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Journal of Virology, July 2005, p. 9228-9235, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9228-9235.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

Matthew R. Reynolds,1,2 Eva Rakasz,1 Pamela J. Skinner,3 Cara White,3,{dagger} Kristina Abel,4,5,6 Zhong-Min Ma,4,5,6 Lara Compton,4,5,6 Gnankang Napoé,1 Nancy Wilson,1 Christopher J. Miller,4,5,6 Ashley Haase,7* and David I. Watkins1,2*

Wisconsin Primate Research Center,1 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53715,2 Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108;,3 Center for Comparative Medicine, California National Primate Research Center,4 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine,5 Department of Infectious Disease, School of Medicine, University of California, Davis, California 95616,6 Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 554557

Received 6 December 2004/ Accepted 2 March 2005

In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is "too late and too little" to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

* Corresponding author. Mailing address for Ashley Haase: Department of Microbiology, University of Minnesota, MMC 196, 420 Delaware St. S.E., Minneapolis, MN 55455. Phone: (612) 624-4442. Fax: (612) 626-0623. E-mail: haase001{at}umn.edu. Mailing address for David I. Watkins: Wisconsin Primate Research Center, 1220 Capitol Ct., Madison, WI 53715. Phone: (608) 265-3380. Fax: (608) 263-4031. E-mail: Watkins{at}primate.wisc.edu.

{dagger} Present address: Rio Grande City High School, Rio Grande City, TX 78582.

Journal of Virology, July 2005, p. 9228-9235, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.9228-9235.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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