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. 2018 Sep 30;63(18):1223-1234.
doi: 10.1016/j.scib.2018.07.009. Epub 2018 Jul 20.

Activation and counteraction of antiviral innate immunity by KSHV: an Update

Xiaoqin Wei  1 , Ke Lan  2
Affiliations

Activation and counteraction of antiviral innate immunity by KSHV: an Update

Xiaoqin Wei et al. Sci Bull (Beijing). .

Abstract

The innate immune responses triggering production of type I interferons and inflammatory cytokines constitute a nonspecific innate resistance that eliminates invading pathogens including viruses. The activation of innate immune signaling through pattern recognition receptors (PRRs) is by sensing pathogen-associated molecular patterns derived from viruses. According to their distribution within cells, PRRs are classified into three types of receptors: membrane, cytoplasmic, and nuclear. Kaposi's sarcoma-associated herpesvirus (KSHV), a large DNA virus, replicates in the nucleus. Its genome is protected by capsid proteins during transport in the cytosol. Multiple PRRs are involved in KSHV recognition. To successfully establish latent infection, KSHV has evolved to manipulate different aspects of the host antiviral innate immune responses. This review presents recent advances in our understanding about the activation of the innate immune signaling in response to infection of KSHV. It also reviews the evasion strategies used by KSHV to subvert host innate immune detection for establishing a persistent infection.

