Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes.
OBJECTIVE
Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell.


METHODS
Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes.


RESULTS
Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies.


CONCLUSIONS
Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.
Fofana
Isabel
I
Inserm, U748, Strasbourg, France.
Krieger
Sophie E
SE
Grunert
Fritz
F
Glauben
Sandra
S
Xiao
Fei
F
Fafi-Kremer
Samira
S
Soulier
Eric
E
Royer
Cathy
C
Thumann
Christine
C
Mee
Christopher J
CJ
McKeating
Jane A
JA
Dragic
Tatjana
T
Pessaux
Patrick
P
Stoll-Keller
Francoise
F
Schuster
Catherine
C
Thompson
John
J
Baumert
Thomas F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000918:Antibody Specificity; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D062445:Claudin-1; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D005838:Genotype; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; C568108:CLDN1 protein, human; D062445:Claudin-1; D000939:Epitopes; D008565:Membrane Proteins