Here we determined whether the CD8 T cell response to S598 could be enhanced so that it now elicited a more potent T cell response that protected mice against the development of CTL escape at S510 and subsequent clinical disease. We modified epitope S598 (S598 Q600Y ) such that it elicited a high-avidity CTL response and using the crystal structures of the H-2K b /S598 and H-2K b /S598 Q600Y complexes, determined the basis of this enhanced immune response. We then introduced this more immunogenic S598 epitope into a recombinant version of JHMV and showed that these high-avidity S598-specific CTLs protected against escape variants in the immunodominant S510 epitope. Immunization with the modified peptide resulted in an improved response to the native S598 epitope, demonstrating a true heteroclitic effect and suggesting that this strategy may have clinical applications for reducing viral titer and preventing CTL escape during chronic infections.