Transgenic models for Hepatitis C virus pathogenesis

Fimia, Gian María; Tripodi, Marco; Alonzi, Tonino

doi:10.1038/sj.cdd.4401114

Cited by 12 publications

(6 citation statements)

References 17 publications

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“…steatosis, necrosis, sensitivity to Fas-induced apoptosis and HCC (reviewed by Koike, 1999;Fimia et al, 2003). The hepatic alterations observed in the A1AT/HCV mice are partially in agreement with these published reports.…”

Section: Discussionsupporting

confidence: 80%

Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice

Alonzi

Agrati

Costabile

et al. 2004

Journal of General Virology

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To assess the effects of constitutive hepatitis C virus (HCV) gene expression on liver, transgenic mice carrying the entire HCV open reading frame inserted in the a1 antitrypsin (A1AT) gene were generated. Expression of A1AT/HCV mRNA was found to be mainly limited to perivascular areas of the liver as indicated by in situ hybridization analysis. HCV core protein was detected in Western blots of liver extracts, whereas the expression of E2, NS3 and NS5 proteins was revealed by immunostaining of liver samples using HCV-specific antisera. Histological analysis of HCV transgenic mice showed that these animals develop extensive steatosis, but very little necrosis of liver tissue. Moreover, a consistent T cell infiltrate and a slight hepatocyte proliferation were observed. Phenotypic analysis of cells infiltrating the liver indicated that recruitment and/or expansion of residing CD8 + , NK, NKT and cd T cells occurred in transgenic animals. Among these cells, a large fraction of CD8 + T lymphocytes released mainly IL-10 and, to a lesser extent, IFN-c upon mitogenic stimulation in vitro. Furthermore, both intrahepatic lymphocytes and splenocytes did not produce cytokines in response to HCV antigens. Thus, these data indicate that constitutive expression of HCV proteins may be responsible for intrahepatic lymphocyte recruitment in absence of viral antigen recognition. This response is likely to be driven by virus-induced cellular factors and may play a significant role in the immunopathology of chronic HCV infection and liver disease. INTRODUCTIONHepatitis C virus (HCV) is a member of the Flaviviridae and is the major cause of non-A, non-B hepatitis (Choo et al., 1989;Houghton et al., 1991;Kuo et al., 1989). HCV has a single-stranded RNA genome of positive polarity of about 9?5 kb that contains a long open reading frame (ORF) encoding a polyprotein of approximately 3000 amino acids Kato et al., 1990;Takamizawa et al., 1991). The polyprotein precursor has the following gene order: NH 2 C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b COOH (Eckart et al., 1993;Grakoui et al., 1993; Hijikata et al., 1993a, b;Lin et al., 1994;Tomei et al., 1993) C is an RNA-binding protein (Santolini et al., 1994) and is considered to be the viral nucleocapsid; E1 and E2 are thought to be the virion glycoproteins; p7 is a protein involved in the formation of ion channels (Griffin et al., 2004) and is inefficiently cleaved from the E2 polypeptide (Mizushima et al., 1994). Processing of the structural polypeptides is mediated by cellular signal peptidase (Hijikata et al., 1993b;Santolini et al., 1994). The HCVencoded metalloproteinase and serine protease located in the NS2 to NS3 region and N-terminal one-third of NS3 protein, respectively, mediate cleavages in the nonstructural region (Clarke, 1997).More than 170 million people worldwide are infected with HCV, and the complications of liver cirrhosis and hepatocellular carcinoma cause significant morbidity and mortality. The virus is cleared in a minority of patients and 70-80 % develop chronic infec...

