Mutations in Immunodominant T Cell Epitopes Derived from the Nonstructural 3 Protein of Hepatitis C Virus Have the Potential for Generating Escape Variants That May Have Important Consequences for T Cell Recognition

Abstract

Abstract One of the most disturbing features of hepatitis C virus (HCV) is its long-term persistence in the host. One hypothesis to explain this phenomenon is that HCV escapes immune recognition through its intrinsic hypermutability. To determine whether immunodominant T cell epitopes derived from HCV nonstructural 3 (NS3) protein might be subject to sequence variations leading to escape mutants, we examined sequence variations of one IL-2-producing epitope, NS3358–375, and one IL-10-producing epitope, NS3505–521. By PCR amplification, cloning, and sequencing, we observed significant sequence variations in the two epitopes, although the selection intensity for each epitope was different. For NS3358–375, more variants were observed, and for NS3505–521, fewer mutations were observed. Moreover, functional studies revealed that three NS3358–375 and one NS3505–521 variants failed to stimulate T cell proliferation, and two other NS3358–375 and NS3505–521 variants weakly stimulated T cell responses. Our results are consistent with immune selection of viral variants at the epitope level, which may enable HCV to evade host defenses over time.