Tupaia CD81, SR-BI, Claudin-1, and Occludin Support Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV)-related research has been hampered by the lack of appropriate small-animal models. It has been reported that tree shrews, or tupaias (Tupaia belangeri), can be infected with serum-derived HCV. However, these reports do not firmly establish the tupaia as a reliable model of HCV infection. Human CD81, scavenger receptor class B type I (SR-BI), claudin 1 (CLDN1), and occludin (OCLN) are considered essential receptors or coreceptors for HCV cell entry. In the present study, the roles of these tupaia orthologs in HCV infection were assessed. Both CD81 and SR-BI of tupaia were found to be able to bind with HCV envelope protein 2 (E2). In comparison with human CD81, tupaia CD81 exhibited stronger binding activity with E2 and increased HCV pseudoparticle ( Hepatitis C virus (HCV) is a major cause of liver disease. A total of 170 million individuals worldwide are estimated to be infected with HCV and are at risk of developing cirrhosis and hepatocellular carcinoma (32,33). Unfortunately, there is presently no effective HCV vaccine available, and current treatments are far from satisfactory (22, 28). The development of antiviral therapies and effective vaccines has been hampered greatly by the lack of a convenient small-animal model. Chimpanzees (Pan troglodytes) are the only nonhuman primate host serving as an HCV infection model. However, experiments using chimpanzees are both expensive and ethically problematic. To date, three small-animal models of HCV infection have been reported: the immunotolerized rat model, Trimera mouse model, and uPA/SCID mouse model (16,25,39). However, these models are difficult to prepare, and the abnormal immune status of each greatly limits their application.The tree shrew or tupaia (Tupaia belangeri) is a small, squirrel-like mammal that is closely related to primates (6). Since the 1980s, tupaias have been used as an animal model of various infectious agents and their associated diseases. Tupaia has been shown to be susceptible to a variety of human viruses, including herpes simplex virus and hepatitis B virus (HBV) (9,38). Early in 1998 it was reported that inoculation with HCV RNA-positive serum could lead to short-term viremia and the appearance of anti-HCV IgG in tupaia (40). Furthermore, primary tupaia hepatocytes (PTHs) can be infected in vitro with serum derived from chronic hepatitis C patients (2, 18, 21, 36), although it is not clear whether the viral RNA measured is due to de novo production and/or from the virus inoculum. Recently, independent observations showed that inoculating tupaia with hepatitis C patient serum or viral particles reconstituted from full-length HCV cDNA caused mild hepatitis and intermittent viremia (1). However, these reports do not firmly establish the tupaia as a reliable model of HCV replication and pathogenesis. Importantly, patient sera often exhibit very weak infectivity (15,36). Although these results show promise, additional work has to be conducted to evaluate the value of pursuing the tupaia system in HCV research.The e...

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

“…This finding explains the recent observation that an HCV variant selected to utilize murine CD81 with efficiency equal to that of human CD81 was able to enter cells expressing only murine entry factors (4). In line with this, primary hepatocytes of the small mammal Tupaia belangeri were recently reported to be susceptible to HCVcc entry (39). Moreover, the alanine-to-glycine exchanges in positions 223 and 224 account for this difference in coreceptor efficiency, as was predicted by HCVpp assays (29), indicating that despite differences in particle architecture, HCVpp remain a model strongly predictive of the behavior of HCVcc.…”

Genome of the Chinese tree shrew

“…Current studies suggest that a total of 163 human genes were reported to respond in HBV and HCV infection 39,40 . The counterparts of most of those genes are present in the tree shrew genome and shared a relatively high sequence identity with human ( Fig.…”

“…3), in which recurrent viral antagonism has led to a convergent evolution of escape from hepaciviral antagonism in primates 42 . Note that a recent study by Tong et al 40 provided functional data that tree shrew CD81, SR-BI, claudin-1 and occludin support HCV infection.…”

Ficolin-2 Inhibits Hepatitis C Virus Infection, whereas Apolipoprotein E3 Mediates Viral Immune Escape

“…Production and infection of Huh7.5.1 cells using infectious HCV JFH1 (a genotype 2a isolate) or murine leukemia virus-based HCVpp were performed as described (29,30). Pseudotyped particles harboring glycoprotein of the vesicular stomatitis virus (VSVGpp) onto murine leukemia virus were used as a control.…”