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Journal of Virology, August 2003, p. 8354-8365, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8354-8365.2003

Improved Protection of Rhesus Macaques against Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge by a Replication-Competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag Recombinant Priming/gp120 Boosting Regimen

Jun Zhao,1 Joel Pinczewski,1 Victor R. Gómez-Román,1 David Venzon,2 V. S. Kalyanaraman,3 Phillip D. Markham,3 Kristine Aldrich,1 Matthew Moake,1 David C. Montefiori,4 Yuanmei Lou,1 George N. Pavlakis,5 and Marjorie Robert-Guroff1*

Basic Research Laboratory,1 Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,2 Advanced BioScience Laboratories, Inc., Kensington, Maryland 20895,3 Center for AIDS Research, Duke University Medical Center, Durham, North Carolina 27710,4 Basic Research Laboratory, National Cancer Institute—Frederick, National Institutes of Health, Frederick, Maryland 217025

Received 18 December 2002/ Accepted 13 May 2003

In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virusmac251. Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIVmac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A*01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8+ T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.

* Corresponding author. Mailing address: NIH, NCI, 41 Library Dr., Bldg. 41, Rm. D804, Bethesda, MD 20892-5055. Phone: (301) 496-2114. Fax: (301) 496-8394. E-mail: guroffm{at}exchange.nih.gov.

Journal of Virology, August 2003, p. 8354-8365, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8354-8365.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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