title: The antiviral efficacy of simian immunodeficiency virus-specific CD8+ T cells is unrelated to epitope specificity and is abrogated by viral escape.
abstract: CD8(+) T lymphocytes appear to play a role in controlling human immunodeficiency virus (HIV) replication, yet routine immunological assays do not measure the antiviral efficacy of these cells. Furthermore, it has been suggested that CD8+ T cells that recognize epitopes derived from proteins expressed early in the viral replication cycle can be highly efficient. We used a functional in vitro assay to assess the abilities of different epitope-specific CD8+ T-cell lines to control simian immunodeficiency virus (SIV) replication. We compared the antiviral efficacies of 26 epitope-specific CD8+ T-cell lines directed against seven SIV epitopes in Tat, Nef, Gag, Env, and Vif that were restricted by either Mamu-A*01 or Mamu-A*02. Suppression of SIV replication varied depending on the epitope specificities of the CD8+ T cells and was unrelated to whether the targeted epitope was derived from an early or late viral protein. Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T-cell lines were consistently superior at suppressing viral replication compared to the other five SIV-specific CD8+ T-cell lines. We also investigated the impact of viral escape on antiviral efficacy by determining if Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T-cell lines could suppress the replication of an escaped virus. Viral escape abrogated the abilities of Tat(28-35)SL8- and Gag(181-189)CM9-specific CD8+ T cells to control viral replication. However, gamma interferon (IFN-gamma) enzyme-linked immunospot and IFN-gamma/tumor necrosis factor alpha intracellular-cytokine-staining assays detected cross-reactive immune responses against the Gag escape variant. Understanding antiviral efficacy and epitope variability, therefore, will be important in selecting candidate epitopes for an HIV vaccine.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 555 Science Drive, Madison, WI 53711, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Loffredo
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burwitz
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.forename: Sean P
authors.initials: SP
authors.lastname: Spencer
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Stephany
authors.forename: Juan Pablo Giraldo
authors.initials: JP
authors.lastname: Vela
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Martin
authors.forename: Jason
authors.initials: J
authors.lastname: Reed
authors.forename: Shari M
authors.initials: SM
authors.lastname: Piaskowski
authors.forename: Jessica
authors.initials: J
authors.lastname: Furlott
authors.forename: Kim L
authors.initials: KL
authors.lastname: Weisgrau
authors.forename: Denise S
authors.initials: DS
authors.lastname: Rodrigues
authors.forename: Taeko
authors.initials: T
authors.lastname: Soma
authors.forename: Gnankang
authors.initials: G
authors.lastname: Napoé
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015683:Gene Products, gag / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta; D017354:Point Mutation; D012367:RNA, Viral / Q000097:blood; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma