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

Abstract

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 ELI-SPOT 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.