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Journal of Virology, March 2005, p. 3358-3369, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3358-3369.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells

Gerald V. Quinnan Jr.,^1* Xiao-Fang Yu,² Mark G. Lewis,^3,4 Peng Fei Zhang,¹ Gerd Sutter,⁵ Peter Silvera,³ Ming Dong,¹ Anil Choudhary,¹ Phuong T. N. Sarkis,² Peter Bouma,¹ Zhiqiang Zhang,¹ David C. Montefiori,⁶ Thomas C. VanCott,^7, and Christopher C. Broder¹

Uniformed Services University of the Health Sciences, Bethesda,¹ Johns Hopkins University School of Public Health, Baltimore,² Southern Research Institute, Frederick,³ BIOQUAL, Inc.,⁴ Military HIV Program, Rockville, Maryland,⁷ Division of Virology, Paul-Ehrlich-Institut, Langen, Germany,⁵ Department of Surgery, Laboratory for AIDS Vaccine Research and Development, Duke University Medical Center, Durham, North Carolina⁶

Received 9 August 2004/ Accepted 26 October 2004

We studied the capacity of active immunization of rhesus monkeys with HIV-1 envelope protein (Env) to induce primary virus cross-reactive neutralizing antibodies to prevent infection following intravenous challenge with simian-human immunodeficiency virus (SHIV). Monkeys were immunized with the human immunodeficiency type 1 (HIV-1) strain R2 Env. Initially, the Env was expressed in vivo by an alphavirus replicon particle system, and then it was administered as soluble oligomeric gp140. Concurrently, groups of monkeys received expression vectors that encoded either simian immunodeficiency virus (SIV) gag/pol genes or no SIV genes in vivo to test the additional protective benefit of concurrent induction of virus-specific cell-mediated immune (CMI) responses. Groups of control monkeys received either the gag/pol regimen or sham immunizations. The antibodies induced by the Env immunization regimen neutralized diverse primary HIV-1 strains. Similarly, potent CMI responses were induced by the gag/pol regimen, as measured by gamma interferon enzyme-linked immunospot assays. Differences in the responses among groups of monkeys strongly suggested that there was interference between the Env and gag/pol immunization regimens. Complete protection of some of the monkeys against infection after intravenous challenge with the partially pathogenic SHIV_{DH12R (Clone 7)} was associated independently with both neutralizing antibody and CMI responses. Protection was associated with SHIV_{DH12 (Clone 7)} serum neutralizing antibody titers of 1:80 or with cellular immune responses corresponding to >2,000 spot forming cells per 10⁶ peripheral blood mononuclear cells. Immunization was also associated with a reduction in the magnitude and duration of virus load. Induction of cross-reactive, primary HIV-1-neutralizing antibodies is feasible and, when potent, may result in complete protection against infection with a heterologous challenge virus strain.

Present address: Advanced Bioscience Laboratories, Inc., Kensington, MD 20895.

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