Antigen Processing Influences HIV-specific Cytotoxic T Lymphocyte Immunodominance

Overview

Journal Nat Immunol

Date 2009 May 5

PMID 19412183

Citations 102

Authors

Stefan Tenzer

Edmund Wee

Anne Burgevin

Guillaume Stewart-Jones

Lone Friis

Kasper Lamberth

Chih-Hao Chang

Mikkel Harndahl

Mirjana Weimershaus

Jan Gerstoft

Nadja Akkad

Paul Klenerman

Lars Fugger

E Yvonne Jones

Andrew J McMichael

Soren Buus

Hansjorg Schild

Peter van Endert

Astrid K N Iversen

Affiliations

Soon will be listed here.

Abstract

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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