Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway

Table 1

Summary of positive and negative regulations of the Nrf2 pathway by various pathogenic viruses.

Virus	Disease	Host cells or animals	Viral ROS inducer	ROS level	Effect on redox defense system	Effect on Nrf2	Effect on Nrf2 target genes	Effect on others	Reference
MoMuLV ts1	Neurodegenerative disease	Immortalized astrocytes	gPr80env	H2O2↓	GSH↑, cysteine↑, γ-GT↑, CAT↑	↑	xCT↑, GCLC↑, GCLM↑, GPx↑	Sensitivity to cystine deprivation↑, Bcl-2↑, xCT antiporter↑, GRP78↑, GRP94↑, CalR↑	Qiang et al. [58]
HIV	Neurodegenerative disease	Astrocytes	gp120	↑	ND	↑	NQO1↑, HO-1↑	Ca^2+↑	Reddy et al. [8, 9]
	Neurocognitive disorder	Human neuroblastoma cells	Tat	H2O2↑	ND	↑	NQO1↑, CAT↑, SOD1↑, SOD2↑, HO-1↑	NMDA receptor↑, SMO↑, spermidine↑	Mastrantonio et al. [65]
	AIDS	HeLa-CD4-LTR-β-galactosidase cells	Tat	↑	GSH↓	↑	NQO1↑, HO-1↑, AKR1C1↑	Tat-induced LTR transactivation↓, NF-κB↑	Zhang et al. [63], Zhang et al. [64]
	Respiratory disorder	Alveolar epithelial cells	gp120, Tat	↑	GSH↓	↓	ND	TER↓	Fan et al. [51]
	Respiratory disorder	Monocyte-derived macrophages	gp120, Tat	ND	ND	↓	NQO1↓, GCLC↓	H2O2 scavenging↓, phagocytosis↓	Staitieh et al. [53]
	AIDS	Transgenic rats	gp120, Tat	↑	ND	↓	HO-1↓	Senescence↑	Davinelli et al. [50]
HCV	Viral hepatitis	Hepatoma cells	ND	ND	ND	Phosphorylation↑	NQO1↑, HO-1↑, GCL↑	p38↑, JNK↑, phospho-Bad↑, phospho-Akt↑	Burdette et al. [48]
	Viral hepatitis	Hepatoma cells	Core, NS5A	↑	ND	Nuclear localization↑	HO-1↑, NQO1↑	PKC↑, CK2↑, PI-3K↑	Ivanov et al., 2011; Smirnova et al., 2016
	Viral hepatitis	Persistently infected hepatoma cells	ND	ND	ND	Phosphorylation↑, nuclear localization↑	NQO1↑, GCLC↑, Maf G↑, G6PD↑, MTHFD2↑, ASNS↑	LD↑, cholesterol↑, triacylglycerol↑	Sugiyama et al. [77]
	HCC	Hepatoma cells	ND	ND	GSH↑	↑	PGD↑, GCLC↑, NQO1↑, UGDH↑	Tolerance to anticancer drug↑, phospho-p62↑, interaction with KEAP1↑	Saito et al. [78]; Medvedev et al., 2017
	Viral hepatitis	Hepatoma cells	Core, NS3	↑	ND	↓	NQO1↓, GCLC↓, GPx↓	sMaf↑, sMaf delocalization↑, proteasomal activity↓, PSMB5↓, sMaf-NS3 interaction↑	Carvajal-Yepes et al. [49]
Influenza virus	Respiratory disease	Human primary alveolar type I-like cells	ND	↑	ND	Nuclear localization↑	HO-1↑	Caspase 1↑, caspase 3↑, IL-8↑	Kosmider et al. [44]
	Respiratory disease	Human bronchial adenocarcinoma cells	ND	↑	ND	Phosphorylation↓	ND	Fibronectin↓	Simon et al. [84]
RSV	Respiratory disease	Human alveolar type II-like epithelial cells and small airway epithelial cells	ND	↑	GSH↓	↓	SOD1↓, SOD2↑, SOD3↓, GST↓, CAT↓, GPx↓	F2-isoprostane↑, NOX↑, RANTES↑, IL-8↑	Hosakote et al., 2009
	Respiratory disease	Nrf2(+/+) mice	ND	↑	ND	Nuclear ARE binding↑↓	GCLC↑↓, UGT1↑↓, NQO1↑↓, HO-1↑↓, GST↑↓, GPx↑↓	ND	Cho et al. [19]
	Respiratory disease	Murine bronchoalveolar lavage, patient samples	ND	↑	GSH↓	Nuclear form↓	SOD1↓, SOD3↓, CAT↓, GST↓, GPx↓	F2-isoprostane↑, MDA↑	Hosakote et al. [20], Komaravelli and Casola [89]
	Respiratory disease	Human bronchial epithelial cells	ND	↑	ND	ND	HO-1↓, GPx↓	ICAM-1↑, b-tubulin↓, Foxj1↓, Dnai2↓, MUC5AC↑, hCLCA1↑, IL-13↑, IL-8↑, IL-6↑, TNF-α↑	Mata et al. [88]
	Respiratory disease	Human alveolar type II-like epithelial cells (A549) and small airway epithelial cells	ND	↑	ND	↓	NQO1↓, CAT↓, SOD1↓	CBP↓, HDAC1↑, HDAC2↑	Komaravelli et al. [90]
	Respiratory disease	Human alveolar type II-like epithelial cells and small airway epithelial cells	ND	ND	ND	↓	CAT↓, SOD1↓	Nrf2-SUMO2/3↑, PML↑, Nrf2-PML↑	Komaravelli et al. [43]
HBV	Viral hepatitis	HepG2.2.15, HepAD38	HBx and LHBs	↓	8-OHdG↓, DNPH↓	↑	NQO1↑, GPx↑, GCL↑	c-Raf↑, constitutive proteasome↑, immunoproteasome↓, Mafs↓	Schaedler et al. [99]
	Viral hepatitis	HepG2 cells	HBx	↑	ND	↑	HO-1↑, NQO1↑	p-ATM↑, p-Chk2↑, PKC-d↑	Matsuda et al. [100]
	Viral hepatitis	HepG2, HepG2.2.15, Huh7	HBx	ND	ND	↑	G6PD↑, NQO1↑, GST↑, Cyp2a5↑	p62-KEAP1↑, immobilized KEAP1↑, cell proliferation↑	Liu et al. [46]
	Viral hepatitis	HepG2, Huh7.5, HepAD38, HBV transgenic mice	ND	ND	ND	↑	NQO1↑, GCLC↑, HBsAg↑	PCNA↓, insulin receptor inside↑, insulin receptor surface↓, ALT↑, AST↑, insulin binding↓, α-taxillin↑, insulin response↓	Barthel et al. [101]
	Viral hepatitis	Huh7.5 and HepG2	HBsAg	↑	ND	↓	NQO1↓, AP1↓, GPx↓	HBsAg↓, HBeAg↓, subviral particles accumulate at ER due to preS1preS2 domain	Peiffer et al. [52]
HSV	Encephalitis-associated neurotoxicity	Herpes encephalitic mice, microglial cells	ND	↑	GSH↓	↑	HO-1↑, GPx↑	ND	Schachtele et al. [105]
HCMV	Congenital abnormalities	Human foreskin fibroblasts	ND	ND	GSH↑	↑	SOD↑, GPx↑, GCLC↑, HO-1↑, NQO1↑	Maintenance of mTOR activity	Tilton et al. [106]
	Congenital abnormalities	Primary human foreskin fibroblasts	Viral gene products	↑	ND	↑	HO-1↑, GCLC↑	IE1↑, IE2↑, CK2↑, cell viability↑, GSH↑	Lee et al. [11, 42]
KSHV	Sarcoma	Human dermal microvascular endothelial cells	ORF71, vFLIP	↑	ND	Nuclear localization↑	HO-1↑, NQO1↑, GCL↑	LANA-1↑, Src↑, PKC↑, VEGF↑, COX-2↑, PGE2↑, LANA1-Nrf2↑, KEAP1-Nrf2↑	Gjyshi et al. [45]
DENV	Fever	Monocyte-derived dendritic cell	ND	↑	↑	↑	HO-1↑, NQO1↑, SOD2↑, GCLM↑, GCLC↑	IRF3↑, STAT1↑, RIG-I↑, IFIT1↑, LANA-1↑, NOX↑, TNF-α, IL-6↑, IFN-β1↑, ISG↑, annexin V↑	Olagnier et al. [39]
	Fever	Mononuclear phagocytes	NS2B3	ND	↑	↑	ND	CLEC5A↑, TNF-α↑, ER stress↑, PERK↑	Cheng et al. [47]
Marburg virus	Hemorrhagic fever	293T, Huh7, and Vero E6 cells	VP24	ND	ND	Nuclear localization↑	HO-1↑, NQO1↑, GCLM↑	VP24-KEAP1 Kelch domain interaction↑, VP24-KEAP1 mislocalization	Page et al. [113], Edwards et al. [112]
	Hemorrhagic fever	Human monocytic cells	VP24	ND	ND	↑	ND	VP24 dimmerization↓, VP24 monomer cysteines-KEAP1↑	Johnson et al. [114]
SVCV	Spring viremia	Epithelioma papulosum cyprini cells	ND	ND	↑	↑	HO-1↑, SOD1↑	8-OHdG↑, FRAP↑	Yang et al. [117], Shao et al. [116]
WNV	Arboviral encephalitis	BHK cells	ND	↑	GSH↑	↑	GCLC↑, SOD↑, GPx↑	Arsenite-induced stress granule↓, ATF4↑, arsenite-induced mitochondrial damage↓, mitochondrial morphology change↑	Basu et al. [121]
RGNNV	Fish disease	The grouper fin cells	ND	↑	SOD↑, CAT↑	↑	SOD↑, CAT↑	Apoptosis↑, mitochondrial potential↓	Chang et al. [123]

Virus names, diseases caused by viruses, host cells or animals used for infection, ROS level after infection, effect on the redox defense system, effect on Nrf2 and its target genes, and other effects were listed accordingly. ND indicates “not determined.” Abbreviations used within the table are as follows. 