Hepatitis C virus structural proteins induce liver cell injury in transgenic mice

Honda, Arata; Arai, Yasuhiro; Hirota, Norio; Sato, Takako; Ikegaki, Junichi; Hatano, Masahiko; Kohara, Michinori; Moriyama, Takashi; Imawari, Michio; Shimotohno, Kunitada; Tokuhisa, Takeshi

doi:10.1002/(sici)1096-9071(199911)59:3<281::aid-jmv4>3.0.co;2-s

Cited by 39 publications

(21 citation statements)

References 51 publications

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“…In subjects with hepatitis C virus infection, it is suggested that hepatitis C virus core and envelope proteins may be one causative agent of spontaneous liver cell injury by themselves. 21 When filamentous HBsAg particles accumulate in HBV-infected hepatocytes to extremely high levels, the death of hepatocytes will be induced by severely compromised endoplasmic reticulum function. 22 Noticeably, functionally normal HBsAg-positive hepatocytes are exquisitely hypersensitive to destruction, as reported that HBsAg-positive hepatocytes of HBV transgenic mice were hypersensitive to cytolytic effect of IFN-␥.…”

Section: Discussionmentioning

confidence: 99%

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

et al. 2007

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“…Honda et al reported that liver samples from HCV core-E1-E2 transgenic mice showed higher Fasmediated cell damage compared with non transgenic mice. 13 Dumoulin et al reported that HCV core protein or HCV E2 protein individually do not prevent TNF-␣ or Fas induced-apoptosis in transient transfected HepG2 cells. 14 Lasarte et al reported that a recombinant adenovirus encoding HCV core and E1 proteins protects liver cells from cytokine-induced hepatocellular damage in experimental models of TNF-mediated hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis†

et al. 2005

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We developed hepatitis C virus (HCV) core-E1-E2 and HCV core transgenic mice on a common genetic background to assess the contribution of HCV structural proteins to hepatocarcinogenesis. Eight-week-old core-E1-E2, core, and nontransgenic mice inbred on the FVB؋C57Bl/6 background were treated with diethylnitrosamine (DEN) and sacrificed at 32 weeks old. Proliferation and apoptosis were assessed by immunohistochemistry. H epatitis C virus (HCV) infects an estimated 170 million people worldwide, and 2.7 million people in the United States harbor active HCV infection. 1 Chronic HCV infection has been independently established as a leading cause of hepatocellular carcinoma (HCC). Unlike hepatitis B virus (HBV), the RNA genome of HCV does not integrate into the host chromosome. HCV-related hepatocarcinogenesis is, therefore, not likely to involve insertional mutagenesis. Rather, it has been hypothesized that HCV produces HCC through the cumulative effects of chronic infection, injury and repair. Whether HCV proteins are directly oncogenic has not been established. Unfortunately, the lack of an appropriate small animal model of HCV has impeded progress in defining the molecular mechanisms of HCV-induced carcinogenesis.We originally developed an HCV transgenic mouse model encoding the core, E1, and E2 structural proteins under the control of the albumin promoter on the FVB background; despite high-level protein expression, this model did not develop hepatic pathology. 2 However, more recently, Moriya et al. developed a transgenic mouse model on the C57Bl/6 background that overexpresses Abbreviations: HCV, hepatitis C virus; DEN, diethylnitrosamine; HCC, hepatocellular carcinoma; AI, apoptotic index; PI, proliferation index. From the

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“…In addition to these reported effects of NS proteins on cellular processes, a large and often contradictory body of literature exists concerning the impact of expression of the viral structural proteins on cellular processes. Most prominent and best documented of these is the effect of core protein expression on fatty acid metabolism and storage, resulting in the accumulation of excess numbers of lipid-laden droplets in vitro, and steatosis in transgenic mice (4,22,24,25,40,45). All of these studies suggest the possibility that one or more manifestations of hepatitis C may reflect direct disruption of normal cellular control processes by the viral proteins.…”

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Virus-Host Cell Interactions during Hepatitis C Virus RNA Replication: Impact of Polyprotein Expression on the Cellular Transcriptome and Cell Cycle Association with Viral RNA Synthesis

Scholle¹,

Li²,

Bodola³

et al. 2004

J Virol

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Hepatitis C is the most common cause of clinically significant liver disease in the United States. Although acute infection with hepatitis C virus (HCV) is usually subclinical, persistent infection develops in up to 80% of initially infected patients (2). The majority of persistently infected individuals develop evidence of chronic liver injury and are at risk for progressive hepatic fibrosis leading to cirrhosis and ultimately death due to liver failure or hepatocellular carcinoma. Approximately 10,000 individuals die each year with chronic liver disease associated with HCV infection in the United States alone (1), rendering this virus a very significant public health problem.HCV is classified within a distinct genus, Hepacivirus, in the family Flaviviridae (15). Its genome consists of positive sense, single-stranded RNA of approximately 9.5 kb in length (9). The genomic RNA contains a single open reading frame, from which one large polyprotein is expressed, and flanking 5Ј and 3Ј untranslated regions. Translation of the viral RNA occurs through a cap-independent mechanism via an internal ribosomal entry site (IRES) located in the 5Ј untranslated region. A combination of cellular and virally encoded protease activities leads to processing of the polyprotein into individual structural and nonstructural proteins. Three structural proteins have been identified with the core protein forming a poorly defined viral capsid, and E1 and E2, both glycosylated envelope proteins, forming heterodimers. These structural proteins are processed by host signal peptidases. C terminal to E2, further proteolytic processing by host peptidases yields a short hydrophobic peptide, p7, which may function as a membrane channel (44), followed by the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. NS2 and the amino-terminal protease domain of NS3 are responsible for proteolytic cleavage at the NS2-NS3 junction (20, 52), whereas other proteolytic cleavage events involved in the maturation of the NS proteins are carried out by the major viral serine protease, NS3, in association with its cofactor, NS4A (5,7,35). In addition to its function as a protease, NS3 also contains helicase and nucleoside triphosphatase activities within its C-terminal domain (28). Specific replicative functions have not been identified for NS4B and NS5A, but both are likely to contribute to the viral replicase complex. NS5B constitutes the HCV RNA-dependent RNA polymerase and is thus the catalytic core of the replicase.In addition to functions related to RNA replication, both NS3/4A and NS5A appear to play important roles in modulating antiviral responses within infected cells and in promoting long-term persistence of the virus. The NS3/4A protease blocks

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Hepatitis C virus structural proteins induce liver cell injury in transgenic mice

Cited by 39 publications

References 51 publications

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis†

Virus-Host Cell Interactions during Hepatitis C Virus RNA Replication: Impact of Polyprotein Expression on the Cellular Transcriptome and Cell Cycle Association with Viral RNA Synthesis

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