Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire

Matthias Wölfl, Alleluiah Rutebemberwa, Timothy Mosbruger, Qing Mao, Hong Mei Li, Dale Netski, Stuart C. Ray, Drew Pardoll, John Sidney, Alessandro Sette, Todd Allen, Thomas Kuntzen, Daniel G. Kavanagh, Jürgen Kuball, Philip D. Greenberg, Andrea L. Cox

Research output: Contribution to journalArticlepeer-review


Hepatitis C virus (HCV) infection frequently persists despite eliciting substantial virus-specific immune responses. Thus, HCV infection provides a setting in which to investigate mechanisms of immune escape that allow for viral persistence. Viral amino acid substitutions resulting in decreased MHC binding or impaired Ag processing of T cell epitopes reduce Ag density on the cell surface, permitting evasion of T cell responses in chronic viral infection. Substitutions in viral epitopes that alter TCR contact residues frequently result in escape, but via unclear mechanisms because such substitutions do not reduce surface presentation of peptide-MHC complexes and would be expected to prime T cells with new specificities. We demonstrate that a known in vivo HCV mutation involving a TCR contact residue significantly diminishes T cell recognition and, in contrast to the original sequence, fails to effectively prime naive T cells. This mutant epitope thus escapes de novo immune recognition because there are few highly specific cognate TCR among the primary human T cell repertoire. This example is the first on viral immune escape via exploitation of a "hole" in the T cell repertoire, and may represent an important general mechanism of viral persistence.

Original languageEnglish (US)
Pages (from-to)6435-6446
Number of pages12
JournalJournal of Immunology
Issue number9
StatePublished - Nov 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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