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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900581v1 183/4/2425    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Honda, M. Articles by Nabel, G. J. PubMed PubMed Citation Articles by Honda, M. Articles by Nabel, G. J.

Different Vaccine Vectors Delivering the Same Antigen Elicit CD8⁺ T Cell Responses with Distinct Clonotype and Epitope Specificity¹

Mitsuo Honda^*,, Rui Wang, Wing-Pui Kong^*, Masaru Kanekiyo^*, Wataru Akahata^*, Ling Xu^*, Kazuhiro Matsuo, Kannan Natarajan, Howard Robinson, Tedi E. Asher^*, David A. Price^*,¶, Daniel C. Douek^*, David H. Margulies and Gary J. Nabel^2,*

^* Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan; Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Brookhaven National Laboratory, Upton, NY 11973; and ^¶ Department of Medical Biochemistry and Immunology, Cardiff University Medical School, Cardiff, United Kingdom

Prime-boost immunization with gene-based vectors has been developed to generate more effective vaccines for AIDS, malaria, and tuberculosis. Although these vectors elicit potent T cell responses, the mechanisms by which they stimulate immunity are not well understood. In this study, we show that immunization by a single gene product, HIV-1 envelope, with alternative vector combinations elicits CD8⁺ cells with different fine specificities and kinetics of mobilization. Vaccine-induced CD8⁺ T cells recognized overlapping third V region loop peptides. Unexpectedly, two anchor variants bound H-2D^d better than the native sequences, and clones with distinct specificities were elicited by alternative vectors. X-ray crystallography revealed major differences in solvent exposure of MHC-bound peptide epitopes, suggesting that processed HIV-1 envelope gave rise to MHC-I/peptide conformations recognized by distinct CD8⁺ T cell populations. These findings suggest that different gene-based vectors generate peptides with alternative conformations within MHC-I that elicit distinct T cell responses after vaccination.

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 the intramural research program of the Vaccine Research Center and the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Support for beamline X29 of the National Synchrotron Light Source comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the U.S. Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. D.A.P. is a Medical Research Council (United Kingdom) Senior Clinical Fellow.

² Address correspondence and reprint requests to Dr. Gary J. Nabel, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Building 40, Room 4502, Bethesda, MD 20892. E-mail address: gnabel{at}nih.gov

³ Abbreviations used in this paper: Env, HIV-1 envelope; Ad, adenovirus; β₂m, β₂-microglobulin; BCG, Mycobacterium bovis bacillus Calmette-Guérin; CM, central memory; EM, effector memory; V3, third V region.

⁴ The online version of this article contains supplemental material.