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J Immunol. 2015 Sep 1;195(5):2493-501. doi: 10.4049/jimmunol.1500956. Epub 2015 Jul 31.

Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.

Author information

1
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany;
2
Division of Virology, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
3
Centre International de Recherche en Infectiologie, Virus Enveloppés, Vecteurs et Réponses Innées Équipe, INSERM U1111, Centre National de la Recherche Scientifique, Unités Mixtes de Recherche 5308, Université de Lyon-1, École Normale Supérieure de Lyon, 69007 Lyon, France;
4
Host Pathogen Interactions, Paul-Ehrlich-Institut, 63225 Langen, Germany;
5
Institute of Medical Virology, University of Zurich, CH-8057 Zurich, Switzerland;
6
Central Animal Unit, Paul-Ehrlich-Institut, 63225 Langen, Germany;
7
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, D-60596 Frankfurt, Germany;
8
3rd Department of Medicine-Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
9
Centre International de Recherche en Infectiologie, Virus Enveloppés, Vecteurs et Réponses Innées Équipe, INSERM U1111, Centre National de la Recherche Scientifique, Unités Mixtes de Recherche 5308, Université de Lyon-1, École Normale Supérieure de Lyon, 69007 Lyon, France; INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Équipe 3, 06204 Nice, France; and.
10
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany; German Cancer Consortium, 69120 Heidelberg, Germany christian.buchholz@pei.de.

Abstract

Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.

PMID:
26232436
DOI:
10.4049/jimmunol.1500956
[Indexed for MEDLINE]
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