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Journal of Virology, February 2003, p. 2400-2409, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2400-2409.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the Salmonella Type III Secretion Antigen Delivery System

David T. Evans,1 Li-Mei Chen,2 Jacqueline Gillis,1 Kuei-Chin Lin,1 Brian Harty,1 Gail P. Mazzara,3 Ruben O. Donis,4 Keith G. Mansfield,1 Jeffrey D. Lifson,5 Ronald C. Desrosiers,1 Jorge E. Galán,2 and R. Paul Johnson1,6*

New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102,1 Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of Medicine, New Haven, Connecticut 06536,2 Therion Biologics Corporation, Cambridge, Massachusetts 02142,3 Department of Veterinary and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0905,4 Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702,5 Infectious Disease Unit and Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 021156

Received 29 July 2002/ Accepted 18 November 2002

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested {Delta}phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01+ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189-specific T-cell population in each animal also expressed the intestinal homing receptor {alpha}4ß7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

* Corresponding author. Mailing address: Division of Immunology, New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Dr., Southborough, MA 01772-9102. Phone: (508) 624-8148. Fax: (508) 624-8172. E-mail: paul_johnson{at}hms.harvard.edu.

Journal of Virology, February 2003, p. 2400-2409, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2400-2409.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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