Keywords: Evasion strategies; Innate immune response; KSHV; PRRs.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Figure 1.
Figure 1.
(a) Schematic presentation of KSHV structure. KSHV virions exhibit an icosahedral nucleocapsid surrounded by a lipid bilayer envelope, and a tegument layer between the capsid and envelope. (b) Schematic representation of KSHV life cycle in infected cells. KSHV life cycle contains two phases of infection: a short lytic replication and a persistent latent replication. During latency, LANA protein tethers KSHV episome to host cell chromosome. KSHV episome replicates along with host cell dividing during KSHV latent infection. Upon exogenous stimuli, e.g. cellular stress, valproate, butyrate etc., KSHV can be induced to switch from latency to lytic replication. During this phase, the RTA promoter is activated and most viral genes are expressed. During lytic replication, the KSHV genome replicates in a rolling cycle mechanism. Linear genomes are packaged into capsids, and then host cell are destroyed, leading to release of new virions to infect new host cells.
Figure 2.
Figure 2.
Activation and evasion of membrane PRR-mediated antiviral response by KSHV. Following KSHV infection of cells, specific TLRs are activated, initiating recruitment of adaptor proteins MyD88 or TRIF. MyD88 recruits IRAK4, IRAK1, IRAK2 and TRAF6, triggering activation of IKK complex of NEMO and IKKαβ that mediate nuclear translocation of NF-κB, essential for IFN-β production. Recruitment of TRIF to TLRs activates recruitment of TRAF3 and subsequent activation of virus-mediated kinases (TBK1 and IKKε), triggering IRF3/7 phosphorylation, which homodimerizes, translocates to the nucleus, and triggers type I IFN induction. KSHV-encoded proteins (red) inhibit immune responses initiated by TLRs. K4.2, ORF21 and ORF31 inhibit TLR2-dependent signaling activation. RTA encoded by ORF50 reduces TLR2 and TLR4 and disrupts plasma membrane localization of TLR2 and TLR4. TLR4 is targeted by vGPCR, central in TLR4 downregulation. E3 ubiquitin ligase KSHV RTA promotes proteasomal degradation of MyD88 and TRIF. KSHV miR-K9 and miR-K5 inhibit TLR signaling by targeting MyD88 and IRAK1. ORF57 inhibits TLR3-mediate signaling by blocking TLR3 phosphorylation. KSHV uses CO (green) to inhibit TLR4 signaling.
Figure 3.
Figure 3.
Activation and evasion of cytoplasmic PRR-mediated antiviral response by KSHV. Following KSHV infection, RIG-I exposes its CARD domain for TRIM25 binding, which conjugates K63-polyubiquitin chains to RIG-I and activates RIG-I. Activation of RIG-I causes binding to adaptor protein MAVS on mitochondria, activating IRF3/7 and NF-κB and inducing production of type I IFN and pro-inflammatory cytokines. Viral deubiquitinase KSHV ORF64 (red) targets and inhibits TRIM25-mediated RIG-I ubiquitination and blocks IFN signaling. KSHV uses cell protein NLRX1 (green) to block RIG-I-mediated signaling. On activation, NLRP1/3 binds downstream adaptor ASC and substrate procaspase-1, forming the inflammasome. Caspase-1is activated, processing pro-IL-1 and pro-IL-18 into active IL-1 and IL-18 and regulating type I IFN and inflammatory pathways. KSHV encodes ORF63 protein (red), a viral homolog of human NLRP1 without CARD and PYD effector domains of its cellular counterpart, suppressing NLRP1- and NLRP3-mediated signaling by interacting with NLRP1 and NLRP3.
Figure 4.
Figure 4.
Activation and evasion of cytoplasmic DNA sensors-mediated antiviral response by KSHV. DNA binding to cGAS and DNA-binding partner PQBP1 activates enzymatic activity. CGAS catalyzes production of cGAMP, a second messenger that activates STING, a dimer that recruits TBK1 to promote its phosphorylation. Phosphorylated STING recruits IRF3 and triggers IRF3 phosphorylation by TBK1. Activation of IRF3 causes NF-κB to enter the nucleus and trigger innate immune responses. KSHV-encoded proteins (red) inhibit cGAS and STING-dependent responses. Tegument protein ORF52 binds DNA and cGAS and directly inhibits cGAS-dependent DNA sensing. Cytoplasmic LANA isoforms inhibit cGAS-STING-dependent induction of interferon by directly interacting with cGAS. KSHV protein. VIRF1 disrupts STING-TBK1 interaction and prevents STING phosphorylation and activation by interacting with STING. Cytoplasmic Rad50, Mre11 and CARD9 sense cytoplasmic DNA and activate NF-κB-mediated innate antiviral responses. Cytoplasmic KSHV LANA isoforms (red) target Rad50 and Mre11 to interfere with activation of the NF-κB cascade.
Figure 5.
Figure 5.
Activation of nuclear DNA sensor-mediated antiviral response by KSHV with regulation of downstream kinases of PRR-mediated signal pathways. After KSHV genome entry into the nucleus, IFI16 associates with BRCA1-H2B or BRCA1 and binds the viral genome, leading to BRCA1-mediated p300 recruitment, interaction with IFI16, and acetylation (Ac) of IFI16 and H2B by p300. Acetylated IFI16-H2B-BRCA1 complex transports to the cytoplasm and associates with STING, leading into TBK1 and IRF3/7 phosphorylation, IRF3/7 nuclear translocation and type I IFN production. Acetylated IFI16-BRCA1 interacts with ASC and procaspase-1 in the nucleus. BRCA1-IFI16-ASC-procaspase-1 complex is transported to the cytoplasm via Ran-GTP, activating caspase-1. IL-1β generation results in inflammasome-IL-1β responses. Signaling pathways activated by the different classes of PRRs converge at the level of the IKK complex and related kinases IKKε and TBK1 to activate IRF3/7, inducing IFN production. KSHV encodes proteins (red) that block downstream signaling cascades of PRRs. KSHV miR-K12–11 inhibits IKKε-mediated IRF1/7 phosphorylation by inhibiting IKKε expression. KSHV harbors four viral IRFs (vIRF1–4) with different mechanisms to block IRF3/7-mediated IFN transcriptional activity. KSHV RTA promotes proteasome-dependent degradation of IRF3/7 by directly targeting IRF7 or associating with cellular E3 ligase. KSHV ORF45 interacts with ORF7 and competitively inhibits IRF7 phosphorylation by IKKε and TBK1. KSHV encodes K-bZIP protein that binds directly to the IFN-β promoter and prevents IRF3 from binding to the IFN-β promoter, inhibiting type I IFN production.
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