Autophagy in hepatitis C virus-host interactions: Potential roles and therapeutic targets for liver-associated diseases

Table 1 Roles of autophagy in hepatitis C virus-host cell interactions

HCV genotype	Expression	Model	Analysis of autophagy activation	Physiological significance	Ref.
HCV-H77 (1a)	Transfection of viral RNA	IHH cells	1 Detection of GFP-LC3 punctate structure formation	Promotion of viral RNA replication	Ait-Goughoulte et al[8]
			2 Accumulated autophagosome in TEM analysis
			3 Upregulation of Beclin expression and ATG5-ATG12 conjugate
HCV-JFH1 (2a)	Transfection of viral RNA	Huh7.5 cells	1 Upregulated expression of LC3-II	Promotion of viral RNA replication	Sir et al[11]
			2 No overlapping signal of GFP-LC3 punctate with lysosome
			3 Autophagic activation by UPR
			4 An incomplete autophagic process lacking enhanced autophagic degradation of long-lived proteins and p62
HCV-JFH1 (2a)	HCVcc infection	Huh7 cells	1 Upregulation of LC3-II	Enhanced translation of the incoming viral RNA	Dreux et al[9]
			2 Accumulation of GFP-LC3 dot-like vesicles
			3 No colocalization of autophagic vacuoles with viral proteins
HCV-JFH1 (2a)	HCVcc infection	Huh7.5-1 cells	1 Increase of GFP-LC3 dot-like structures	Promotion of virion assembly	Tanida et al[207]
			2 No colocalization of autophagic vacuoles with viral proteins
HCV-JFH1 (2a)	HCVcc infection	Huh7 cells	1 Transient interaction of ATG5 with NS5B and NS4B	Promotion of viral RNA replication by organizing membranous web	Guévin et al[205]
			2 Association of ATG5 with membranous web
HCV-JFH1 (2a) infection	HCVcc infection	Huh7 cells	1 Detection of early- and late-stage autophagic vacuoles by TEM analysis	Promotion of viral RNA replication by suppressing antiviral immunity	Ke et al[10]
			2 Colocalization of autophagic vacuoles with lysosome
			3 Accumulated LC3B-II expression by interference with autolysosome maturation
			4 Complete autophagic process by HCV infection
HCV-H77 (1a); HCV-JFH1 (2a)	HCVcc infection	IHH	1 Activated IFN response in the HCV-infected cells by silencing of Beclin and ATG7	Promotion of viral RNA replication by suppressing antiviral immunity	Shrivastava et al[203]
			2 Increased caspase-dependent apoptosis by knockdown of Beclin and ATG7 in the HCV-infection cells
HCV-Con1 (1b) and JFH1 (2a)	Replicon viral RNA transfection	Huh7 cells; Huh7.5-1 cells; Liver biopsy	1 An inverse correlation between hepatic steatosis and activation of autophagy in liver biopsy samples of infected patients	Promotion of catabolism of LDs	Vescovo et al[208]
			2 Colocalization of autophagic vacuoles with LDs
HCV-JFH1 (2a)	Replicon viral RNA transfection	Huh7 cells; HCV-transgenic mice	1 Enhanced ROS level in mitochondria in HCV viral RNA-transfected cells	Regulation of oxidative response in mitochondria	Chu et al[210]
			2 Activated autophagy by expression of HCV NS proteins
			3 Alteration of antioxidant response by upregulation of antioxidant enzymes in HCV NS protein-expressing cells
HCV-JFH1 (2a)	HCVcc infection	Huh7 cells; Huh7.5-1 cells	1 Accumulation of mito autolysosome in HCV-infected cells	Elimination of damaged mitochondria and promotion of viral RNA replication	Kim et al[209]
			2 Stimulation of Parkin and Pink 1 expression in HCV-infected cells
			3 Activation of mitophagy via a Parkin-dependent pathway
HCV-JFH1 (2a) HCV-N (1b)	HCVcc infection; Replicon viral RNA transfection	Huh7 cells	1 Activation of autophagy through AKT1-TSC-mTORC1 signaling	Promotion of viral RNA replication	Huang et al[214]
			2 Activation of autophagy via UPR
HCV-JC1 (2a) infection; HCV NS4B	HCVcc infection; Ectopic overexpression	Huh7.5 cells	1 Activation of autophagy by HCV NS4B amino acid 1-190	Organization of virus replication site	Su et al[216]
			2 Requirement of Rab5 and PI3K for autophagic activation
HCV-JFH1 (2a)	HCVcc infection	IHH cells	1 Transcriptional activation of Beclin gene expression	Promotion of viral RNA replication	Shrivastava et al[215]
			2 Autophagy activation in a Bcl2-Beclin dissociation- and mTOR inhibition-independent manner
HCV-JFH1 (2a)	HCVcc infection	Huh7.5 cells	1 Activation of autophagy through IRGM	Promotion of viral RNA replication; modulation of innate immunity (?)	Grégoire et al[237]
			2 Interaction of HCV NS3 with IRGM

HCV: Hepatitis C virus; ROS: Reactive oxygen species; NS: Nonstructural; IRGM: Immunity-associated GTPase family M; UPR: Unfolded protein response; ATG: Autophagy-related gene; GFP-LC3: Green fluorescence protein-conjugated microtubule-associated protein 1 light chain 3; LDS: Lipid droplets.