title: Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells.
abstract: The role of CD8(+) T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8(+) responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8(+) T cells is associated with protection from dengue virus disease.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.forename: Elzinandes L
authors.initials: EL
authors.lastname: de Azeredo
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Jason A
authors.initials: JA
authors.lastname: Greenbaum
authors.forename: Anira N
authors.initials: AN
authors.lastname: Fernando
authors.forename: Anne
authors.initials: A
authors.lastname: Broadwater
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Kolla
authors.forename: Aruna D
authors.initials: AD
authors.lastname: De Silva
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Mattia
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.forename: Howard M
authors.initials: HM
authors.lastname: Grey
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003715:Dengue / Q000453:epidemiology* / Q000276:immunology*; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D009000:Monocytes / Q000378:metabolism; D020815:Polyproteins / Q000276:immunology / Q000378:metabolism; D016036:Seroepidemiologic Studies; D013188:Sri Lanka / Q000453:epidemiology
chemical_list: D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D020815:Polyproteins