Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission.
Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal antibodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins representing the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell transmission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver.
Brimacombe
Claire L
CL
Hepatitis C Research Group, Institute For Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, United Kingdom.
Grove
Joe
J
Meredith
Luke W
LW
Hu
Ke
K
Syder
Andrew J
AJ
Flores
Maria Victoria
MV
Timpe
Jennifer M
JM
Krieger
Sophie E
SE
Baumert
Thomas F
TF
Tellinghuisen
Timothy L
TL
Wong-Staal
Flossie
F
Balfe
Peter
P
McKeating
Jane A
JA
D057134:Antibodies, Neutralizing / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D062445:Claudin-1; D018920:Coculture Techniques; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018937:Hepatitis C Antibodies / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D062793:Occludin; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D060225:Tetraspanin 28; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism
D057134:Antibodies, Neutralizing; D015703:Antigens, CD; C554798:CD81 protein, human; C568108:CLDN1 protein, human; D062445:Claudin-1; D018937:Hepatitis C Antibodies; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D011991:Receptors, Virus; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28