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Journal of Virology, September 2006, p. 8880-8890, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00894-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Vaginal Protection and Immunity after Oral Immunization of Mice with a Novel Vaccine Strain of Listeria monocytogenes Expressing Human Immunodeficiency Virus Type 1 gag

Xinyan Zhao, Manxin Zhang, Zhongxia Li, and Fred R. Frankel*

University of Pennsylvania School of Medicine, Department of Microbiology, Philadelphia, Pennsylvania 19104

Received 2 May 2006/ Accepted 24 June 2006

Natural transmission of human immunodeficiency virus (HIV) occurs at mucosal surfaces. During acute infection, intestinal and other mucosae are preferential sites of virus replication and rapidly become depleted of CD4+ T cells. Therefore, mucosal immunity may be critical to control both initial infection and the massive early spread of virus. An attenuated D-alanine-requiring strain of the oral intracellular microorganism Listeria monocytogenes expressing HIV type 1 gag was shown to induce protective cell-mediated immunity in mice against viruses that express HIV gag when immunization occurs in the presence of a transient supply of D-alanine. In this study, we examined the efficacy of new attenuated strains that are able to synthesize D-alanine from a heterologous dal gene tightly regulated by an actA-promoted resolvase recombination system. In the absence of D-alanine, Gag-specific cytotoxic T lymphocytes (CTLs) were induced systemically after intravenous immunization, and one strain, Lmdd-gag/pARS, induced strong dose-dependent Gag-specific CTLs after oral immunization. A significant level of Gag-specific CD8+ T cells was induced in the mucosal-associated lymphoid tissues (MALTs). Upon intravaginal challenge of these orally immunized mice with recombinant vaccinia virus (rVV) expressing HIV gag, gamma interferon- and tumor necrosis factor alpha-secreting Gag-specific CD8+ T cells were dramatically increased in the spleen and MALTs. Oral immunization with Lmdd-gag/pARS led to complete protection against vaginal challenge by a homologous clade B gag-expressing rVV. In addition, strong cross-clade protection was seen against clades A and C and partial protection against clade G gag-expressing rVV. These results suggest that Lmdd-gag/pARS may be considered as a novel vaccine candidate for use against HIV/AIDS.

* Corresponding author. Mailing address: 203C Johnson Pavilion, Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 898-8730. Fax: (215) 898-9557. E-mail: frankelf{at}mail.med.upenn.edu.

Journal of Virology, September 2006, p. 8880-8890, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00894-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rowe, J. H., Johanns, T. M., Ertelt, J. M., Way, S. S. (2008). PDL-1 Blockade Impedes T Cell Expansion and Protective Immunity Primed by Attenuated Listeria monocytogenes. J. Immunol. 180: 7553-7557 [Abstract] [Full Text]  
  • Li, Z., Zhang, M., Zhou, C., Zhao, X., Iijima, N., Frankel, F. R. (2008). Novel Vaccination Protocol with Two Live Mucosal Vectors Elicits Strong Cell-Mediated Immunity in the Vagina and Protects against Vaginal Virus Challenge. J. Immunol. 180: 2504-2513 [Abstract] [Full Text]  
  • Orr, M. T., Orgun, N. N., Wilson, C. B., Way, S. S. (2007). Cutting Edge: Recombinant Listeria monocytogenes Expressing a Single Immune-Dominant Peptide Confers Protective Immunity to Herpes Simplex Virus-1 Infection. J. Immunol. 178: 4731-4735 [Abstract] [Full Text]  


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