Strong HLA Class I–Restricted T Cell Responses in Dengue Hemorrhagic Fever: A Double-Edged Sword?

• Published in: The Journal of infectious diseases Vol. 184; no. 11; pp. 1369 - 1373
• Main Authors: Loke, Hsin, Bethell, Delia B., Phuong, C. X. T., Dung, Minh, Schneider, Joerg, White, Nicholas J., Day, Nicholas P., Farrar, Jeremy, Hill, Adrian V. S.
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.12.2001; University of Chicago Press; Oxford University Press
• Subjects: Adolescent; Adult; Alleles; Antigens, Viral - immunology; Arboviroses; Biological and medical sciences; Case-Control Studies; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Child; Child, Preschool; Dengue; Dengue fevers; Dengue hemorrhagic fever; Dengue virus; Dengue Virus - immunology; Epitopes; Epitopes - immunology; Female; Genetic Predisposition to Disease; Genetic Variation; histocompatibility antigen HLA; HLA A antigens; HLA antigens; HLA-A Antigens - genetics; Human viral diseases; Humans; Infections; Infectious diseases; Interferon-gamma - biosynthesis; Lymphocyte Activation; Major Articles; Major Histocompatibility Complex; Male; Marburg disease, ebola disease; Medical sciences; Polymorphism, Genetic; Severe Dengue - genetics; Severe Dengue - immunology; T lymphocytes; Tropical viral diseases; Viral diseases; Viruses; Human; HLA-System; Hemorrhagic fever; Dengue hemorrhagic fever; Pathogenesis; Dengue; Cellular immunity; Vaccine; Case control study; Dengue virus; Flavivirus; Infection; Virus; Case study; Sensitivity; HLA-A-Locus; Histocompatibility restriction; Viral disease; Dengue group virus; Arbovirus disease; T-Lymphocyte; Development; Flaviviridae; Class I histocompatibility antigen
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/324320

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