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Journal of Virology, April 2008, p. 3561-3573, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02080-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Efficient In Vitro Expansion of Human Immunodeficiency Virus (HIV)-Specific T-Cell Responses by gag mRNA-Electroporated Dendritic Cells from Treated and Untreated HIV Type 1-Infected Individuals

Virology Unit, Department of Microbiology, Institute of Tropical Medicine of Antwerp (ITMA), Antwerp, Belgium,¹ Department of Biomedical Sciences, Faculty of Pharmaceutical, Veterinary and Biomedical Sciences, University of Antwerp, Antwerp, Belgium,² HIV/STD Unit, Department of Clinical Sciences, ITMA, Antwerp, Belgium,³ Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VIDI), Faculty of Medicine, University of Antwerp (UA), and the Center for Cellular Therapy and Regenerative Medicine, Antwerp University Hospital (UZA), Antwerp, Belgium⁴

Received 19 September 2007/ Accepted 18 January 2008

Developing an immunotherapy to keep human immunodeficiency virus type 1 (HIV-1) replication suppressed while discontinuing highly active antiretroviral therapy (HAART) is an important challenge. In the present work, we evaluated in vitro whether dendritic cells (DC) electroporated with gag mRNA can induce HIV-specific responses in T cells from chronically infected subjects. Monocyte-derived DC, from therapy-naïve and HAART-treated HIV-1-seropositive subjects, that were electroporated with consensus codon-optimized HxB2 gag mRNA efficiently expanded T cells, secreting gamma interferon (IFN-) and interleukin 2 (IL-2), as well as other cytokines and perforin, upon restimulation with a pool of overlapping Gag peptides. The functional expansion levels after 1 week of stimulation were comparable in T cells from HAART-treated and treatment-naïve patients and involved both CD4⁺ and CD8⁺ T cells, with evidence of bifunctionality in T cells. Epitope mapping of p24 showed that stimulated T cells had a broadened response toward previously nondescribed epitopes. DC, from HAART-treated subjects, that were electroporated with autologous proviral gag mRNA equally efficiently expanded HIV-specific T cells. Regulatory T cells did not prevent the induction of effector T cells in this system, whereas the blocking of PD-L1 slightly increased the induction of T-cell responses. This paper shows that DC, loaded with consensus or autologous gag mRNA, expand HIV-specific T-cell responses in vitro.

Published ahead of print on 30 January 2008.