title: The majority of currently circulating human immunodeficiency virus type 1 clade B viruses fail to prime cytotoxic T-lymphocyte responses against an otherwise immunodominant HLA-A2-restricted epitope: implications for vaccine design.
abstract: Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr59-67) that is targeted by acute-phase HIV-1-specific CD8+ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I60L variant all developed these responses. The I60L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic T-lymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Boston, MA 02129, USA. maltfeld@partners.org
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Kalife
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Bianca R
authors.initials: BR
authors.lastname: Mothe
authors.forename: Almas
authors.initials: A
authors.lastname: Rathod
authors.forename: Laura L
authors.initials: LL
authors.lastname: Reyor
authors.forename: Jason
authors.initials: J
authors.lastname: Harlow
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Beth
authors.initials: B
authors.lastname: Perkins
authors.forename: Loren K
authors.initials: LK
authors.lastname: Robinson
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D016915:AIDS Vaccines; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D015195:Drug Design; D000939:Epitopes / Q000276:immunology; D016336:Gene Products, vpr / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D016336:Gene Products, vpr; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D054325:vpr Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma