Neutralizing host responses in hepatitis C virus infection target viral entry at postbinding steps and membrane fusion.
OBJECTIVE
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis worldwide. Viral attachment and entry, representing the first steps of virus-host cell interactions, are major targets of adaptive host cell defenses. The mechanisms of antibody-mediated neutralization by host neutralizing responses in HCV infection are only poorly understood. Retroviral HCV pseudotypes (HCVpp) and recombinant cell culture-derived HCV (HCVcc) have been successfully used to study viral entry and antibody-mediated neutralization.


METHODS
In this study, we used these model systems to investigate the mechanism of antibody-mediated neutralization by monoclonal antienvelope antibodies and polyclonal anti-HCV immunoglobulins purified from HCV-infected patients.


RESULTS
Using a panel of monoclonal antienvelope antibodies, we identified an epitope within the E1 glycoprotein targeted by human neutralizing antibodies during postbinding events. Interestingly, we observed that host neutralizing responses in the majority of HCV-infected individuals include antibodies targeting HCV entry after binding of the virus to the target cell membrane. Using a kinetic assay based on HCVpp and HCVcc entry, we demonstrate that purified antiviral immunoglobulins derived from individual HCV-infected patients appear to inhibit HCV infection at an entry step closely linked to CD81 and scavenger receptor BI (SR-BI).


CONCLUSIONS
Our results indicate that host neutralizing responses in HCV-infected patients target viral entry after HCV binding most likely related to HCV-CD81, and HCV-SR-BI interactions, as well as membrane fusion. These findings have implications not only for the understanding of the pathogenesis of HCV infection but also for the design of novel immunotherapeutic and preventive strategies.
Haberstroh
Anita
A
Department of Medicine II, University of Freiburg, Freiburg, Germany.
Schnober
Eva K
EK
Zeisel
Mirjam B
MB
Carolla
Patric
P
Barth
Heidi
H
Blum
Hubert E
HE
Cosset
François-Loic
FL
Koutsoudakis
George
G
Bartenschlager
Ralf
R
Union
Ann
A
Depla
Erik
E
Owsianka
Ania
A
Patel
Arvind H
AH
Schuster
Catherine
C
Stoll-Keller
Françoise
F
Doffoël
Michel
M
Dreux
Marlène
M
Baumert
Thomas F
TF
D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016174:Hepacivirus / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology; D008561:Membrane Fusion / Q000187:drug effects*; D008875:Middle Aged; D011991:Receptors, Virus; D051122:Scavenger Receptors, Class B / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C554798:CD81 protein, human; D018937:Hepatitis C Antibodies; D007074:Immunoglobulin G; D011991:Receptors, Virus; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus