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* Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal Saint-Luc,
Laboratoire d’Immunologie, Département de Microbiologie et d’Immunologie and
Institut National de la Santé et de la Recherche Médicale U743, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montréal, and
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada;
¶ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
|| Vaccine Discovery, Wyeth Lederle, Pearl River, NY 19065;
# Human Retrovirus Pathogenesis Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702;
** BIOQUAL, Rockville, MD 20850; and
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218
DNA vaccination is an invaluable approach for immune therapy in that it lacks vector interference and thus permits repeated vaccination boosts. However, by themselves, DNA-based vaccines are typically poor inducers of Ag-specific immunity in humans and non-human primates. Cytokines, such as IL-12 and IL-15, have been shown to be potent adjuvants for the induction and maintenance of cellular immune responses, in particular during HIV infection. In this study, we examined the ability of therapeutic vaccination with SIV-DNA+IL-12 or IL-15 as molecular adjuvants to improve DNA vaccine potency and to enhance memory immune responses in SIV-infected macaques. Our results demonstrate that incorporating IL-12 into the vaccine induces SIV-specific CD8 effector memory T cell (TEM) functional responses and enhances the capacity of IFN-
-producing CD8 TEM cells to produce TNF. Lower levels of PD-1 were expressed on T cells acquiring dual function upon vaccination as compared with mono-functional CD8 TEM cells. Finally, a boost with SIV-DNA+IL-15 triggered most T cell memory subsets in macaques primed with either DNA-SIV or placebo but only CD8 TEM in macaques primed with SIV-DNA+IL-12. These results indicate that plasmid IL-12 and IL-15 cytokines represent a significant addition to enhance the ability of therapeutic DNA vaccines to induce better immunity.
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 work was supported by grants awarded to R.H. from the Canadian Institutes of Health Research and to R.-P.S. from the U.S. National Institutes of Health, the Canadian Institutes of Health Research, the Canadian Network for Vaccine and Immunotherapeutics, Genome Québec, Genome Canada, and the Fonds de la recherche en Santé du Québec (FRSQ) AIDS network. R.-P.S. is the Canada Research Chair in Human Immunology.
2 R.H. and J.D.B. are co-first authors.
3 Address correspondence and reprint requests to Dr. Rafick-Pierre Sékaly, Centre de recherche du Centre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, 264, René-Lévesque est, Bureau 1317, Montréal, Québec, Canada H2X 1P1. E-mail address: rafick-pierre.sekaly{at}umontreal.ca
4 Abbreviations used in this paper: ART, antiretroviral therapy; SEM, SEA+SEB; SFC, spot forming cells; TEM, effector memory T cell; TCM, central memory T cell; SLA, simian leukocyte Ag; DC, dendritic cell; PMPA, 9-[9(R)-2(phosphonomethoxy) propyl]adenine; ICS, intracellular staining; int, intermediate.
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