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Sequence flexibility of the immunodominant HLA A*0201 restricted ppUL83 CD8 T‐cell epitope of human cytomegalovirus
Author(s) -
Kopycinski Jakub,
Osman Mohamed,
Griffiths Paul D.,
Emery Vincent C.
Publication year - 2010
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.21668
Subject(s) - epitope , biology , t cell receptor , virology , cd8 , cytotoxic t cell , t cell , peptide , microbiology and biotechnology , mutant , context (archaeology) , human leukocyte antigen , antigen , immune system , in vitro , genetics , gene , biochemistry , paleontology
Abstract The cytomegalovirus ppUL83 protein contains an immunodominant A*0201 restricted epitope between residues 495 and 503. We investigated the tolerance of this epitope to sequence variation in the context of peptide binding to HLA A*0201 and the ability to induce an Interferon gamma (IFNγ) response through engagement with the T‐cell receptor (TCR). The majority of mutations investigated resulted in a decrease in the production of IFNγ indicating that if such variants occurred in vivo they would not be recognized by CD8 T‐cell clones specific for the wild‐type epitope. The mechanistic basis for the majority of the mutant peptides was their failure to bind and stabilize class I HLA cell surface expression. However, one peptide with a mutation at the P5 position (methionine to cysteine) resulted in a significant enhanced binding to HLA A*0201 and also an increase in cell surface expression over the wild‐type peptide but was unable to engage with the CD8 TCR and trigger IFNγ production. This peptide acted as a competitive inhibitor of the wild‐type peptide but could not fully inhibit IFNγ production by the latter. We subsequently investigated whether mutations of the HLA A*0201 epitope were evident in immunocompromized patients experiencing either rapid exponential or persistent cytomegalovirus replication. J. Med. Virol. 82:94–103, 2010. © 2009 Wiley‐Liss, Inc.