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Hepatitis C Virus Immune Escape via Exploitation of a Hole in the T Cell Repertoire¹

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^|| and Andrea L. Cox^2,*,

^* Department of Medicine, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; ^¶ Partners AIDS Research Center, Charlestown, MA 02129; and ^|| Fred Hutchinson Cancer Research Center, Seattle, WA 98109

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from The Damon Runyon Foundation, The Dana Foundation, The W. W. Smith Charitable Trust, and Grants K08 DA11880, U19 AI040035, and R01 DK57998 from the U.S. Public Health Service. This work is also supported by Grants CA33084 and CA18029 from the National Institutes of Health, Grant 7040–03 from Leukemia & Lymphoma Society, and by the Bill and Melinda Gates Foundation (to P.D.G.). M.W. and J.K. were supported by a research fellowship of the Deutsche Krebshilfe, Germany. T.K. was supported by a research fellowship from the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Andrea L. Cox, Department of Medicine, Johns Hopkins Medical Institutions, Suite 530, 855 N. Wolfe Street, Baltimore, MD 21205. E-mail address: acox{at}jhmi.edu

³ Abbreviations used in this paper: HCV, hepatitis C virus; HBV, hepatitis B virus; DC, dendritic cell; CD62L, CD62 ligand; MFI, mean fluorescence intensity.