It has been suggested that short-lived species should limit their investment in immunity to immediate, innate responses, as the energetic costs associated with mounting specific immune reactions are unlikely to be outweighed by the benefits of increased long-term survival [1] . The dependence on innate responses may be greater for species with limited energetic reserves (such as S. araneus), as even a mild immune challenge is likely to result in starvation if allowed to persist for more than a short time [1] . Here, however, the presence of numerous active secondary follicles in the spleen and pancreas of Aselli, the development of small lymphatic follicles in portal areas in the liver and the generally high number of plasma cells in the pancreas of Aselli all indicate that common shrews remain consistently able to mount systemic, specific immune responses. We also observed macro- phage-dominated (granulomatous) inflammatory reactions with lymphocyte involvement in both sub-adult and adult shrews, which included reactions to helminths in tissues. The increasing number of plasma cells in the medulla of the pancreas of Aselli and in lymph nodes with advancing age might even suggest a 'refocusing' of the immune system, from reacting to novel antigens in follicles as a young animal, to combating previously experienced parasites or pathogens with appropriate antibody responses as an adult. Plasma cells are long-lived and can survive for weeks after immunisation, particularly when not too tightly packed [50] ; perhaps young common shrews invest in long term immunity by producing and storing plasma cells in the pancreas of Aselli, which can then be used to mount efficient responses against previously encountered parasites in adulthood, when reproduction places greater demands on internal resources [8] . While this strategy may allow older animals to react effectively to previously encountered parasites, infection by novel agents or eventual depletion of plasma cell reserves, could still be factors in the near-synchronous mortality of adult shrews observed shortly after the breeding season [12, 13, 18]  Prevention of Cytotoxic T Cell Escape Using a Heteroclitic Subdominant Viral T Cell Determinant High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2K(b) to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3) increased the stability of the engineered determinant in complex with H-2K(b). The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity. Despite the antigenic complexity of microbes, primary pathogen-specific cytotoxic CD8+ T lymphocyte (CTL) responses are commonly directed to just one or a few determinants. Furthermore, even when multiple epitopes are targeted, distinct patterns of epitope hierarchy often emerge. Such immunodominant epitopes commonly elicit high-magnitude CTL responses characterized by potent cytolytic function, whereas subdominant determinants generate responses that are relatively lower in magnitude and often less efficacious. In general, potent anti-viral CTL strongly correlate with control of infection and less clinical disease. Viral progeny selected on the basis of CTL surveillance can evolve to evade T cell responses. This selective pressure results in mutations in immunodominant CTL determinants that abrogate recognition. CTL escape virus is commonly observed in humans and nonhuman primates infected with HIV-1, hepatitis C virus (HCV) or simian immunodeficiency virus (SIV) and its selection often correlates with disease progression [1] [2] [3] [4] . Escape mutations may diminish binding to the restricting MHC class I molecule, interfere with T cell receptor (TcR) recognition or interfere with antigen processing [5] [6] [7] . Escape mutations are usually detected in epitopes targeted by CTL that exhibit high functional avidity because the corresponding potent CTL response exerts high selective pressure on the virus [2] . In some HIVinfected patients, CTL escape occurs without an associated enhancement of virus replication, suggesting that the mutations compromised virus fitness or, alternatively, the variant determinant elicited a de novo CTL response [8, 9] . Virus fitness is sometimes restored, with concomitant increased virus replication, when a second, compensatory mutation is selected [10, 11] . Collectively these results suggest that given the importance of virus diversification (CTL escape) in disease progression, suppression of selection or outgrowth of CTL escape variants should improve outcomes in persistently infected animals and humans.