title: Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity.
abstract: CD8(+) T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8(+) T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8(+) T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8(+) T cells from infected donors. We report that attributes of CD8(+) T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8(+) T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8(+) T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Almeida
authors.forename: Delphine
authors.initials: D
authors.lastname: Sauce
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Laura
authors.initials: L
authors.lastname: Papagno
authors.forename: So Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Arnaud
authors.initials: A
authors.lastname: Moris
authors.forename: Martin
authors.initials: M
authors.lastname: Larsen
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pancino
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.forename: Asier
authors.initials: A
authors.lastname: Sáez-Cirión
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes; D005434:Flow Cytometry; D015488:HIV Antigens / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular; D014779:Virus Replication
chemical_list: D000939:Epitopes; D015488:HIV Antigens