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Journal of Virology, June 2002, p. 6104-6113, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6104-6113.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Comprehensive Analysis of CD8+-T-Cell Responses against Hepatitis C Virus Reveals Multiple Unpredicted Specificities

Georg M. Lauer,1,2 Kei Ouchi,1,2 Raymond T. Chung,3 Tam N. Nguyen,1,2 Cheryl L. Day,1,2 Deborah R. Purkis,3 Markus Reiser,4 Arthur Y. Kim,1,2 Michaela Lucas,5 Paul Klenerman,5 and Bruce D. Walker1,2*

Partners AIDS Research Center,1 Infectious Disease Division,2 Gastrointestinal Unit, Massachusetts General HospitalHarvard Medical School, Boston, Massachusetts 02114,3 Medizinische Universitaetsklinik, Ruhr-Universitaet, 44892 Bochum, Germany,4 Nuffield Department of Clinical Medicine, Oxford University, Oxford OX1 3SY, United Kingdom5

Received 26 December 2001/ Accepted 8 March 2002

The hepatitis C virus (HCV)-specific CD8+-T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8+-T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8+-T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8+-T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition.

* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital East, 149 13th St., Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}helix.mgh.harvard.edu.

Journal of Virology, June 2002, p. 6104-6113, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6104-6113.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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