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mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients

Van Gulck, Ellena,*; Vlieghe, Erikab,*; Vekemans, Marcb,*; Van Tendeloo, Viggo F.I.c,d,*; Van De Velde, Annc,d; Smits, Evelienc,d; Anguille, Sébastienc,d; Cools, Nathaliec,d; Goossens, Hermanc; Mertens, Liesbetb; De Haes, Winnia; Wong, Johnssone; Florence, Ericb,*; Vanham, Guidoa,f,g,*; Berneman, Zwi N.c,d,*

doi: 10.1097/QAD.0b013e32834f33e8
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Background: In an effort to raise protective antiviral immunity, dendritic cell immunotherapy was evaluated in six adults infected with human immunodeficiency virus (HIV)-1 and stable under highly active antiretroviral therapy (HAART).

Design and methods: Autologous monocyte-derived dendritic cells electroporated with mRNA encoding Gag and a chimeric Tat-Rev-Nef protein were administered, whereas patients remained on HAART. Feasibility, safety, immunogenicity and antiviral responses were investigated.

Results: Dendritic cell vaccine preparation and administration were successful in all patients and only mild adverse events were seen. There was a significant increase post-dendritic cell as compared to pre-dendritic cell vaccination in magnitude and breadth of HIV-1-specific interferon (IFN)-γ response, in particular to Gag, and in T-cell proliferation. Breadth of IFN-γ response and T-cell proliferation were both correlated with CD4+ and CD8+ polyfunctional T-cell responses. Importantly, dendritic cell vaccination induced or increased the capacity of autologous CD8+ T cells to inhibit superinfection of CD4+ T cells with the vaccine-related IIIB virus and some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-γ response.

Conclusions: Therapeutic immunization with dendritic cells was safe and successful in raising antiviral cellular immune responses, including effector CD8+ T cells with virus inhibitory activity. The stimulation of those potent immunological and antiviral effects, which have been associated with control of HIV-1, underscores the potential of dendritic cell vaccination in the treatment of HIV-1. The incomplete nature of the response in some patients helped to identify potential targets for future improvement, that is increasing antigenic spectrum and enhancing T-cell response.

aDepartment of Biomedical Sciences, Division of Microbiology, Virology Unit

bDepartment of Clinical Sciences, Medical Service, HIV and STD Unit, Institute of Tropical Medicine, Antwerp

cVaccine and Infectious Disease Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp

dCenter for Cell Therapy and Regenerative Medicine (CCRG) and Division of Hematology, Antwerp University Hospital (UZA), Edegem, Belgium

eDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

fFaculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp

gFaculty of Medicine and Pharmacy, Free University of Brussels (VUB), Brussels, Belgium.

*Ellen Van Gulck, Erika Vlieghe, Marc Vekemans, Viggo F.I. Van Tendeloo, Eric Florence, Guido Vanham, and Zwi N. Berneman contributed equally to the writing of this article.

Correspondence to Zwi Berneman, Center for Cell Therapy and Regenerative Medicine (CCRG), Antwerp University Hospital (UZA), Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: Zwi.Berneman@uza.be

Received 26 September, 2011

Revised 9 November, 2011

Accepted 14 November, 2011

© 2012 Lippincott Williams & Wilkins, Inc.