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Gender Differences in Human Immunodeficiency Virus Type 1-Specific CD8 Responses in the Reproductive Tract and Colon following Nasal Peptide Priming and Modified Vaccinia Virus Ankara Boosting

James W. Peacock,¹ Sushila K. Nordone,^1, Shawn S. Jackson,² Hua-Xin Liao,¹ Norman L. Letvin,² Alicia Gomez Yafal,³ Linda Gritz,³ Gail P. Mazzara,³ Barton F. Haynes,^1,4 and Herman F. Staats^1,4,5*

Departments of Medicine,¹ Pathology,⁵ Immunology, Duke University Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina,⁴ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,² Therion Biologics Corporation, Cambridge, Massachusetts³

Received 12 February 2004/ Accepted 24 March 2004

Induction of mucosal anti-human immunodeficiency virus type 1 (HIV-1) T-cell responses in males and females will be important for the development of a successful HIV-1 vaccine. An HIV-1 envelope peptide, DNA plasmid, and recombinant modified vaccinia virus Ankara (rMVA) expressing the H-2D^d-restricted cytotoxic T lymphocyte P18 epitope were used as immunogens to test for their ability to prime and boost anti-HIV-1 T-cell responses at mucosal and systemic sites in BALB/c mice. We found of all prime-boost combinations tested, an HIV-1 Env peptide subunit mucosal prime followed by systemic (intradermal) boosting with rMVA yielded the maximal induction of gamma interferon (IFN-) spot-forming cells in the female genital tract and colon. However, this mucosal prime-systemic rMVA boost regimen was minimally immunogenic for the induction of genital, colon, or lung anti-HIV-1 T-cell responses in male mice. We determined that a mucosal Env subunit immunization could optimally prime an rMVA boost in female but not male mice, as determined by the magnitude of antigen-specific IFN- responses in the reproductive tracts, colon, and lung. Defective mucosal priming in male mice could not be overcome by multiple mucosal immunizations. However, rMVA priming followed by an rMVA boost was the optimal prime-boost strategy for male mice as determined by the magnitude of antigen-specific IFN- responses in the reproductive tract and lung. Thus, prime-boost immunization strategies able to induce mucosal antigen-specific IFN- responses were identified for male and female mice. Understanding the cellular and molecular basis of gender-determined immune responses will be important for optimizing induction of anti-HIV-1 mucosal immune responses in both males and females.

Present address: Department of Molecular Biological Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.

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