Understanding the interplay between host immunity and Epstein-Barr virus in NPC patients

Figures & data

Table 1 A brief summary of mechanisms exploited by EBV latent products to promote NPC formation and development

General mechanisms	Viral products	Molecular mechanisms	References
Promotion of transformation and angiogenesis	EBNA1	Mediates AP-1 to upregulate IL-8, VEGF, HIF-1α	^Citation25
	LMP1	Upregulates the phosphorylation of histone H3; inhibits the LKB1-AMPK pathway	^Citation30,Citation31
	LMP1	Mediates the NF-κB, MEK-ERK, and JNK pathways to induce endocan; mediates the degradation of prolyl hydroxylases 1 and 3 to upregulate HIF1-α	^Citation32,Citation33,Citation34
	EBERs	Upregulate IGF-1	^Citation54
	BARF1	Increases the cell growth rate	^Citation56
	miR-BART1	Upregulates PSAT1 and PHGDH	^Citation57
	miR-BART3	Inhibits DICE1 tumor suppressor	^Citation58
Inhibition of apoptosis	EBNA1	Disrupts PML nuclear bodies	^Citation26
	LMP1	Inhibits Chk1 to impair the G2 checkpoint; increases p53-mediated survival; mediates EGFR and STAT3 to induce cyclin D1	^Citation43,Citation44,Citation45
	EBERs	Upregulate Bcl-2 and downregulate caspase-3 and PARP	^Citation55
	miR-BART1	Inhibits LMP1-mediated apoptosis	^Citation59
	miR-BART5	Inhibits PUMA	^Citation60
Induction of stem cell-like phenotype	LMP1	Induces the CSC/CPC-like phenotype and self-renewal; activates the hedgehog pathway to induce CD44v6, NGFR (p75NTR), and CXCR4	^Citation46,Citation47
	LMP2A	Activates hedgehog to induce CD133 and CXCR4; induces stem-like cells and self-renewal	^Citation47,Citation51
Enhancement of cell mobility	EBNA1	Upregulates stathmin 1, aspin, and Nm23-H1	^Citation28
	EBNA1	Mediates TGF-β1/miR-200/ZEB to induce EMT	^Citation29
	LMP1	Activates the PI3K/Akt pathway to promote actin stress-fiber formation; interacts with FGD4 to activate Cdc42; mediates the NF-κB pathway to upregulate TNFAIP2	^Citation36,Citation37,Citation38
	LMP1	Downregulates E-cadherin to induce EMT	^Citation39
	LMP1	Upregulates MMPs (e.g., MMP1, 3 and 9)	^Citation40,Citation41,Citation42
	LMP2A	Induces EMT	^Citation51
	LMP2A	Mediates the ERK/Fra-1 pathway to induce MMP9	^Citation52
	miR-BART7	Enhances migration and invasion and inhibits PTEN to induce EMT	^Citation61,Citation62
	miR-BART9	Inhibits E-cadherin to induce EMT	^Citation63

AMPK, AMP-activated protein kinase; AP-1, transcription activator-1; Bcl-2, B-cell lymphoma-2; CSC/CPC, cancer stem cells/cancer progenitor cells; CXCR4, C-X-C chemokine receptor type 4; DICE1, deleted in cancer 1; EGFR, epidermal growth factor receptor; HIF-1α, hypoxia-inducible factor 1α; IGF-1, insulin-like growth factors-1; JNK, c-Jun N-terminal kinase; LMP1, AMPK-liver kinase B1-AMP-activated protein kinase; NGFR, nerve growth factor receptor; PARP, poly-ADP-ribose polymerase; PHGDH, phosphoglycerate dehydrogenase; PSAT1, phosphohydroxythreonine aminotransferase 1; PTEN, phosphatase and tensin homolog located on chromosome 10; PUMA, p53 upregulated modulator of apoptosis; STAT3, signal transducer and activator of transcription; TNFAIP2, tumor necrosis factor-alpha inducible protein-2; VEGF, vascular endothelial growth factor; MEK-ERK, mitogen-activated protein kinase-extracellular signal-regulated kinase.

Table 2 Strategies of cellular response evasion exploited by individual EBV antigens detected in NPC

Strategies	Viral antigens	Mechanisms	References
Switch off immunodominant viral antigens	e.g., EBNA2, the EBNA3 family	Not well-known, epigenetic modification?	^Citation123
Impair the HLA I or HLA II pathway	EBNA1	Blocks proteasomal HLA II pathway degradation via the GAr domain	^Citation128,Citation129
	LMP1	Induces c-Myc via IL6 and the JAK3/STAT3 pathway	^Citation135
	LMP1	Self-aggregation via its first transmembrane domain	^Citation136
	BZLF1 (Zta)	Suppresses the class II transactivator CIITA	^Citation139
	BGLF5	Directly shuts off host HLA I synthesis	^Citation137
	BNLF2a	Inhibits TAP and surface HLA I expression	^Citation138,Citation139
Upregulate immune-inhibitory molecules	LMP1	Induces IL-10 via p38/SAPK2	^Citation143
	EBERs	Induce IL-10 via PKR-independent pathways	^Citation144
	LMP1	Induces DcR3 via NF-κB and PI3K pathways	^Citation147
	EBV (specific antigen, not yet determined)	Induces B7-H1 and ICOS-L	^Citation88
Recruit Tregs and induce T-cell anergy	LMP1	Induces Tregs via chemokines (e.g., IL-10 and TGF-β)	^Citation155
	LMP1	Directly inhibits T-cell proliferation	^Citation156

ICOS-L, inducible costimulatory ligand; JAK3, Janus kinase 3.

short-legendFigure 1.

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