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Antigen-presenting cell-targeted lentiviral vectors do not support the development of productive T-cell effector responses: implications for in vivo targeted vaccine delivery

Gene Therapy volume 24, pages 370–375 (2017)Cite this article

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Abstract

Targeting transgene expression specifically to antigen-presenting cells (APCs) has been put forward as a promising strategy to direct the immune system towards immunity. We developed the nanobody-display technology to restrict the tropism of lentiviral vectors (LVs) to APCs. However, we observed that immunization with APC-targeted LVs (DC2.1-LVs) did not evoke strong antigen-specific T-cell immunity when compared to immunization with broad tropism LVs (VSV.G-LVs). In this study, we report that VSV.G-LVs are more immunogenic than DC2.1-LVs because they transduce stromal cells, which has a role in activating antigen-specific T cells. Moreover, VSV.G-LVs trigger a pro-inflammatory innate immune response through transduction of APCs and stromal cells, while DC2.1-LVs trigger a type I interferon response with anti-viral capacity. These findings question the rationale of targeting LVs to APCs and argue for the development of VSV.G-LVs with an improved safety profile.

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Acknowledgements

We thank Carlo Heirman, Elsy Vaeremans and Petra Roman for cloning and technical assistance. We furthermore thank Claude Libert for providing the IFNAR−/− mice. This work was supported by grants from the following funding agencies: Stichting tegen Kanker, Kom op tegen Kanker, Agency for Innovation by Science and Technology (IWT) and Research Foundation-Flanders (FWO-V, of which Keyaerts M is a senior clinical investigator). YDV was supported by Kom op tegen Kanker and is currently funded via an FWO-SB fellowship.

Author contributions

CG contributed to the design of the study, performed and analyzed experiments and assisted in writing the manuscript. YDV: performed and analyzed experiments, and assisted in writing the manuscript. DE generated several of the lentiviral transfer vectors used in this manuscript, performed and analyzed experiments, and assisted in writing the manuscript. SL performed and analyzed experiments, and assisted in writing the manuscript. MK provided the in vivo bioluminescence imaging protocol and facility, and assisted in writing the manuscript. GR generated and characterized nanobody DC2.1 used in this study, and assisted in writing the manuscript. Karine Breckpot: contributed to the design of the study, performed and analyzed experiments, and assisted in writing of manuscript.

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Author notes

  1. C Goyvaerts and Y De Vlaeminck: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Brussels, Belgium

    C Goyvaerts, Y De Vlaeminck & K Breckpot

  2. Department of Immunomodulation, Navarrabiomed, Pamplona, Spain

    D Escors

  3. Hannover Medical School, ZTL Imaging-Center, Hannover, Germany

    S Lienenklaus

  4. In Vivo Cellular and Molecular Imaging Laboratory, VUB, Brussels, Belgium

    M Keyaerts

  5. Nuclear Medicine Department, UZ Brussel, Brussels, Belgium

    M Keyaerts

  6. Cellular and Molecular Immunology Laboratory VUB, Brussels, Belgium

    G Raes

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  1. C Goyvaerts
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Correspondence to K Breckpot.

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Goyvaerts, C., De Vlaeminck, Y., Escors, D. et al. Antigen-presenting cell-targeted lentiviral vectors do not support the development of productive T-cell effector responses: implications for in vivo targeted vaccine delivery. Gene Ther 24, 370–375 (2017). https://doi.org/10.1038/gt.2017.30

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