Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.
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.
Draenert
Rika
R
Howard Hughes Medical Institute, Charlestown, MA 02129, USA.
Le Gall
Sylvie
S
Pfafferott
Katja J
KJ
Leslie
Alasdair J
AJ
Chetty
Polan
P
Brander
Christian
C
Holmes
Edward C
EC
Chang
Shih-Chung
SC
Feeney
Margaret E
ME
Addo
Marylyn M
MM
Ruiz
Lidia
L
Ramduth
Danni
D
Jeena
Prakash
P
Altfeld
Marcus
M
Thomas
Stephanie
S
Tang
Yanhua
Y
Verrill
Cori L
CL
Dixon
Catherine
C
Prado
Julia G
JG
Kiepiela
Photini
P
Martinez-Picado
Javier
J
Walker
Bruce D
BD
Goulder
Philip J R
PJ
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*
D004279:DNA, Viral; D000939:Epitopes; D015683:Gene Products, gag; D015488:HIV Antigens; D015235:HLA-B Antigens; C103707:HLA-B57 antigen