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Journal of Virology, July 2005, p. 8480-8492, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8480-8492.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

DNA Vaccines Expressing Different Forms of Simian Immunodeficiency Virus Antigens Decrease Viremia upon SIVmac251 Challenge

Margherita Rosati,1 Agneta von Gegerfelt,1 Patricia Roth,1 Candido Alicea,2 Antonio Valentin,1 Marjorie Robert-Guroff,3 David Venzon,4 David C. Montefiori,5 Phil Markham,6 Barbara K. Felber,2 and George N. Pavlakis1*

Human Retrovirus Section,1 Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland,2 Immune Biology of Retroviral Infection Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland,3 Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland,4 Duke University Medical Center, Durham, North Carolina,5 Advanced BioScience Laboratories, Inc., Kensington, Maryland6

Received 30 July 2004/ Accepted 7 March 2005

We have tested the efficacy of DNA immunization as a single vaccination modality for rhesus macaques followed by highly pathogenic SIVmac251 challenge. To further improve immunogenicity of the native proteins, we generated expression vectors producing fusion of the proteins Gag and Env to the secreted chemokine MCP3, targeting the viral proteins to the secretory pathway and to a ß-catenin (CATE) peptide, targeting the viral proteins to the intracellular degradation pathway. Macaques immunized with vectors expressing the MCP3-tagged fusion proteins developed stronger antibody responses. Following mucosal challenge with pathogenic SIVmac251, the vaccinated animals showed a statistically significant decrease in viral load (P = 0.010). Interestingly, macaques immunized with a combination of vectors expressing three forms of antigens (native protein and MCP3 and CATE fusion proteins) showed the strongest decrease in viral load (P = 0.0059). Postchallenge enzyme-linked immunospot values for Gag and Env as well as gag-specific T-helper responses correlated with control of viremia. Our data show that the combinations of DNA vaccines producing native and modified forms of antigens elicit more balanced immune responses able to significantly reduce viremia for a long period (8 months) following pathogenic challenge with SIVmac251.

* Corresponding author. Mailing address: Human Retrovirus Section, Vaccine Branch, Bldg. 535, Rm. 210, NCI-Frederick, Frederick, MD 21702. Phone: (301) 846-1475. Fax: (301) 846-7146. E-mail: pavlakis{at}ncifcrf.gov.

Journal of Virology, July 2005, p. 8480-8492, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8480-8492.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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