title: Human CD8+ T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated With Distinct Patterns of Protein Targets.
abstract: BACKGROUND
  All 4 dengue virus (DENV) serotypes are now simultaneously circulating worldwide and responsible for up to 400 million human infections each year. Previous studies of CD8(+) T-cell responses in HLA-transgenic mice and human vaccinees demonstrated that the hierarchy of immunodominance among structural versus nonstructural proteins differs as a function of the infecting serotype. This led to the hypothesis that there are intrinsic differences in the serotype-specific reactivity of CD8(+) T-cell responses.
  
  
  METHODS
  We tested this hypothesis by analyzing serotype-specific CD8(+) T-cell reactivity in naturally infected human donors from Sri Lanka and Nicaragua, using ex vivo interferon γ-specific enzyme-linked immunosorbent spot assays.
  
  
  RESULTS
  Remarkably similar and clear serotype-specific patterns of immunodominance in both cohorts were identified. Pooling of epitopes that accounted for 90% of the interferon γ response in both cohorts resulted in a global epitope pool. Its reactivity was confirmed in naturally infected donors from Brazil, demonstrating its global applicability.
  
  
  CONCLUSIONS
  This study provides new insight into differential serotype-specific immunogenicity of DENV proteins. It further provides a potentially valuable tool for future investigations of CD8(+) T-cell responses in the typically small sample volumes available from patients with acute fever and children without requiring prior knowledge of either infecting DENV serotype or HLA type.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.affiliation: Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud.
authors.forename: Cristhiam
authors.initials: C
authors.lastname: Cerpas
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bangs
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Division of Clinical Immunology and Allergy (LIM-60), School of Medicine, University of São Paulo, Brazil.
authors.forename: Françoise P
authors.initials: FP
authors.lastname: Sanches
authors.affiliation: Division of Clinical Immunology and Allergy (LIM-60), School of Medicine, University of São Paulo, Brazil.
authors.forename: Cassia G T
authors.initials: CG
authors.lastname: Silvera
authors.affiliation: Division of Clinical Immunology and Allergy (LIM-60), School of Medicine, University of São Paulo, Brazil.
authors.forename: Priscilla R
authors.initials: PR
authors.lastname: Costa
authors.affiliation: Division of Clinical Immunology and Allergy (LIM-60), School of Medicine, University of São Paulo, Brazil.
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
authors.affiliation: Sustainable Sciences Institute, Managua, Nicaragua.
authors.forename: Lionel
authors.initials: L
authors.lastname: Gresh
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology Genetech Research Institute, Colombo, Sri Lanka.
authors.forename: Aruna D
authors.initials: AD
authors.lastname: de Silva
authors.affiliation: Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud.
authors.forename: Angel
authors.initials: A
authors.lastname: Balmaseda
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D001938:Brazil; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000453:epidemiology* / Q000276:immunology*; D003716:Dengue Virus / Q000145:classification / Q000276:immunology*; D006801:Humans; D065288:Serogroup; D013188:Sri Lanka; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D014764:Viral Proteins
keywords: Brazil; CD8+ T cells; Nicaragua; Sri Lanka; dengue virus; serotype specific