Innate immunity
To achieve long-term survival in the host and establish persistent infection, EBV has also evolved many strategies to evade host immune surveillance. First, EBV can downregulate the activation of several PRRs. Second, it can also directly target downstream factors. Finally, it can affect the function of some immune cells. (Table
1)
Table 1
EBV immune evasion proteins and microRNAs.
LMP1 | Latency II | Reducing TLR9 promoter activity; decreasing TLR9 mRNA and protein expression levels | |
Reducing the phosphorylation of Tyk2 and STAT2; inhibiting IFN pathway activation | |
BGLF5 | Lytic immune modulator | Depleting TLR9 mRNA and reducing its protein expression level | |
Inducing host mRNA degradation; blocking the synthesis of MHC-I | |
BPLF1 | Tegument | Removing ubiquitin tags from TRAF6; negatively regulating TLR signaling | |
Mediating DUB-dependent deubiquitination of TBK1 and STING; inhibiting RIG-I-MAVS and cGAS-STING signaling | |
BHRF1 | Lytic immune modulator | Inducing mitochondrial fission; causing MAVS protein degradation; blocking RLRs signaling | |
miR-BART6-3p | EBV-encoded microRNA | Targeting the 3’UTR of RIG-I mRNA; inhibiting the expression of IFN-β | |
BZLF1 (ZTA) | Lytic replication | Binding directly to IRF7; inhibiting IRF7 activation | |
Upregulating SOCS3 expression; indirectly inhibiting IFN-α production | |
Binding to CIITA; inhibiting MHC-II transcription | |
BRLF1 (RTA) | Lytic replication | Reducing the mRNA levels of IRF 3 and IRF7 and the activation of the IFN-β promoter; inhibiting the expression of IFN-β | |
LMP2 | Latency II | Reducing the phosphorylation of Tyk2, STAT1 and JAK; inhibiting ISG transcription and the IFN production | |
LF2 | Lytic immune modulator | Binding to IRF7 to block its dimerization; inhibiting IFN-α production | |
BGLF4 | Late gene expression | Reducing the activity of IFN-β promoter; inhibiting IRF3 signaling | |
Interfering with the interaction between NF-κB and UXT; inhibiting the activity of NF-κB | |
Phosphorylating SAMHD1; decreasing the activity of dNTPase | |
miR-BART18-5p | EBV-encoded microRNA | Targeting MAP3K2; blocking viral replication | |
miR-BART4-5p | EBV-encoded microRNA | Downregulating proapoptotic protein BID activity; inhibiting target cells apoptosis | |
EBNA1 | Latency I | Inhibiting ULBP1 and ULBP5; escaping NK cell recognition | |
BNLF2a | Lytic immune modulator | Inhibiting TAP function; preventing loading of antigenic peptides onto MHC-I | |
BILF1 | Lytic immune modulator | Triggering endocytosis of MHC-I molecules and degradation | |
BZLF2 | Entry glycoprotein | Binding to MHC-II complex; blocking the antigen recognition of CD4 + T cells | |
EBV can reduce TLR expression and/or signal transduction to escape cellular immune responses to TLR activation [
67]. Fathallah et al. found that the EBV oncoprotein LMP1 is a strong inhibitor of TLR9 transcription, and its overexpression regulates NF-κB pathway activation, thereby reducing TLR9 promoter activity and its mRNA and protein expression levels [
68]. Moreover, the EBV exonuclease BGLF5, a protein kinase constituent in all herpesviruses, evades host immune signaling by depleting TLR9 mRNA levels and thereby reducing TLR9 protein expression [
69]. Due to its deubiquitinase (DUB) activity, the EBV large tegument protein BPLF1 can negatively regulate TLR signaling by removing ubiquitin tags from proteins in the TLR signaling cascade [
45].
Oligomeric RIG-I or MDA5 (an RLR family protein), with action mediated by K63-linked ubiquitin chains, interacts with the N-terminal caspase recruitment domain in mitochondrial antiviral signaling (MAVS) located on the mitochondrial membrane and induces RLR-mediated signal transduction. As an anti-apoptotic protein, EBV BHRF1 can induce mitochondrial fission, cause mitochondrial and MAVS protein degradation, block RLR-mediated signal transduction, and weaken antiviral effects [
70]. As an EBV-encoded microRNA, miR-BART6-3p can target the 3’UTR of RIG-I mRNA, thereby inhibiting the expression of IFN-β [
71]. BPLF1 also represses the expression of the RIG-I-MAVS and cGAS-STING pathways via the DUB-dependent deubiquitination of TBK1 and STING [
72].
Moreover, EBV can target DNA sensors. EBV induces the body to produce the E3 ubiquitin ligase tripartite motif-containing protein 29 (TRIM29), which can degrade STING, and the downregulation of STING may inhibit the production of IFN-I and the innate immune response [
73].
In addition to affecting the activation of several PRRs, EBV can also directly target downstream factors to escape the immune system [
74]. Studies have revealed that BZLF1 can directly or indirectly downregulate the expression of IRF7 to inhibit the production of IFN-α [
75,
76]. BRLF1 inhibits the production of IFN-β by reducing the mRNA levels of IRF 3 and IRF7 and reducing the activation of the IFN-β promoter [
77]. LMP-1 inhibits the IFN pathway by reducing the phosphorylation of tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription 2 (STAT2) [
78]. LMP-2 A/B inhibited interferon-stimulated gene (ISG) transcription and IFN production by reducing the phosphorylation of Tyk2, STAT1 and JAK [
79]. As an EBV tegument protein, LF2 inhibits IFN-α production by binding to IRF7 to block its dimerization [
80]. As a viral protein kinase, BGLF4 not only inhibits IRF3 and NF-κB signaling [
81,
82] but also phosphorylates sterile alpha motif and HD domain 1 (SAMHD1), resulting in a decrease in its deoxynucleotide triphosphate hydrolase (dNTPase) activity, allowing EBV to evade host immunity [
83]. Studies have found that cellular dsRNA-dependent protein kinase (PKR) plays a key role in antiviral innate immunity, and EBERs can bind to PKR and inhibit its activation, thereby preventing PKR-mediated apoptosis [
84]. EBV encodes at least 40 kinds of miRNAs, which are located in the
BHRF1 gene and BART transcription sequence in the form of gene clusters [
85]. In addition to the abovementioned miR-BART6-3p, other miRNAs encoded by EBV, mainly miR-BART18-5p and miR-BART4-5p, evade host immunity by maintaining their presence in the latent state and inhibiting the apoptosis of infected cells [
86,
87].
EBNA1 enables newly infected B cells to escape NK cell recognition by inhibiting NK cell receptor ligands UL16-binding protein 1 (ULBP1) and ULBP5 [
88]. EBV evades the immune response by upregulating the expression of T-cell inhibitory factors so that infected pDCs cannot induce a T-cell response [
89].
Adaptive immunity
Notably, EBV has evolved many strategies to evade adaptive immunity. On the one hand, EBV can interfere with MHC-I antigen presentation. The proteasome produces antigenic peptides, transports them to the endoplasmic reticulum through the transporter-associated with antigen processing (TAP) complex, binds to MHC-I, and then transports the peptides to the cell surface, where they are recognized by CD8 + T cells. BGLF5 abrogates MHC-I gene expression through a host-mediated shutdown program [
90]. BNLF2a abrogates the TAP-mediated import of antigenic peptides [
91]. BILF1 triggers endocytosis of MHC-I molecules and their degradation in lysosomes [
92]. On the other hand, EBV can interfere with MHC-I antigen presentation. Class II transactivator (CIITA) can promote the expression of MHC-II, and BZLF1 can bind to CIITA, which inhibits MHC-II transcription [
93]. As a lytic phase protein, BZLF2 can block antigen recognition by CD4 + T cells by binding to the MHC-II complex on the surface of B cells [
94]. It has been reported that EBV can also increase the number of specific regulatory T cells (Tregs), and the action of these EBV-specific Tregs may be related to the escape of tumor cells [
95,
96].