title: Protective efficacy of serially up-ranked subdominant CD8+ T cell epitopes against virus challenges.
abstract: Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Eung-Jun
authors.initials: EJ
authors.lastname: Im
authors.forename: Jessie P
authors.initials: JP
authors.lastname: Hong
authors.forename: Yaowaluck
authors.initials: Y
authors.lastname: Roshorm
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgeman
authors.forename: Sven
authors.initials: S
authors.lastname: Létourneau
authors.forename: Peter
authors.initials: P
authors.lastname: Liljeström
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Potash
authors.forename: David J
authors.initials: DJ
authors.lastname: Volsky
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Tomáš
authors.initials: T
authors.lastname: Hanke
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D016207:Cytokines / Q000032:analysis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015497:HIV-1 / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes