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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 fever (DHF), variation at the HLA-A locus was significantly associated with susceptibility to DHF (P=.02), and specific HLA-A susceptibility and resistance alleles were identified. HLA-A-specific epitopes were predicted from binding motifs, and ELISPOT analyses of patients with DHF revealed high frequencies of circulating CD8 T lymphocytes that recognized both serotype-specific and -cross-reactive dengue virus epitopes. Thus, strong CD8 T cell responses are induced by natural dengue virus infection, and HLA class I genetic 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 serotype-cross-reactive CD8 T cells poses yet another obstacle to successful dengue vaccine development.

Original publication




Journal article


J Infect Dis

Publication Date





1369 - 1373


Adolescent, Adult, Antigens, Viral, CD8-Positive T-Lymphocytes, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Dengue Virus, Epitopes, Female, Genetic Predisposition to Disease, Genetic Variation, HLA-A Antigens, Humans, Interferon-gamma, Lymphocyte Activation, Major Histocompatibility Complex, Male, Polymorphism, Genetic, Severe Dengue