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Journal of Virology, June 2002, p. 6093-6103, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6093-6103.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Molecular and Immunological Significance of Chimpanzee Major Histocompatibility Complex Haplotypes for Hepatitis C Virus Immune Response and Vaccination Studies

Eishiro Mizukoshi,^1, Michelina Nascimbeni,¹ Joshua B. Blaustein,¹ Kathleen Mihalik,² Charles M. Rice,³ T. Jake Liang,¹ Stephen M. Feinstone,² and Barbara Rehermann^1*

Liver Diseases Section, NIDDK, National Institutes of Health,¹ Laboratory of Hepatitis Research, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,² Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10021³

Received 17 January 2002/ Accepted 10 March 2002

The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN--producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.

Present address: First Department of Internal Medicine, Kanazawa University School of Medicine, Kanazawa Ishikawa 920-8641, Japan.

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