Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

TY - JOUR

T1 - Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

AU - Giang, Erick

AU - Dorner, Marcus

AU - Prentoe, Jannick C

AU - Dreux, Marlène

AU - Evans, Matthew J

AU - Bukh, Jens

AU - Rice, Charles M

AU - Ploss, Alexander

AU - Burton, Dennis R

AU - Law, Mansun

PY - 2012/4/17

Y1 - 2012/4/17

N2 - Hepatitis C virus (HCV) infects ∼2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies to HCV.

AB - Hepatitis C virus (HCV) infects ∼2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies to HCV.

KW - Amino Acid Sequence

KW - Animals

KW - Antibodies, Monoclonal

KW - Antibodies, Neutralizing

KW - Antibody Specificity

KW - Antigens, CD81

KW - Cell Line, Tumor

KW - Enzyme-Linked Immunosorbent Assay

KW - Epitopes, B-Lymphocyte

KW - Genotype

KW - HEK293 Cells

KW - Hepacivirus

KW - Hepatitis C

KW - Hepatitis C Antibodies

KW - Humans

KW - Immunoblotting

KW - Mice

KW - Molecular Sequence Data

KW - Peptide Library

KW - Viral Envelope Proteins

KW - Viral Hepatitis Vaccines

U2 - 10.1073/pnas.1114927109

DO - 10.1073/pnas.1114927109

M3 - Journal article

C2 - 22492964

SN - 0027-8424

VL - 109

SP - 6205

EP - 6210

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 16

ER -