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Journal of Virology, October 2005, p. 12425-12433, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12425-12433.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Minimal T-Cell-Stimulatory Sequences and Spectrum of HLA Restriction of Immunodominant CD4+ T-Cell Epitopes within Hepatitis C Virus NS3 and NS4 Proteins{dagger}

J. T. Gerlach,1,3* A. Ulsenheimer,2,3 N. H. Grüner,2,3 M.-C. Jung,2,3 W. Schraut,3 C.-A. Schirren,2 M. Heeg,3 S. Scholz,4 K. Witter,4 R. Zahn,4 A. Vogler,4 R. Zachoval,2 G. R. Pape,2,3 and H. M. Diepolder2,3

Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland,1 Department of Medicine II, Klinikum Großhadern, University of Munich, 81377 Munich, Germany,2 Institute for Immunology, University of Munich, 80336 Munich, Germany,3 Immunogenetics Laboratory, Kinderpoliklinik, University of Munich, 80336 Munich, Germany4

Received 3 February 2005/ Accepted 11 July 2005

The hepatitis C virus (HCV)-specific CD4+ T-cell response against nonstructural proteins is strongly associated with successful viral clearance during acute hepatitis C. To further develop these observations into peptide-based vaccines and clinical immunomonitoring tools like HLA class II tetramers, a detailed characterization of immunodominant CD4+ T-cell epitopes is required. We studied peripheral blood mononuclear cells from 20 patients with acute hepatitis C using 83 overlapping 20-mer peptides covering the NS3 helicase and NS4. Eight peptides were recognized by ≥40% of patients, and specific CD4+ T-cell clones were obtained for seven of these and three additional, subdominant epitopes. Mapping of minimal stimulatory sequences defined epitopes of 8 to 13 amino acids in length, but optimal T-cell stimulation was observed with 10- to 15-mers. While some epitopes were presented by different HLA molecules, others were presented by only a single HLA class II molecule, which has implications for patient selection in clinical trials of peptide-based immunotherapies. In conclusion, using two different approaches we identified and characterized a set of CD4+ T-cell epitopes in the HCV NS3-NS4 region which are immunodominant in patients achieving transient or persistent viral control. This information allows the construction of a valuable panel of HCV-specific HLA class II tetramers for further study of CD4+ T-cell responses in chronic hepatitis C. The finding of immunodominant epitopes with very constrained HLA restriction has implications for patient selection in clinical trials of peptide-based immunotherapies.

* Corresponding author. Mailing address: Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Phone: 41-1-2553419. Fax: 41-1-2554503. E-mail: Tilman.Gerlach{at}usz.ch.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2005, p. 12425-12433, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12425-12433.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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