title: Hepatitis C virus (HCV)-induced immunoglobulin hypermutation reduces the affinity and neutralizing activities of antibodies against HCV envelope protein.
abstract: Hepatitis C virus (HCV) often causes persistent infection despite the presence of neutralizing antibodies against the virus in the sera of hepatitis C patients. HCV infects both hepatocytes and B cells through the binding of its envelope glycoprotein E2 to CD81, the putative viral receptor. Previously, we have shown that E2-CD81 interaction induces hypermutation of heavy-chain immunoglobulin (V(H)) in B cells. We hypothesize that if HCV infects antibody-producing B cells, the resultant hypermutation of V(H) may lower the affinity and specificity of the HCV-specific antibodies, enabling HCV to escape from immune surveillance. To test this hypothesis, we infected human hybridoma clones producing either neutralizing or non-neutralizing anti-E2 or anti-E1 antibodies with a lymphotropic HCV (SB strain). All of the hybridoma clones, except for a neutralizing antibody-producing hybridoma, could be infected with HCV and support virus replication for at least 8 weeks after infection. The V(H) sequences in the infected hybridomas had a significantly higher mutation frequency than those in the uninfected hybridomas, with mutations concentrating in complementarity-determining region 3. These mutations lowered the antibody affinity against the targeting protein and also lowered the virus-neutralizing activity of anti-E2 antibodies. Furthermore, antibody-mediated complement-dependent cytotoxicity with the antibodies secreted from the HCV-infected hybridomas was impaired. These results suggest that HCV infection could cause some anti-HCV-antibody-producing hybridoma B cells to make less-protective antibodies.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Kondo
authors.forename: Jeffrey Y
authors.initials: JY
authors.lastname: Huang
authors.forename: Yung-Chia
authors.initials: YC
authors.lastname: Chen
authors.forename: Kevin T-H
authors.initials: KT
authors.lastname: Cheng
authors.forename: Zhenyong
authors.initials: Z
authors.lastname: Keck
authors.forename: Steven
authors.initials: S
authors.lastname: Foung
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.forename: Vicky M-H
authors.initials: VM
authors.lastname: Sung
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000821:virology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
chemical_list: D000914:Antibodies, Viral; D015703:Antigens, CD; C554798:CD81 protein, human; D007143:Immunoglobulin Heavy Chains; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus