Lars Henrik Fugger

Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Stefan Tenzer, Denmark
  • Edmund Wee, Denmark
  • Anne Burgevin, Denmark
  • Guillaume Stewart-Jones, Denmark
  • Lone Friis, Denmark
  • Kasper Lamberth, Denmark
  • Chih-Hao Chang, Denmark
  • Mikkel Harndahl, Denmark
  • Mirjana Weimershaus, Denmark
  • Jan Gerstoft, Denmark
  • Nadja Akkad, Denmark
  • Paul Klenerman, Denmark
  • Lars Fugger
  • E Yvonne Jones, Denmark
  • Andrew J McMichael, Denmark
  • Søren Buus, Denmark
  • Hansjörg Schild, Denmark
  • Peter van Endert, Denmark
  • Astrid K N Iversen, Denmark
  • The Department of Clinical Immunology
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.
Original languageEnglish
JournalNature Immunology
Pages (from-to)636-46
Publication statusPublished - 2009

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