New animal models for hepatitis C viral infection and pathogenesis studies

Table 1 HCV infection trials in animals

Virus	Animal tested		Infection	Original reference
HCV	Non human primates	Chimpanzee	Yes	Alter et al[2] 1978
		Marmoset	Yes	Feinstone et al[71] 1981
		Cottontop tamarin	No	Garson et al[72] 1997
		Cynomoglus monkey	No
		Rhesus monkey	No
		Green monkey	No
		Japanese monkey	No	Abe et al[73] 1993
		Doguera baboon	No
		Chacma baboon	No	Sithebe et al[74] 2002
	Scandentia	Tupaia	Yes	Xie et al[75] 1998
	Rodents	uPA/SCID mice	Yes	Mercer et al[26] 2001
		Trimera mice	Yes	Galun et al[10] 1995
		Rat	Yes	Wu et al[8] 2005
		Woodchuck	No	Abe et al[73] 1993

Table 2 Characteristics of HCV infection in three rodent models

Rodent models	Humanization	Viremia	Duration of viral infection	Comments	Publications
uPA/SCID mice	Human hepatocyte transplantation	1 × 104 to 8 × 107 copies/mL	Up to 9 mo with maximum viremia as from one month	High viremia
				Variability of primary human hepatocytes	Mercer et al[26] 2001
					Meuleman et al[22] 2005
				Immunosuppressed mice	Kneteman et al[29] 2006
Trimera mice	Xenograft of human liver tissue	Around 7 × 104 copies/mL	Around one month with peak viremia at 18 d	Low viremia
				Variability of human liver tissues	Ilan et al[12] 2002
				Immunosuppressed mice	Eren et al[11] 2006
Rat	Immunotolerization and transplantation of a human hepatoma cell line	1-2 × 104 copies/mL	Minimum 4 mo with peak viremia at 3 mo	Low viremia
				Transplantation of a hepatoma cell line	Wu et al[8] 2005
				Immunocompetent rat

