title: 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 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.
authors.affiliation: Nuffield Department of Medicine, John Radcliffe Hospital and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. hsin.loke@pwcglobal.com
authors.forename: H
authors.initials: H
authors.lastname: Loke
authors.forename: D B
authors.initials: DB
authors.lastname: Bethell
authors.forename: C X
authors.initials: CX
authors.lastname: Phuong
authors.forename: M
authors.initials: M
authors.lastname: Dung
authors.forename: J
authors.initials: J
authors.lastname: Schneider
authors.forename: N J
authors.initials: NJ
authors.lastname: White
authors.forename: N P
authors.initials: NP
authors.lastname: Day
authors.forename: J
authors.initials: J
authors.lastname: Farrar
authors.forename: A V
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000293:Adolescent; D000328:Adult; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003716:Dengue Virus / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008297:Male; D011110:Polymorphism, Genetic; D019595:Severe Dengue / Q000235:genetics* / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D015234:HLA-A Antigens; D007371:Interferon-gamma