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Journal of Virology, October 2008, p. 9629-9638, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00893-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Reduced Protection from Simian Immunodeficiency Virus SIV_mac251 Infection Afforded by Memory CD8⁺ T Cells Induced by Vaccination during CD4⁺ T-Cell Deficiency

Monica Vaccari,¹ Joseph Mattapallil,² Kaimei Song,³ Wen-Po Tsai,¹ Anna Hryniewicz,¹ David Venzon,⁴ Maurizio Zanetti,⁵ Keith A. Reimann,⁶ Mario Roederer,³ and Genoveffa Franchini^1*

Animal Models and Retroviral Vaccines Section,¹ Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892,⁴ Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,² ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892,³ Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093,⁵ Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215⁶

Received 29 April 2008/ Accepted 21 July 2008

Adaptive CD4⁺ and CD8⁺ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4⁺ T-cell deficiency. Depletion of CD4⁺ cells was performed in the immunized macaques at the peak of SIV-specific CD4⁺ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8⁺ T cells prior to challenge exposure to SIV_mac251. Analysis of the quality and quantity of vaccine-induced CD8⁺ T cells demonstrated that SIV-specific CD8⁺ T cells generated under conditions of CD4⁺ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8⁺ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4⁺ T cells are critical for the generation of effective CD8⁺ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4⁺ and CD8⁺ T-cell responses and protect against early depletion of CD4⁺ T cells postinfection.

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* Corresponding author. Mailing address: Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bldg. 41, Room D804, Bethesda, MD 20892. Phone: (301) 496-2386. Fax: (301) 402-0055. E-mail: franchig{at}mail.nih.gov

Published ahead of print on 30 July 2008.

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Journal of Virology, October 2008, p. 9629-9638, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00893-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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