Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

TY - JOUR

T1 - Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

AU - Tenzer, Stefan

AU - Wee, Edmund

AU - Burgevin, Anne

AU - Stewart-Jones, Guillaume

AU - Friis, Lone

AU - Lamberth, Kasper

AU - Chang, Chih-hao

AU - Harndahl, Mikkel

AU - Weimershaus, Mirjana

AU - Gerstoft, Jan

AU - Akkad, Nadja

AU - Klenerman, Paul

AU - Fugger, Lars

AU - Jones, E Yvonne

AU - McMichael, Andrew J

AU - Buus, Søren

AU - Schild, Hansjörg

AU - van Endert, Peter

AU - Iversen, Astrid K N

N1 - Keywords: ATP-Binding Cassette Transporters; Amino Acid Sequence; Antigen Presentation; Evolution, Molecular; HIV Antigens; HIV Core Protein p24; HIV Infections; HIV-1; HLA-A Antigens; Humans; Immunodominant Epitopes; Leucyl Aminopeptidase; Major Histocompatibility Complex; Models, Molecular; Molecular Sequence Data; Mutation; Proteasome Endopeptidase Complex; Protein Binding; T-Lymphocytes, Cytotoxic; gag Gene Products, Human Immunodeficiency Virus

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1038/ni.1728

DO - 10.1038/ni.1728

M3 - Journal article

C2 - 19412183

SN - 1529-2908

VL - 10

SP - 636

EP - 646

JO - Nature Immunology

JF - Nature Immunology

IS - 6

ER -