Strong HLA class I-restricted T cell responses in dengue hemorrhagic fever: A double-edged sword?

Dengue is an increasingly important cause of morbidity and mortality in the tropics, but vaccine development has been impeded by a poor understanding of disease pathogenesis and, in particular, of immunologic enhancement. In a large case-control study of Vietnamese patients with dengue hemorrhagic f ever (DHF), variation at the HLA-A locus was significantly associated with susceptibility to DHF (P = .02), and specific HLA-A susceptibility and resi stance alleles were identified. HLA-A-specific epitopes were predicted from binding motifs, and ELISPOT analyses of patients with DHF revealed high fr equencies of circulating CD8 T lymphocytes that recognized both serotype-sp ecific and -cross-reactive dengue virus epitopes. Thus, strong CD8 T cell r esponses are induced by natural dengue virus infection, and HLA class I gen etic variation is a risk factor for DHF. These genetic and immunologic data support both protective and pathogenic roles for dengue virus-specific CD8 T cell responses in severe disease. The potentially pathogenic role of ser otype-cross-reactive CD8 T cells poses yet another obstacle to successful d engue vaccine development.