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Journal of Virology, September 2003, p. 10113-10118, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.10113-10118.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Magnitude and Diversity of Cytotoxic-T-Lymphocyte Responses Elicited by Multiepitope DNA Vaccination in Rhesus Monkeys

Ramu A. Subbramanian,1 Marcelo J. Kuroda,1 William A. Charini,1 Dan H. Barouch,1 Cristina Costantino,1 Sampa Santra,1 Jörn E. Schmitz,1 Kristi L. Martin,1 Michelle A. Lifton,1 Darci A. Gorgone,1 John W. Shiver,2 and Norman L. Letvin1*

Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215,1 Merck Research Laboratories, West Point, Pennsylvania 194862

Received 2 May 2003/ Accepted 24 June 2003

In an effort to develop an AIDS vaccine that elicits high-frequency cytotoxic-T-lymphocyte (CTL) responses with specificity for a diversity of viral epitopes, we explored two prototype multiepitope plasmid DNA vaccines in the simian-human immunodeficiency virus/rhesus monkey model to determine their efficiency in priming for such immune responses. While a simple multiepitope vaccine construct demonstrated limited immunogenicity in monkeys, this same multiepitope genetic sequence inserted into an immunogenic simian immunodeficiency virus gag DNA vaccine elicited high-frequency CTL responses specific for all of the epitopes included in the vaccine. Both multiepitope vaccine prototypes primed for robust epitope-specific CTL responses that developed following boosting with recombinant modified vaccinia virus Ankara vaccines expressing complete viral proteins. The natural hierarchy of immunodominance for these epitopes was clearly evident in the boosted monkeys. These studies suggest that multiepitope plasmid DNA vaccine-based prime-boost regimens can efficiently prime for CTL responses of increased breadth and magnitude, although they do not overcome predicted hierarchies of immunodominance.

* Corresponding author. Mailing address: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Research East—RE 113, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-2042. Fax: (617) 667-8210. E-mail: nletvin{at}caregroup.harvard.edu.

Journal of Virology, September 2003, p. 10113-10118, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.10113-10118.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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