title: Epitope mapping of HIV-specific CD8+ T cell responses by multiple immunological readouts reveals distinct specificities defined by function.
abstract: The limited success of HIV vaccine candidates to date highlights our need to better characterize protective cell-mediated immunity (CMI). While HIV-specific CD8(+) T cell responses have been defined largely by measuring gamma interferon (IFN-γ), these responses are not always protective, and it is unclear whether the same epitopes would predominate if other functional parameters were examined. Here, we assessed the epitope specificity of HIV-specific CD8(+) T cell responses by multiparametric flow cytometry, measuring five CD8(+) T cell functions (IFN-γ, macrophage inflammatory protein 1β [MIP-1β], tumor necrosis factor alpha [TNF-α], interleukin-2 [IL-2], and proliferative capacity) in 24 chronically HIV-infected individuals. Sixty-nine epitope-specific responses to 50 epitopes within p24 were measured. Surprisingly, most epitope-specific responses were IFN-γ negative (50/69 responses). Many responses had polyfunctional (33%) and proliferative (19%) components. An inverse association between IL-2 and proliferation responses was also observed, contrary to what was described previously. We confirm that long-term nonprogressors (LTNP) have more polyfunctional responses and also have higher-magnitude and broader p24-specific proliferation and higher levels of IL-2 and TNF-α production than do progressing controls. Together, these data suggest that the specificity of CD8(+) T cell responses differs depending on the immunological readout, with a 3.5-fold increase in breadth detected by including multiple parameters. Furthermore, the identification of epitopes that elicit polyfunctional responses reinforces the need for the comprehensive evaluation of HIV vaccine candidates, and these epitopes may represent novel targets for CMI-based vaccines.
authors.affiliation: Department of Medical Microbiology, University of Manitoba, H3440-1015 Arlington St., Winnipeg, MB R3E 3R2 Canada.
authors.forename: Meika
authors.initials: M
authors.lastname: Richmond
authors.forename: Lyle R
authors.initials: LR
authors.lastname: McKinnon
authors.forename: Sandra A Koesters
authors.initials: SA
authors.lastname: Kiazyk
authors.forename: Charles
authors.initials: C
authors.lastname: Wachihi
authors.forename: Makobu
authors.initials: M
authors.lastname: Kimani
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.forename: Francis A
authors.initials: FA
authors.lastname: Plummer
authors.forename: T Blake
authors.initials: TB
authors.lastname: Ball
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D054407:Chemokine CCL4 / Q000378:metabolism; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006678:HIV / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha
chemical_list: C066507:CCL4 protein, human; D054407:Chemokine CCL4; D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma