title: Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load.
abstract: An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.
authors.affiliation: National Institute for Communicable Diseases, Johannesburg, South Africa.
authors.forename: Agatha
authors.initials: A
authors.lastname: Masemola
authors.forename: Tumelo
authors.initials: T
authors.lastname: Mashishi
authors.forename: Greg
authors.initials: G
authors.lastname: Khoury
authors.forename: Phineas
authors.initials: P
authors.lastname: Mohube
authors.forename: Pauline
authors.initials: P
authors.lastname: Mokgotho
authors.forename: Efthyia
authors.initials: E
authors.lastname: Vardas
authors.forename: Mark
authors.initials: M
authors.lastname: Colvin
authors.forename: Lynn
authors.initials: L
authors.lastname: Zijenah
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.forename: Rosemary
authors.initials: R
authors.lastname: Musonda
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Newton
authors.initials: N
authors.lastname: Kumwenda
authors.forename: Taha
authors.initials: T
authors.lastname: Taha
authors.forename: Glenda
authors.initials: G
authors.lastname: Gray
authors.forename: James
authors.initials: J
authors.lastname: McIntyre
authors.forename: Salim Abdool
authors.initials: SA
authors.lastname: Karim
authors.forename: Haynes W
authors.initials: HW
authors.lastname: Sheppard
authors.forename: Clive M
authors.initials: CM
authors.lastname: Gray
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D019562:Viral Load; D014766:Viremia / Q000276:immunology / Q000821:virology
chemical_list: D000939:Epitopes; D015488:HIV Antigens