Enhancing the immune responses to pathogens is a chief goal of vaccine development. Here, we describe the development of an engineered CD8+ T cell epitope that elicits an immune response to the native epitope that is more potent than the one that occurs during the natural infection. We showed that this ''improved'' (heteroclitic) epitope protects against clinical disease and against cytotoxic T cell escape that frequently occurs in the immunodominant epitope expressed by the virus. We also performed structural analyses and showed that enhanced immunogenicity was associated with changes in the conformations of both the peptide and the region of the MHC class I molecule that is in close association with the peptide. These studies provide a model for designing T cell epitopes with enhanced immunogenicity that will be useful in vaccine development, with particular emphasis on diseases, such as HIV and hepatitis C, in which epitope mutation and escape is common. Seven days p.i., total RNA was harvested from the brains of mice and relative representation of virus template was determined via RT-PCR and direct sequencing of PCR products. The relative proportion of animals in which only rJ, only rJ.S Q600Y , or a mixture of the two viruses is shown. (D) High-ability to elicit a CTL response, we included a reducing agent (TCEP, Tris [2-carboxyethyl] phosphine) in the cultures. TCEP enhanced the stimulatory capacity of the S598 peptides ( Figure  S1B ), indicating that a proportion of the unmodified S598 peptide stock had undergone oxidation. Thus, we stimulated CNS-and spleen-derived CTL ex vivo in the presence of 500 mM TCEP, a concentration consistent with other work with Cys containing peptides [23, 26] .