Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation.
End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.
Fafi-Kremer
Samira
S
Institut National de la Santé et de la Recherche Médicale, Unité 748, Strasbourg, France.
Fofana
Isabel
I
Soulier
Eric
E
Carolla
Patric
P
Meuleman
Philip
P
Leroux-Roels
Geert
G
Patel
Arvind H
AH
Cosset
François-Loïc
FL
Pessaux
Patrick
P
Doffoël
Michel
M
Wolf
Philippe
P
Stoll-Keller
Françoise
F
Baumert
Thomas F
TF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology / Q000635:transmission* / Q000821:virology; D018937:Hepatitis C Antibodies / Q000494:pharmacology*; D006801:Humans; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects*; D055815:Young Adult
D015703:Antigens, CD; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; D018937:Hepatitis C Antibodies; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins