title: Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.
abstract: Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.
authors.affiliation: Howard Hughes Medical Institute, Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, MA, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Kristin M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Bianca R
authors.initials: BR
authors.lastname: Mothe
authors.forename: Paul K
authors.initials: PK
authors.lastname: Lee
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Kalife
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cohen
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Freedberg
authors.forename: Daryld A
authors.initials: DA
authors.lastname: Strick
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
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: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000235:genetics*; D015488:HIV Antigens / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015791:HLA-A3 Antigen / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D008969:Molecular Sequence Data; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics*; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015488:HIV Antigens; D015791:HLA-A3 Antigen; D016056:Immunodominant Epitopes; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1