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

Authors

David T. Evans, Harvard Medical School
Li-Mei Chen, Yale School of Medicine
Jacqueline Gillis, Harvard Medical School
Kuei-Chin Lin, Harvard Medical School
Brian Harty, Harvard Medical School
Gail P. Mazzara, Therion Biologics Corporation
Ruben O. Donis, University of Nebraska-LincolnFollow
Keith G. Mansfield, Harvard Medical School
Jeffrey D. Lifson, National Cancer Institute at Frederick
Ronald C. Desrosiers, Harvard Medical School
Jorge E. Galán, Yale School of Medicine
R. Paul Johnson, Harvard Medical SchoolFollow

Date of this Version

2003

Citation

Journal of Virology, Feb. 2003, p. 2400–2409 Vol. 77, No. 4

Comments

U.S. Government Work

Abstract

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 ∆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 Gag_181-189 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 Gag_181-189-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 α4β7. Additionally, Gag_181-189-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.