In conclusion, we have demonstrated that crystal structures are useful in gaining an understanding of the basis of heteroclitic epitopes and can also prove valuable in guiding the rational design of ''better'' CTL epitopes. In our mouse system, immunization with the heteroclitic determinant resulted in the generation of unique populations of CTL that respond with high functional avidity to an otherwise modestly immunogenic viral epitope. The generation of unique populations of CTL that respond with high functional avidity to weakly immunogenic epitopes will be useful for the treatment and prevention of human infectious diseases. Our proposed structure-guided approach has direct application to HIV, HCV and other chronic infections in which virus persistence and CTL escape occurs. By modulating T cell immunity through prophylactic or therapeutic peptide-based vaccination, virus titers may be reduced and CTL escape and other consequences of viral persistence circumvented.