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Journal of Virology, December 2005, p. 15556-15566, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15556-15566.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cytotoxic T-Lymphocyte Escape Does Not Always Explain the Transient Control of Simian Immunodeficiency Virus SIVmac239 Viremia in Adenovirus-Boosted and DNA-Primed Mamu-A*01-Positive Rhesus Macaques

Adrian B. McDermott,1 David H. O'Connor,1 Sarah Fuenger,1 Shari Piaskowski,1 Sarah Martin,1 John Loffredo,1 Matthew Reynolds,1 Jason Reed,1 Jessica Furlott,1 Timothy Jacoby,1 Cara Riek,1 Elizabeth Dodds,1 Kendall Krebs,1 Mary-Ellen Davies,2 William A. Schleif,2 Danilo R. Casimiro,2 John W. Shiver,2 and D. I. Watkins1*

Wisconsin National Primate Research Center and Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, University of Wisconsin, Madison, Wisconsin,1 Department of Vaccine and Biologics Research, Merck Research Laboratories, Merck & Co., 770 Sumneytown Pike, West Point, Pennsylvania2

Received 14 April 2005/ Accepted 20 August 2005

Adenovirus 5 (Ad5) vectors show promise as human immunodeficiency virus vaccine candidates. Indian rhesus macaques vaccinated with Ad5-gag controlled simian-human immunodeficiency virus SHIV89.6P viral replication in the absence of Env immunogens that might elicit humoral immunity. Here we immunized 15 macaques using either a homologous Ad5-gag/Ad5-gag (Ad5/Ad5) or a heterologous DNA-gag/Ad5-gag (DNA/Ad5) prime-boost regimen and challenged them with a high dose of simian immunodeficiency virus SIVmac239. Macaques vaccinated with the DNA/Ad5 regimen experienced a brief viral load nadir of less than 10,000 viral copies per ml blood plasma that was not seen in Mamu-A*01-negative DNA/Ad5 vaccinees, Mamu-A*01-positive Ad5/Ad5 vaccinees, or vaccine-naive controls. Interestingly, most of these animals were not durably protected from disease progression when challenged with SIVmac239. To investigate the reasons underlying this short-lived vaccine effect, we investigated breadth of the T-cell response, immunogenetic background, and viral escape from CD8+ lymphocytes that recognize immunodominant T-cell epitopes. We show that these animals do not mount unusually broad cellular immune response, nor do they express unusual major histocompatibility complex class I alleles. Viral recrudescence occurred in four of the five Mamu-A*01-positive vaccinated macaques. However, only a single animal in this group demonstrated viral escape in the immunodominant Gag181-189CM9 response. These results suggest that viral "breakthrough" in vaccinated animals and viral escape are not inextricably linked and underscore the need for additional research into the mechanisms of vaccine failure.

* Corresponding author. Mailing address: Wisconsin National Primate Center, 1220 Capitol Court, Madison, WI 53715. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu.

Journal of Virology, December 2005, p. 15556-15566, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15556-15566.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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