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...

Background: HVR1 spans 27 residues at the N terminus of the HCV envelope glycoprotein E2 and is the most variable region within the HCV polyprotein. Results: Three independent functional microdomains were identified in HCV HVR1. Conclusion: Different microdomains in HVR1 cooperate to mediate HCV cell entry and immune evasion. Significance: The data provide novel insights into understanding the mechanisms of HCV infection and immune evasion.

Hepatitis C virus (HCV) glycoproteins E1 and E2 form a heterodimer to constitute viral envelope proteins, which play an essential role in virus entry. E1 does not directly interact with host receptors, and its functions in viral entry are exerted mostly through its interaction with E2 that directly binds the receptors. HCV enters the host cell via receptor-mediated endocytosis during which the fusion of viral and host endosomal membranes occurs to release viral genome to cytoplasm. A putative fusion peptide in E1 has been proposed to participate in membrane fusion, but its exact role and underlying molecular mechanisms remain to be deciphered. Recently solved crystal structures of the E2 ectodomains and N-terminal of E1 fail to reveal a classical fusion-like structure in HCV envelope glycoproteins. In addition, accumulating evidence suggests that E1 also plays an important role in virus assembly. In this mini-review, we summarize current knowledge on HCV E1 including its structure and biological functions in virus entry, fusion, and assembly, which may provide clues for developing HCV vaccines and more effective antivirals.

Hepatitis C virus (HCV) is an enveloped RNA virus belonging to the Flaviviridae family. It infects mainly human hepatocytes and causes chronic liver diseases, including cirrhosis and cancer. HCV encodes two envelope proteins, E1 and E2, that form a heterodimer and mediate virus entry. While E2 has been extensively studied, less has been done so for E1, and its role in the HCV life cycle still needs to be elucidated. Here we developed a new cell culture model for HCV infection based on the trans-complementation of E1. Virus production of the HCV genome lacking the E1-encoding sequence can be efficiently rescued by the ectopic expression of E1 in trans. The resulting virus, designated HCVΔE1, can propagate in packaging cells expressing E1 but results in only single-cycle infection in naive cells. By using the HCVΔE1 system, we explored the role of a putative fusion peptide (FP) of E1 in HCV infection. Interestingly, we found that the FP not only contributes to HCV entry, as previously reported, but also may be involved in virus morphogenesis. Finally, we identified amino acid residues in FP that are critical for biological functions of E1. In summary, our work not only provides a new cell culture model for studying HCV but also provides some insights into understanding the role of E1 in the HCV life cycle. IMPORTANCE Hepatitis C virus (HCV), an enveloped RNA virus, encodes two envelope proteins, E1 and E2, that form a heterodimeric complex to mediate virus entry. Compared to E2, the biological functions of E1 in the virus life cycle are not adequately investigated. Here we developed a new cell culture model for single-cycle HCV infection based on the trans-complementation of E1. The HCV genome lacking the E1-encoding sequence can be efficiently rescued for virus production by the ectopic expression of E1 in trans. This new model renders a unique system to dissect functional domains and motifs in E1. Using this system, we found that a putative fusion peptide in E1 is a multifunctional structural element contributing to both HCV entry and morphogenesis. Our work has provided a new cell culture model to study HCV and provides insights into understanding the biological roles of E1 in the HCV life cycle. KEYWORDS E1, envelope proteins, fusion peptide, hepatitis C virus, transcomplementation, virus entry, virus morphogenesis H epatitis C virus (HCV) is a major human pathogen that infects about 170 million people worldwide and can lead to chronic hepatitis and more severe liver diseases such as cirrhosis and hepatocellular carcinoma (1-3). For a long time, standard therapy for chronic HCV infection consisted of the administration of pegylated interferon alpha Functional analysis of hepatitis C virus (HCV) envelope protein E1 using a transcomplementation system reveals a dual role of a putative fusion peptide of E1 in both HCV entry and morphogenesis. J Virol 91:e02468-16.