A better understanding of the role

A better understanding of the role of CD8+ T cells in DENV infection is critical in the development of a vaccine, yet the lack of a good mouse model has hampered mechanistic investigations. The difficulty in developing a mouse model for DENV infections is largely due to the inability of human clinical isolates to replicate well in mice. However, we recently isolated a DENV2 strain, D2S10, which is more virulent in mice than the clinical isolate parental strain (19). S221, a triple-plaque-purified clone from the D2S10 population, was used in the present study to determine whether CD8+ T cells contribute to a protective host response against DENV. The specificity of the CD8+ T cell response in mice was mapped using a predictive algorithm to identify MHC class I-binding peptides from the entire proteome of DENV, which is approximately 3390 aa and encodes three structural (core (C), envelope (E), and membrane (M)) and seven nonstructural (NS) (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. A broad anti-DENV CD8+ T cell response was observed, with the recognition of 12 epitopes derived from 6 DENV proteins in H-2b mice. We found that depletion of CD8+ T cells resulted in increased DENV replication, DENV-specific CD8+ T cells demonstrated in vivo cytotoxic activity, and immunization with dominant epitopes led to enhanced viral clearance, thereby revealing an important contribution of CD8+ T cells to the anti-DENV-immune response.