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Absence of viral escape within a frequently recognized HLA-A26-restricted CD8⁺ T-cell epitope targeting the functionally constrained hepatitis C virus NS5A/5B cleavage site

Christoph Neumann-Haefelin^1,

Thomas Killinger^1,

¹ Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
² Department of Medicine I, University Hospital Bochum (BG Kliniken Bergmannsheil), Bochum, Germany
³ Epimmune, San Diego, CA, USA

Correspondence
Robert Thimme
thimme{at}med1.ukl.uni-freiburg.de

CD8⁺ T-cell responses are central for the resolution of hepatitis C virus (HCV) infection, and viral escape from these CD8⁺ T-cell responses has been suggested to play a major role in HCV persistence. However, the factors determining the emergence of CD8 escape mutations are not well understood. Here, the first identification of four HLA-A26-restricted CD8⁺ T-cell epitopes is reported. Of note, two of these four epitopes are located in the NS3/4A and NS5A/5B cleavage sites. The latter epitope is targeted in all (three of three) patients with acute, resolving HCV infection and in a relatively high proportion (four of 14) of patients with chronic HCV infection. Importantly, the epitope corresponding to the NS5A/5B cleavage site is characterized by the complete absence of sequence variations, despite the presence of functional virus-specific CD8⁺ T cells in our cohort. These results support previous findings that showed defined functional constraints within this region. They also suggest that the absence of viral escape may be determined by viral fitness cost and highlight an attractive target for immunotherapies.

These authors contributed equally to this work.

A table with details of the study population and a figure showing that cleavage at the NS5A/5B cleavage site is highly sensitive to mutations at the P1 and P1' positions are available as supplementary material with the online version of this paper.

This article has been cited by other articles:

				C. Neumann-Haefelin, D. N. Frick, J. J. Wang, O. G. Pybus, S. Salloum, G. S. Narula, A. Eckart, A. Biezynski, T. Eiermann, P. Klenerman, et al. Analysis of the Evolutionary Forces in an Immunodominant CD8 Epitope in Hepatitis C Virus at a Population Level J. Virol., April 1, 2008; 82(7): 3438 - 3451. [Abstract] [Full Text] [PDF]