Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor.
Several cell surface molecules have been proposed as receptor candidates, mediating cell entry of hepatitis C virus (HCV) on the basis of their physical association with virions or with soluble HCV E2 glycoproteins. However, due to the lack of infectious HCV particles, evidence that these receptor candidates support infection was missing. Using our recently described infectious HCV pseudotype particles (HCVpp) that display functional E1E2 glycoprotein complexes, here we show that HCV is a pH-dependent virus, implying that its receptor component(s) mediate virion internalization by endocytosis. Expression of the CD81 tetraspanin in non-permissive CD81-negative hepato-carcinoma cells was sufficient to restore susceptibility to HCVpp infection, confirming its critical role as a cell attachment factor. As a cell surface molecule likely to mediate endosomal trafficking, we demonstrate that the human scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein-internalization molecule that we previously proposed as a novel HCV receptor candidate due to its affinity with E2 glycoproteins, is required for infection of CD81-expressing hepatic cells. By receptor competition assays, we found that SR-B1 antibodies that blocked binding of soluble E2 could prevent HCVpp infectivity. Furthermore, we establish that the hyper-variable region 1 of the HCV E2 glycoprotein is a critical determinant mediating entry in SR-B1-positive cells. Finally, by correlating expression of HCV receptors and infectivity, we suggest that, besides CD81 and SR-B1, additional hepatocyte-specific co-factor(s) are necessary for HCV entry.
Bartosch
Birke
B
Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, Institut Fédératif de Recherche 128, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon Cedex 07, France.
Vitelli
Alessandra
A
Granier
Christelle
C
Goujon
Caroline
C
Dubuisson
Jean
J
Pascale
Simona
S
Scarselli
Elisa
E
Cortese
Riccardo
R
Nicosia
Alfredo
A
Cosset
François-Loïc
FL
D015703:Antigens, CD / Q000502:physiology*; D018955:CD36 Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000166:cytology / Q000821:virology; D008565:Membrane Proteins / Q000502:physiology*; D011971:Receptors, Immunologic; D011973:Receptors, LDL / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011991:Receptors, Virus / Q000502:physiology*; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology
D015703:Antigens, CD; D018955:CD36 Antigens; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; C400562:HVR1 protein, Hepatitis C virus; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011991:Receptors, Virus; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C091015:glycoprotein E2, Hepatitis C virus