase [124]. In contrast to the fact that BST2 is known to prevent the egress of HSV-1 [123] and KSHV [124], recently it was shown that BST2 expressing HFF, HEK293 or hematopoetic cells increased HCMV entry and thereby infection to these cells [125]. BST2 is also present in HCMV virion particles, and it is speculated that BST2 of host cell surface and viral BST2 interact with each other to enhance membrane fusion and thereby viral entry [125]. This shows that ISGs do not always act against the infecting viruses, rather their presence sometimes help the virus for establishing the infection (Figure 1 and Table 3). CONCLUSIONS The HHVs, as a most common type of human virus, infect almost 90% of the world’s population at some point of one’s lifetime. HHVs hijack host cellular machineries for cellular transportation, replication, and establishment of successful infection. REFERENCES

Primary infection and lytic reactivation following latency both stimulate immune response, which is mainly mediated by IFN-Is, which act as a primary barrier. HHVs evolve to evade antiviral activities by timely targeting several immune signaling molecules to block the immune signaling pathway. In different phases of their life-cycle, HHVs use their components to curtail various signaling molecules either by degrading them, reducing their mRNA accumulation, or by interfering with the formation of transcription complex or signalosome. Although, therapeutics are available for treating herpes infection, which are based on targeting viral DNA polymerases, however inadequate knowledge of herpesviral molecules involved in immune evasion limits the development of therapeutics against HHV infection. To understand host-viral interaction with the perspective of human herpesviral immune evasion, more HHV molecules and their homologues should be screened across the spectrum of herpesviruses for their activity towards inhibiting immune pathways. This would enhance the knowledge for developing anti-herpesviral therapeutics and vaccines. CONFLICT OF INTEREST The authors have no competing interest. ACKNOWLEDGEMENTS P. K. is supported by the Council of Scientific & Industrial Research (CSIR). H. K. is supported by research grant numbers SR/S2/RJN-55/2009 and BT/PR6009/GBD/27/382/2012 from the Department of Science and Technology (DST) and Department of Biotechnology (DBT), Government of India. S. N. was supported by research grant number 2012/37B/31/BRNS from the Department of Atomic Energy (DAE), Government of India. Authors are also supported by Intramural Research Grants of Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India.

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