Table 3 Transgenic mice expressing HCV proteins

Viral protein	Original reference of the transgenic mouse	Mouse strain	Promoter	Comments	References
Core	Moriya et al[42] 1997	C57BL/6	HBV	Steatosis	Moriya et al[40] 1998
				HCC	Moriya et al[42] 1997
				Oxidative stress	Moriya et al[41] 2001
				Increased concentration of monounsaturated fatty acids	Moriya et al[37] 2001
				Inhibition of microsomal triglyceride transfer protein activity and VLDL secretion.	Perlemuter et al[38] 2002
				Alcohol and core protein increase lipid peroxidation	Perlemuter et al[39] 2003
				Alteration of intrahepatic cytokine expression and AP-1 activation	Tsutsumi et al[45] 2002
				Interaction with retinoid X receptor alpha	Tsutsumi et al[43] 2002
				Cooperation with ethanol activation of MAPK	Tsutsumi et al[44] 2003
				Insulin resistance	Shintani et al[34] 2004
					Koike et al[33] 2006
				Modulation of interferon pathway (Inhibition of SOCS-1 expression)	Miyoshi et al[47] 2005
				ER stress, apoptosis	Benali-Furet et al[78] 2005
Core	Honda et al[52] 2000	C57BL/6	HBV	Modulated sensitivity to Fas-mediated apoptosis	Honda et al[52] 2000
				Insulin resistance via down-regulation hepatic IRS1 and 2	Kawaguchi et al[35] 2004
				Constitutive activation of STAT3, implication in HCC	Yoshida et al[46] 2002
Core	Pasquinelli et al[50] 1997	C57BL/6	Major urinary protein	No liver disease	Pasquinelli et al[50] 1997
Core (Korean wt and mutants)	Wang et al[79] 2004	C57BL/6J	HBV	Cell dysplasia for S99Q core mutant	Wang et al[79] 2004
Core (in T cell)	Soguero et al[53] 2002	C57BL/6	CD2	Increased Fas-mediated apoptosis and liver infiltration of peripheral T cells	Soguero et al[53] 2002
Double Tg core X TCR	Cruise et al[55] 2005	C57BL/6 × DO11.10 (H-2d)		Increased Fas ligand expression of CD4+ T cells associated with liver inflammation	Cruise et al[55] 2005
				Role of CXCR3 ligands via Fas induction, during the inflammatory response	Cruise et al[54] 2006
Core	Ishikawa et al[48] 2003	C57BL/6N	serum amyloid	Malignant lymphoma and Hepatocellular adenoma in old mice	Ishikawa et al[48] 2003
Core	Kato et al[49] 2003	C57BL/6	serum amyloid P	Adenoma and HCC development in transgenic mice following repeated CCl4 administrations.	Kato et al[49] 2003
Core Core-E1-E2	Kamegaya et al[51] 2005	FVB × C57BL/6	Albumin	After DEN treatment, core-E1-E2 mice develop tumors with a larger size than core mice (diminution of apoptotic index)	Kamegaya et al[51] 2005
Core-E1-E2-p7	Lerat et al[62] 2002	C57BL/6	Albumin	Steatosis	Lerat et al[62] 2002
				HCC (rare)
				Sensitivity to oxidative stress	Okuda et al[80] 2002
Core-E1-E2-p7	Korenaga et al[81] 2005	C57BL/6J	Albumin	Increase in ROS production by mitochondrial electron transport complex I	Korenaga et al[81] 2005
Core-E1-E2	Kawamura et al[82] 1997	FVB	Albumin or major urinary protein	No liver disease	Kawamura et al[82] 1997
Core-E1-E2	Honda et al[56] 1999	C57BL/6	H2-Kd	Sensitivity to anti-fas administration	Honda et al[56] 1999
Core-E1-E2	Naas et al[57] 2005	C57BL/6	CMV	Steatosis.	Naas et al[57] 2005
				Acceleration of liver and lymphoid tumor development
Core-E1-E2-NS2	Wakita et al[59] 1998	Balb/C	Cre/Lox system (CAG promoter)	Hepatitis injury associated with HCV-specific CTL response	Wakita et al[59] 1998 Wakita et al[58] 2000
				Suppression of Fas-mediated cell death	Machida et al[83] 2001
				HCV-specific CD8+ CTLs specifically induce liver injury	Takaku et al[62] 2003
E1-E2	Koike et al[63] 1995	CD1	HBV	No liver disease	Koike et al[63] 1995
				Expression in salivary glands
				Exocrinopathy resembling Sjogren syndrome	Koike et al[84] 1997
E2	Pasquinelli et al[50] 1997	C57BL/6	Albumin	No liver disease	Pasquinelli et al[50] 1997
NS3-NS4A	Frelin et al[64] 2006	C57BL/6	Major urinary protein	No liver disease.	Frelin et al[64] 2006
				Alteration of hepatic immune cell subsets.
				Reduced sensitivity to TNF alpha mediated liver disease.
NS5	Majumder et al[65] 2002	FVB	ApoE	No liver disease	Majumder et al[65] 2002
				Protection against TNF alpha mediated liver disease (inhibition of NF-kappaB activation)	Majumder et al[66] 2003
Full polyprotein	Alonzi et al[60] 2004	C57BL/6	Alpha1 antitrypsin	Steatosis	Alonzi et al[60] 2004
	Blindenbacher et al[67] 2003			T cell infiltrate
				Inhibition of IFN alpha-induced signaling	Blindenbacher et al[67] 2003
				Increased expression of protein phosphatase 2A	Duong et al[68] 2004
Full polyprotein	Lerat et al[62] 2002	C57BL/6	Albumin	Hepatic steatosis, HCC	Lerat et al[62] 2002
				Impairment of intrahepatic immune response (absence of elimination of adenovirus-infected hepatocytes)	Disson et al[85] 2004
				Down-regulation of pro-apoptotic CIDE-B protein in adenovirus-infected transgenic mice	Erdtmann et al[86] 2003
				Iron overload induces increase the risk of HCC (mitochondrial injury)	Furutani et al[87] 2006