title: Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors.
abstract: Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bitzegeio
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bankwitz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hueging
authors.forename: Sibylle
authors.initials: S
authors.lastname: Haid
authors.forename: Christiane
authors.initials: C
authors.lastname: Brohm
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Marcus
authors.initials: M
authors.lastname: Iken
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D062445:Claudin-1; D016174:Hepacivirus / Q000472:pathogenicity*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D011991:Receptors, Virus / Q000276:immunology; D051122:Scavenger Receptors, Class B / Q000502:physiology; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C568108:CLDN1 protein, human; C554799:Cd81 protein, mouse; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins; D011991:Receptors, Virus; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins