title: 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 (HCVpp) cell entry 2-fold. The 293T cells transfected with tupaia CLDN1 became susceptible to HCVpp infection. Moreover, simultaneous transfection of the four tupaia factors into mouse NIH 3T3 cells made the cells susceptible to HCVpp infection. HCVpp of diverse genotypes were able to infect primary tupaia hepatocytes (PTHs), and this infection could be blocked by either anti-CD81 or anti-SR-BI. PTHs could be infected by cell culture-produced HCV (HCVcc) and did produce infectious progeny virus in culture supernatant. These findings indicate that PTHs possess all of the essential factors required for HCV entry and support the complete HCV infection cycle. This highlights both the mechanisms of susceptibility of tupaia to HCV infection and the possibility of using tupaia as a promising small-animal model in HCV study.
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Tong
authors.forename: Yongzhe
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xueshan
authors.initials: X
authors.lastname: Xia
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Xian
authors.initials: X
authors.lastname: Hua
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Feitelson
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism*; D002460:Cell Line; D062445:Claudin-1; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D062793:Occludin; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D060225:Tetraspanin 28; D014417:Tupaia / Q000821:virology*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; D018955:CD36 Antigens; C554798:CD81 protein, human; C568108:CLDN1 protein, human; C554799:Cd81 protein, mouse; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus