Hepatitis C virus induces CD81 and claudin-1 endocytosis.
Hepatitis C virus (HCV) leads to progressive liver disease and hepatocellular carcinoma. Current treatments are only partially effective, and new therapies targeting viral and host pathways are required. Virus entry into a host cell provides a conserved target for therapeutic intervention. Tetraspanin CD81, scavenger receptor class B member I, and the tight-junction proteins claudin-1 and occludin have been identified as essential entry receptors. Limited information is available on the role of receptor trafficking in HCV entry. We demonstrate here that anti-CD81 antibodies inhibit HCV infection at late times after virus internalization, suggesting a role for intracellular CD81 in HCV infection. Several tetraspanins have been reported to internalize via motifs in their C-terminal cytoplasmic domains; however, CD81 lacks such motifs, leading several laboratories to suggest a limited role for CD81 endocytosis in HCV entry. We demonstrate CD81 internalization via a clathrin- and dynamin-dependent process, independent of its cytoplasmic domain, suggesting a role for associated partner proteins in regulating CD81 trafficking. Live cell imaging demonstrates CD81 and claudin-1 coendocytosis and fusion with Rab5 expressing endosomes, supporting a role for this receptor complex in HCV internalization. Receptor-specific antibodies and HCV particles increase CD81 and claudin-1 endocytosis, supporting a model wherein HCV stimulates receptor trafficking to promote particle internalization.
Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
Michelle J
MJ
Farquhar
Ke
K
Hu
Helen J
HJ
Harris
Christopher
C
Davis
Claire L
CL
Brimacombe
Sarah J
SJ
Fletcher
Thomas F
TF
Baumert
Joshua Z
JZ
Rappoport
Peter
P
Balfe
Jane A
JA
McKeating
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D000915:Antibody Affinity / Q000276:immunology; D002460:Cell Line; D062445:Claudin-1; D004705:Endocytosis; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011991:Receptors, Virus / Q000378:metabolism; D060225:Tetraspanin 28 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D011991:Receptors, Virus; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins