Strong HLA class I--restricted T cell responses in dengue hemorrhagic fever: a double-edged sword?
Loke H., Bethell DB., Phuong CX., Dung M., Schneider J., White NJ., Day NP., Farrar J., Hill AV.
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.