title: Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences.
abstract: The antigenic diversity of human immunodeficiency virus type 1 (HIV-1) represents a significant challenge for vaccine design as well as the comprehensive assessment of HIV-1-specific immune responses in infected persons. In this study we assessed the impact of antigen variability on the characterization of HIV-1-specific T-cell responses by using an HIV-1 database to determine the sequence variability at each position in all expressed HIV-1 proteins and a comprehensive data set of CD8 T-cell responses to a reference strain of HIV-1 in infected persons. Gamma interferon Elispot analysis of HIV-1 clade B-specific T-cell responses to 504 overlapping peptides spanning the entire expressed HIV-1 genome derived from 57 infected subjects demonstrated that the average amino acid variability within a peptide (entropy) was inversely correlated to the measured frequency at which the peptide was recognized (P = 6 x 10(-7)). Subsequent studies in six persons to assess T-cell responses against p24 Gag, Tat, and Vpr peptides based on autologous virus sequences demonstrated that 29% (12 of 42) of targeted peptides were only detected with peptides representing the autologous virus strain compared to the HIV-1 clade B consensus sequence. The use of autologous peptides also allowed the detection of significantly stronger HIV-1-specific T-cell responses in the more variable regulatory and accessory HIV-1 proteins Tat and Vpr (P = 0.007). Taken together, these data indicate that accurate assessment of T-cell responses directed against the more variable regulatory and accessory HIV-1 proteins requires reagents based on autologous virus sequences. They also demonstrate that CD8 T-cell responses to the variable HIV-1 proteins are more common than previously reported.
authors.affiliation: Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Raj
authors.initials: R
authors.lastname: Shankarappa
authors.forename: Paul K
authors.initials: PK
authors.lastname: Lee
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Almas
authors.initials: A
authors.lastname: Rathod
authors.forename: Jason
authors.initials: J
authors.lastname: Harlow
authors.forename: Kristin
authors.initials: K
authors.lastname: O'Sullivan
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D010455:Peptides; D014764:Viral Proteins