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Journal of Virology, July 2004, p. 7052-7060, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7052-7060.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protection against Lethal Vaccinia Virus Challenge in HLA-A2 Transgenic Mice by Immunization with a Single CD8+ T-Cell Peptide Epitope of Vaccinia and Variola Viruses

James T. Snyder,1 Igor M. Belyakov,1* Amiran Dzutsev,1 François Lemonnier,2 and Jay A. Berzofsky1*

Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1578,1 Institut Pasteur, Paris, France2

Received 3 December 2003/ Accepted 1 March 2004

CD8+ T lymphocytes have been shown to be involved in controlling poxvirus infection, but no protective cytotoxic T-lymphocyte (CTL) epitopes are defined for variola virus, the causative agent of smallpox, or for vaccinia virus. Of several peptides in vaccinia virus predicted to bind HLA-A2.1, three, VETFsm(498-506), A26L(6-14), and HRP2(74-82), were found to bind HLA-A2.1. Splenocytes from HLA-A2.1 transgenic mice immunized with vaccinia virus responded only to HRP2(74-82) at 1 week and to all three epitopes by ex vivo enzyme-linked immunosorbent spot (ELISPOT) assay at 4 weeks postimmunization. To determine if these epitopes could elicit a protective CD8+ T-cell response, we challenged peptide-immunized HLA-A2.1 transgenic mice intranasally with a lethal dose of the WR strain of vaccinia virus. HRP2(74-82) peptide-immunized mice recovered from infection, while naïve mice died. Depletion of CD8+ T cells eliminated protection. Protection of HHD-2 mice, lacking mouse class I major histocompatibility complex molecules, implicates CTLs restricted by human HLA-A2.1 as mediators of protection. These results suggest that HRP2(74-82), which is shared between vaccinia and variola viruses, may be a CD8+ T-cell epitope of vaccinia virus that will provide cross-protection against smallpox in HLA-A2.1-positive individuals, representing almost half the population.

* Corresponding author. Mailing address: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1578. Phone for I. M. Belyakov: (301) 435-8341. Fax: (301) 402-0549. E-mail: belyakov{at}mail.nih.gov. Phone for J. A. Berzofsky: (301) 496-6874. Fax: (301) 402-0549. E-mail: berzofsk{at}heliz.nih.gov.

Journal of Virology, July 2004, p. 7052-7060, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7052-7060.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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