title: HLA-DRB1 Alleles Are Associated With Different Magnitudes of Dengue Virus-Specific CD4+ T-Cell Responses.
abstract: Each year dengue virus (DENV) infects 400 million human but causes symptomatic disease in only a subset of patients, suggesting that host genetic factors may play a role. HLA molecules that restrict T-cell responses are one of the most polymorphic host factors in humans.
  
  
  
  Here we map HLA DRB1-restricted DENV-specific epitopes in individuals previously exposed to DENV, to identify the breadth and specificity of CD4(+) T-cell responses. To investigate whether HLA-specific variations in the magnitude of response might predict associations between dengue outcomes and HLA-DRB1 alleles, we assembled samples from hospitalized patients with known severity of disease.
  
  
  
  The capsid protein followed by nonstructural protein 3 (NS3), NS2A, and NS5 were the most targeted proteins. We further noticed a wide variation in magnitude of T-cell responses as a function of the restricting DRB1 allele and found several HLA alleles that showed trends toward a lower risk of hospitalized disease were associated with a higher magnitude of T-cell responses.
  
  
  
  Comprehensive identification of unique CD4(+) T-cell epitopes across the 4 DENV serotypes allows the testing of T-cell responses by use of a simple, approachable technique and points to important implications for vaccine design.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Alba
authors.initials: A
authors.lastname: Grifoni
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: O'Rourke
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California Genetech Research Institute.
authors.forename: Aruna D
authors.initials: AD
authors.lastname: De Silva
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Department of Zoology and Environmental Science, Science Faculty, University of Colombo.
authors.forename: Sunil
authors.initials: S
authors.lastname: Premawansa
authors.affiliation: North Colombo Teaching Hospital, Ragama.
authors.forename: Gayani
authors.initials: G
authors.lastname: Premawansa
authors.affiliation: National Institute of Infectious Diseases, Gothatuwa, Sri Lanka.
authors.forename: Ananda
authors.initials: A
authors.lastname: Wijewickrama
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, California.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000276:immunology* / Q000473:pathology*; D003716:Dengue Virus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D059811:HLA-DRB1 Chains / Q000378:metabolism*; D006801:Humans
chemical_list: D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains
keywords: CD4+ T cells; Dengue virus; HLA; disease association