Transgenic expression of hepatitis C virus structural proteins in the mouse

Abstract

lies. 3,4 In general, the genome is flanked in its 5 -untranslated Although hepatitis C virus (HCV) is a leading cause region by a highly conserved (ú98%) 341 nucleotide seof morbidity and mortality worldwide, the role of viral quence, which appears to play a key role in translational cytopathic effects remains unclear. To study the biosyncontrol. 1,5,6 The coding region encodes structural proteins in thesis of HCV structural proteins and their pathogenic its N-terminal portion that include a nonglycosylated core role, we constructed transgenic mice, expressing type protein (p22), which associates with genomic RNA to form 1b HCV structural proteins (core, E1, and E2) in liver the nucleocapsid. The C-terminal 20 amino acids of the core tissues. Two liver-specific promoters were used. The protein are highly hydrophobic and may act as a signal semouse major urinary protein (MUP) promoter has been quence for processing of adjacent polypeptides. 7,8 Immedishown to be developmentally regulated with little or no ately downstream from the core are two proteins, designated expression in utero but high-level expression after birth.E1 and E2/NS1, which correspond to the putative envelope The albumin (Alb) promoter provides constitutive, high glycoproteins. These proteins, designated gp33 and gp70 levels of transgenes in liver. Expression of both HCV respectively, are extensively N-glycosylated and appear to transgenes was detected in several lines by Northern function as membrane-associated proteins essential for virion blots, HCV-specific reverse transcriptase-polymerase assembly. The presence of a hypervariable region in the Nchain reactions (RT-PCR), and Western immunoblotting.terminal portion of the E2/NS1 domain to which an active Alb HCV lines showed higher levels of HCV expression humoral response is directed in infected individuals suggests than the MUP HCV lines. Immunohistochemical analysis that this region is subjected to immune selection. 4,9 This rerevealed a predominantly cytoplasmic presence of core gion exhibits significant variation not only among HCV isoprotein with occasional nuclear staining, and both cytolates but also within infected individuals over the course of plasmic and membrane expression of the E2 protein in time. 10 the transgenic livers. In both transgenes, the highest lev-HCV is an important cause of morbidity and mortality els of both antigens were seen in perivenular hepatoworldwide, causing a spectrum of liver disease ranging from cytes, suggesting potential processing specificity in the asymptomatic carrier state to end-stage liver disease. those cells. At six months of age, the livers of allCompared to other hepatotropic viruses, there is a higher transgenic lineages remained histologically normal. We rate of chronicity after HCV infection, with at least 70% of concluded that HCV structural proteins are not directly those infected developing chronic liver disease. 11 In addition cytopathic in this animal model. (HEPATOLOGY 1997;25: to the morbidity and mortality caused by chronic l...

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

“…2 We used the albumin promoter as did Lerat et al 9 The transgenic mice developed by Kawamura et al demonstrated high core expression, 2 whereas those by Lerat et al showed much lower core protein expression, suggesting that levels of core protein expression alone do not explain the HCC phenotype, and that the FVB background may have a protective role in hepatocarcinogenesis. Indeed, saline-treated control animals expressing the core and core-E1-E2 construction on the FVBϫC57Bl/6 background both failed to develop HCC, unless they were exposed to a chemical carcinogen.…”

“…2 However, more recently, Moriya et al developed a transgenic mouse model on the C57Bl/6 background that overexpresses HCV core protein under the control of the HBV enhancer that is capable of inducing HCC in a subset of animals following the development of steatosis. [3][4][5][6] These apparently contradictory findings could be due to inherent differences in the transgenes, HCV core dose effect, mouse genetic background, or a combination of these.…”

Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

“…127 These contradictory findings may be due to the young age at which the livers were analysed (up to 6 months), since neoplasms were not observed in mice younger than 13 or 16 months in the studies reported by Lerat et al and Koike et al,respectively. 124,126 However, a different study by Pasquinelli et al also observed "no significant liver injury" in transgenic mice expressing HCV core protein up to 18 months of age.…”

Influence of human t-cell lymphotropic virus type 1 (HTLV-1) Infection on laboratory parameters of patients with chronic hepatitis C virus

“…At the same time, co-infection increases the persistence of HCV infection and, subsequently, the risk of developing liver disease 30 . As several studies have suggested, liver damage is related mainly to immune mediated mechanisms, with the stimulation of cytotoxic T cell (CTL) response against hepatocytes infected with HCV 9,10,20,32 . This response would lead to hepatocyte lysis and consequent increased release of liver transaminases in plasma.…”