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Engineered lentivector targeting of dendritic cells for in vivo immunization

Abstract

We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell–surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN–specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens.

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Figure 1: Lentivector bearing engineered Sindbis viral glycoprotein targets to DC-SIGN-expressing cells.
Figure 2: Lentivector encoding a reporter GFP gene and bearing SVGmu can selectively transduce dendritic cells in vitro and in vivo.
Figure 3: Mouse bone marrow-derived dendritic cells (mBMDCs) transduced by a SVGmu enveloped lentivector encoding an OVA gene can stimulate OVA-specific CD8+ and CD4+ T cells in vitro.
Figure 4: In vivo stimulation of antigen specific T cell and antibody responses in wild-type B6 mice following a subcutaneous injection of the dendritic cell–targeting lentivector FOVA/SVGmu.
Figure 5: Preventive and therapeutic anti-tumor immune responses elicited through in vivo administration of the dendritic cell–targeted lentivector FOVA/SVGmu in a murine E.G7 tumor model.

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Acknowledgements

We are grateful to James Strauss for providing reagents and April Tai for a critical reading of the manuscript. This work was supported by a grant from the National Institute of Health (R01AI068978), a grant from the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative, and by the Skirball Foundation.

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L.Y. and H.Y. designed research, performed experiments, discussed the results, wrote the paper. K.R., T.C., K.J., L.Z., A.E., A.W., D.Y. performed experiments. D.B. designed research, discussed the results, wrote the paper and provided financial support. P.W. designed research, performed experiments, discussed results, wrote the paper, provided financial support and coordinated the whole project.

Corresponding authors

Correspondence to David Baltimore or Pin Wang.

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Yang, L., Yang, H., Rideout, K. et al. Engineered lentivector targeting of dendritic cells for in vivo immunization. Nat Biotechnol 26, 326–334 (2008). https://doi.org/10.1038/nbt1390

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