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Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virus_mac251-Infected Macaques¹

Anna Hryniewicz^2,*,, David A. Price^2,, Marcin Moniuszko^2,*,, Adriano Boasso, Yvette Edghill-Spano^*,*, Sadie M. West^¶, David Venzon^||, Monica Vaccari^*, Wen-Po Tsai^*, Elzbieta Tryniszewska^*,, Janos Nacsa^*, Francois Villinger^#, Aftab A. Ansari^#, Christopher J. Trindade^*, Michel Morre^**, David Brooks, Philip Arlen, Helen J. Brown, Christina M. R. Kitchen^*, Jerome A. Zack, Daniel C. Douek, Gene M. Shearer, Mark G. Lewis^*, Richard A. Koup^¶ and Genoveffa Franchini^3,*

^* Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD 20892; Medical University of Bialystok, Bialystok, Poland; Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892; ^¶ Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; ^|| Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892; ^# Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; ^** Cytheris, Issy les Moulineaux, France; David Geffen School of Medicine, University of California, Los Angeles, CA 90095; ^* Bioqual, Rockville, MD 20850; and ^* Southern Research Institute, Frederick, MD 21701; ^* Department of Biostatistics, UCLA School of Public Health, University of California, Los Angeles, CA 90095

The loss of CD4⁺ T cells and the impairment of CD8⁺ T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIV_mac251-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4⁺ or CD8⁺ memory T cells, clonal recruitment to the SIV-specific CD8⁺ T cell pool, or CD8⁺ T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4⁺ effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF- expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the National Institute of Allergy and Infectious Diseases, Division of AIDS.

² A.H., D.A.P., and Ma. M. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Genoveffa Franchini, National Cancer Institute, Building 41/Room D804, Bethesda, MD 20892. E-mail address: franchig{at}mail.nih.gov

⁴ Abbreviations used in this paper: T_reg, regulatory T cell; ART, antiretroviral therapy; gpe, gag, pol, and env genes of SIV_mac251; IUPM, infectious units per million cells; Mamu, Macaca mulatta.

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