Hepatitis C virus (HCV)-induced immunoglobulin hypermutation reduces the affinity and neutralizing activities of antibodies against HCV envelope protein

Keigo Machida, Yasuteru Kondo, Jeffrey Y. Huang, Yung Chia Chen, Kevin T.H. Cheng, Zhenyong Keck, Steven Foung, Jean Dubuisson, Vicky M.H. Sung, Michael M.C. Lai

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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 (VH) in B cells. We hypothesize that if HCV infects antibody-producing B cells, the resultant hypermutation of VH 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 VH 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.

Original languageEnglish
Pages (from-to)6711-6720
Number of pages10
JournalJournal of virology
Volume82
Issue number13
DOIs
Publication statusPublished - 2008 Jul

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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