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.
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We thank the patients for donating samples; B. Baadegaard and L.P. Jensen for patient management; D. Hass, T. Rostron, J. Frankland and J. Forsch for technical assistance; and N. Willcox for discussions. Supported by the Novo Nordisk Foundation, the Danish AIDS foundation, the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 490, E6, Z3), the Genomes2Vaccines Specific Targeted Research Project, Sixth Framework Programme (LSHB-CT-2003-503231), the Hochschulbauförderungsgesetz Program (HBFG-122-605), the Forschungszentrum Immunologie at the University of Mainz, the Nuffield Dominions Trust, Cancer Research UK, the European Union (LSHG-CT-2006-031220, LSHC-CT-2006-518234 and HEALTH-2007-222773), the Wellcome Trust, The James Martin 21st Century School at the University of Oxford, the National Institute for Health Research Biomedical Research Centre Programme, and the UK Medical Research Council.
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Tenzer, S., Wee, E., Burgevin, A. et al. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10, 636–646 (2009) doi:10.1038/ni.1728
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