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Exclusive transduction of human CD4+ T Cells upon systemic delivery of CD4-targeted lentiviral vectors


Zhou, Q; Uhlig, K M; Muth, A; Kimpel, J; Lévi, C; Münch, R C; Seifried, J; Pfeiffer, A; Trkola, A; Coulibaly, C; von Laer, D; Wels, W S; Hartwig, U F; Verhoeyen, E; Buchholz, C J (2015). Exclusive transduction of human CD4+ T Cells upon systemic delivery of CD4-targeted lentiviral vectors. Journal of Immunology, (195):2493-2501.

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 CD42- 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.

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 CD42- 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.

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9 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:31 July 2015
Deposited On:15 Feb 2016 15:31
Last Modified:08 Dec 2017 17:51
Publisher:American Association of Immunologists
ISSN:0022-1767
Funders:German Federal Ministry for Education and Research: CI3 Cluster Grant 031A024C, Bundesministerium für Gesundheit: Grant 2510-790 FSB-705, LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst: Grant III L 4-518/17.004 (2010)
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.4049/jimmunol.1500956
Official URL:http://www.jimmunol.org/search?fulltext=Exclusive+Transduction+of+Human+CD4%2B+T+Cells+upon+Systemic+Delivery+of+CD4-Targeted+Lentiviral+Vectors&submit=yes&x=14&y=6
PubMed ID:26232436

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