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Section: Discussionsupporting

confidence: 80%

Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice

Alonzi

Agrati

Costabile

et al. 2004

Journal of General Virology

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“…Further work needs to be done to reconcile the discrepancy of data generated from human liver and that from animal models of liver disease and from the expression of viral proteins into hepatic cell lines. It is possible that viral proteins interact via species‐specific mechanisms [39] and that complex regulatory networks in human liver are disrupted in isolated cells. Numerous genes appear to be regulated following HCV infection [40].…”

Section: Discussionmentioning

confidence: 99%

Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver

Desmond

Slavin

Congiu

2010

Journal of Viral Hepatitis

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Hepatitis C virus (HCV) infection is frequently associated with hepatic steatosis, particularly in patients with HCV genotype-3 (HCVGT3). It has variously been hypothesized, largely from in-vitro studies, to be the result of increased synthesis, decreased metabolism and export of triglycerides. We measured by real-time PCR the expression of genes involved in lipid metabolism [acetyl-Coenzyme A carboxylase alpha, apolipoprotein B (APOB), diacylglycerol O-acyltransferase 2, fatty acid-binding protein 1, fatty acid synthase, microsomal triglyceride transfer protein (MTTP), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) and sterol regulatory element-binding transcription factor 1 (SREBF1)] in liver biopsies from patients infected with HCV genotype-1 (HCVGT1), HCVGT3 and Hepatitis B (HBV) using β-glucuronidase (GUSB) and splicing factor arginine/serine-rich 4 (SFRS4) as housekeeping genes. Patients infected with HCVGT3 were younger than those infected with HCVGT1 (36.3 ± 2.5 vs 45.6 ± 1.5, P < 0.05, Mann-Whitney) and were more likely to have steatosis (69.2%vs 11.8%). No significant difference was found in the expression of genes involved in lipogenesis or transport in patients infected with HBV or HCV of either genotype. Contrary to expectation, given the greater degree of steatosis in HCVGT3-infected liver, expression of enzymes involved in lipogenesis was not elevated in HCVGT3 compared with HCVGT1 or HBV-infected liver. Significantly less mRNA for SREBF1 was found in HCVGT3-infected liver tissue compared with HCVGT1-infected liver (1.00 ± 0.06 vs 0.70 ± 0.15 P < 0.05). These results suggest that steatosis in patients infected with HCVGT3 is not the result of a sustained SREBF1 driven increase in expression of genes involved in lipogenesis. In addition, a significant genotype-independent correlation was found between the expression of APOB, MTTP, PRKAA1 and PPARA, indicating that these networks are functional in HCV-infected liver.

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“…Indeed, HCV core protein has been reported to induce intracytoplasmic triglyceride-rich droplet accumulation in transfected cells [Barba et al, 1997]. Consistent with this data, Alonzi et al [2004] and others have reported that expression of viral proteins only causes steatosis in several transgenic animal models [reviewed in Fimia et al, 2003].…”

Section: Introductionmentioning

confidence: 58%

“…On the other hand, several mouse models have demonstrated that HCV proteins can induces steatosis [Fimia et al, 2003]. Recently, it has been reported that in patients infected with HCV mRNA levels of microsomal TG transfer protein, which is essential for hepatic lipoprotein assembly and secretion, are inversely correlated with the degree of steatosis, independently of the HCV genotype [Mirandola et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

Very low density lipoprotein and low density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism

Napolitano

Giuliani

Alonzi

et al. 2007

Journal of Medical Virology

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Several abnormalities of lipid metabolism, including hypo-beta-lipoproteinemia and liver steatosis are associated with infection by hepatitis C virus (HCV). The aim of this study was to determine whether circulating lipoproteins of patients with HCV infection could directly cause alterations of lipid cellular metabolism. To this end the metabolic response of human monocyte-derived macrophages (HMDM) to very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), measuring the cholesteryl ester (CE) and triglyceride (TG) production was analyzed. Lipoproteins were isolated from 18 patients infected with hepatitis C virus (HCV-VLDL and HCV-LDL) and from normal healthy donors (ct-VLDL and ct-LDL). In comparison to ct-lipoproteins, HCV-lipoproteins induced significant differences in HMDM CE and TG production. HCV-VLDL decreased CE and TG production; while HCV-LDL induced an increased TG synthesis. The present findings suggest that HCV infection modifies VLDL and LDL molecular composition, affecting cellular lipid metabolism, thus promoting intracellular lipid accumulation and hypo-beta-lipoproteinemia.

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Transgenic models for Hepatitis C virus pathogenesis

Abstract: [No abstract available

Cited by 12 publications

References 17 publications

Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice

Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice

Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver

Very low density lipoprotein and low density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism

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