Journal
JOURNAL OF VIROLOGY
Volume 82, Issue 13, Pages 6711-6720Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02582-07
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [CA108302, R01 CA108302] Funding Source: Medline
- NHLBI NIH HHS [HL079381, R01 HL079381] Funding Source: Medline
- NIAID NIH HHS [R01 AI047355, AI047355, N01AI40038, AI 40038] Funding Source: Medline
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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.
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