8-OHdG: 8-hydroxydeoxyguanosine; AIDS: acquired immunodeficiency syndrome; AKR1C: aldo-ketoreductase 1C1; Akt: protein kinase B; ALT: alanine aminotransferase; AP-1: transcription factor composed of cFos and cJun dimer; ARE: antioxidant response element; ASNS: asparagine synthetase; AST: aspartate aminotransferase; ATM: ATM serine/threonine inase; Bad: bcl-2-associated death promoter; Bcl-2: B-cell lymphoma 2; CalR: calreticulin; CAT: catalase; CBP: CREB-binding protein; Chk2: checkpoint kinase 2; CK2: casein kinase 2; CLEC5A: c-type lectin domain family 5, member A; COX-2: cyclooxygenase 2; c-Raf: RAF protooncogene serine/threonine-protein kinase; Cyp2a5: cytochrome P450 2A5; DENV: dengue virus; Dnai2: dynein intermediate chain 2; DNPH: 2,4-dinitrophenylhydrazine; Foxj1: forkhead box protein J1; FRAP: ferric reducing ability of plasma reagent; G6PD: glucose 6 phosphate dehydrogenase; GCLC: glutamate cysteine ligase catalytic subunit; GCLM: glutamate cysteine ligase regulatory subunit; γ-GT: gamma-glutamyl transpeptidase; GPx: glutathione peroxidase; GRP78: glucose-responsive proteins 78; GRP94: glucose-responsive proteins 94; GSH: glutathione; GST: glutathione S transferase; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBx: hepatitis B virus protein X; HCC: hepatocellular carcinoma; hCLCA1: human chloride channel accessory 1; HCMV: human cytomegalovirus; HCV: hepatitis C virus; HDAC: histone deacetylase; HIV: human immunodeficiency virus; HO-1: heme oxygenase; HSV: herpes simplex virus; ICAM-1: intercellular adhesion molecule 1; IE1: immediate early protein 1; IE2: immediate early protein 2; IFIT1: interferon-induced protein with tetra-tricopeptide repeats 1; IFN: interferon; IL-13: interleukin 13; IL-6: interleukin 6; IL-8: interleukin 8; IRF: IFN regulatory factor 3; ISG: interferon-stimulated gene; JNK: c-Jun kinase; KEAP1: Kelch-like ECH-associated protein 1; KSHV: Kaposi’s sarcoma-associated herpesvirus; LANA-1: latency-associated nuclear antigen 1; LD: lipid droplet; LHBs: hepatitis B virus large surface protein; LTR: long terminal repeat; Maf: transcription factor Maf; MDA: malondialdehyde; MoMuLV ts1: Moloney murine leukemia virus ts1; MTHFD2: methylenetetrahydrofolate dehydrogenase 2; mTOR: mammalian target of rapamycin; MUC5AC: mucin 5AC; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA: N-methyl-D-aspartate; NOX: NADPH oxidase; NQO1: NAD(P)H dehydrogenase quinone 1; NS2B3: nonstructural protein 2B3; NS3: nonstructural protein 3; NS5A: nonstructural protein 5A; ORF71: open reading frame 71; PCNA: proliferating cell nuclear antigen; PERK: protein kinase R-like ER kinase; PGD: phosphogluconate dehydrogenase; PGE2: prostaglandin E2; PI3K: phosphatidyl inositol 3 kinase; PKC: protein kinase C; PML: promyelocytic leukemia protein; PSMB5: proteasome subunit beta type-5; RANTES: regulated on activation, normal T cell expressed and secreted; RGNNV: red-spotted grouper nervous necrosis virus; RIG-I: RIG-I-like receptor; RSV: respiratory syncytial virus; sMaf: small musculoaponeurotic fibrosarcoma; SMO: spermine oxidase; SOD: superoxide dismutase; Src: protooncogene tyrosine-protein kinase; STAT1: signal transducer and activator of transcription 1; SUMO: small ubiquitin-like modifier; SVCV: spring viremia of carp virus; TER: transepithelial electrical resistance; TNF-α: tumor necrosis factor alpha; UGDH: UDP-glucose dehydrogenase; VEGF: vascular endothelial growth factor; vFLIP: viral FLICE-like inhibitory protein; WNV: West Nile virus; xCT: cell surface cysteine-glutamate antiporter.