Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance.
Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.
Institute of Immunology, University of Mainz, Mainz, Germany.
Stefan
S
Tenzer
Edmund
E
Wee
Anne
A
Burgevin
Guillaume
G
Stewart-Jones
Lone
L
Friis
Kasper
K
Lamberth
Chih-hao
CH
Chang
Mikkel
M
Harndahl
Mirjana
M
Weimershaus
Jan
J
Gerstoft
Nadja
N
Akkad
Paul
P
Klenerman
Lars
L
Fugger
E Yvonne
EY
Jones
Andrew J
AJ
McMichael
Søren
S
Buus
Hansjörg
H
Schild
Peter
P
van Endert
Astrid K N
AK
Iversen
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D019143:Evolution, Molecular; D015488:HIV Antigens / Q000276:immunology* / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D015488:HIV Antigens; D016655:HIV Core Protein p24; D015234:HLA-A Antigens; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase; D046988:Proteasome Endopeptidase Complex