title: Nonneutralizing human antibody fragments against hepatitis C virus E2 glycoprotein modulate neutralization of binding activity of human recombinant Fabs.
abstract: Evidence from clinical and experimental studies indicates that hepatitis C virus E2 (HCV/E2) glycoprotein is the major target of a putatively protective immune response. However, even in the presence of a vigorous production of anti-HCV/E2 antibodies, reinfection can occur. Dissection of the human immune response against HCV/E2 indicated that blocking of binding of HCV/E2 to target cells [neutralization of binding (NOB) activity] varies widely among antibody clones. Moreover, in vivo, simultaneous binding of antibodies to distinct epitopes can induce conformational changes and synergies that may be relevant to understanding the anti-HCV immune response. In this study, human recombinant Fabs were generated by affinity-selecting a phage display repertoire library with antibody-coated HCV/E2. These Fabs, which share the same complementarity-determining region DNA sequences, had higher affinity than other anti-HCV/E2 Fabs but showed no NOB activity even at the highest concentrations. Binding of Fabs to HCV/E2 caused conformational changes modifying Fab-binding patterns and reducing, with a negative synergistic effect, Fab-mediated NOB activity. These data suggest that some antibody clones have the potential to modify HCV/E2 conformation and that, in this state, binding of this glycoprotein to its cellular target is less prone to inhibition by some antibody clones. This can explain why high anti-HCV/E2 antibody titers do not directly correlate with protection from infection. Information on the interactions among different antibody clones can contribute to understanding virus-host interplay and developing more effective vaccines.
authors.affiliation: Institute of Microbiology, Università di Ancona, Ancona, 60020, Italy. r.burioni@libero.it
authors.forename: R
authors.initials: R
authors.lastname: Burioni
authors.forename: F
authors.initials: F
authors.lastname: Bugli
authors.forename: N
authors.initials: N
authors.lastname: Mancini
authors.forename: D
authors.initials: D
authors.lastname: Rosa
authors.forename: C
authors.initials: C
authors.lastname: Di Campli
authors.forename: G
authors.initials: G
authors.lastname: Moroncini
authors.forename: A
authors.initials: A
authors.lastname: Manzin
authors.forename: S
authors.initials: S
authors.lastname: Abrignani
authors.forename: P E
authors.initials: PE
authors.lastname: Varaldo
authors.forename: M
authors.initials: M
authors.lastname: Clementi
authors.forename: G
authors.initials: G
authors.lastname: Fadda
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology*; D000915:Antibody Affinity; D000937:Antigen-Antibody Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology*; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000276:immunology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000276:immunology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019151:Peptide Library; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D019151:Peptide Library; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus