title: Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.
abstract: Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.
authors.affiliation: Howard Hughes Medical Institute, Charlestown, MA 02129, USA.
authors.forename: Rika
authors.initials: R
authors.lastname: Draenert
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.forename: Katja J
authors.initials: KJ
authors.lastname: Pfafferott
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Leslie
authors.forename: Polan
authors.initials: P
authors.lastname: Chetty
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Chang
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
authors.forename: Danni
authors.initials: D
authors.lastname: Ramduth
authors.forename: Prakash
authors.initials: P
authors.lastname: Jeena
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thomas
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Tang
authors.forename: Cori L
authors.initials: CL
authors.lastname: Verrill
authors.forename: Catherine
authors.initials: C
authors.lastname: Dixon
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
authors.forename: Photini
authors.initials: P
authors.lastname: Kiepiela
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001483:Base Sequence; D002999:Clone Cells; D004279:DNA, Viral / Q000235:genetics; D000939:Epitopes / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D014644:Genetic Variation; D015488:HIV Antigens / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D004279:DNA, Viral; D000939:Epitopes; D015683:Gene Products, gag; D015488:HIV Antigens; D015235:HLA-B Antigens; C103707:HLA-B57 antigen