Mutations in immunodominant T cell epitopes derived from the nonstructural3 protein of hepatitis C virus have the potential for generating escape variants that may have important consequences for T cell recognition

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 nonstr uctural 3 (NS3) protein might be subject to sequence variations leading to escape mutants, we examined sequence variations of one IL-2-producing epito pe, NS3(358-375) and one IL-10-producing epitope, NS3(505-521). By PCR ampl ification, cloning, and sequencing, we observed significant sequence variat ions in the two epitopes, although the selection intensity for each epitope was different. For NS3(358-375), more variants were observed, and for NS3( 505-521), fewer mutations mere observed. Moreover, functional studies revea led that three NS3(358-375) and one NS3(505-521) variants failed to stimula te T cell proliferation, and two other NS3(358-375) and NS3(505-521) varian ts weakly Stimulated T cell responses. Our results are consistent,vith immu ne selection of viral variants at the epitope level, which may enable HCV t o evade host defenses over time.