Immunization of mice with lentiviral vectors targeted to MHC class II+ cells is due to preferential transduction of dendritic cells in vivo

PLoS One. 2014 Jul 24;9(7):e101644. doi: 10.1371/journal.pone.0101644. eCollection 2014.

Abstract

Gene transfer vectors such as lentiviral vectors offer versatile possibilities to express transgenic antigens for vaccination purposes. However, viral vaccines leading to broad transduction and transgene expression in vivo, are undesirable. Therefore, strategies capable of directing gene transfer only to professional antigen-presenting cells would increase the specific activity and safety of genetic vaccines. A lentiviral vector pseudotype specific for murine major histocompatibilty complex class II (LV-MHCII) was recently developed and the present study aims to characterize the in vivo biodistribution profile and immunization potential of this vector in mice. Whereas the systemic administration of a vector pseudotyped with a ubiquitously-interacting envelope led to prominent detection of vector copies in the liver of animals, the injection of an equivalent amount of LV-MHCII resulted in a more specific biodistribution of vector and transgene. Copies of LV-MHCII were found only in secondary lymphoid organs, essentially in CD11c+ dendritic cells expressing the transgene whereas B cells were not efficiently targeted in vivo, contrary to expectations based on in vitro testing. Upon a single injection of LV-MHCII, naive mice mounted specific effector CD4 and CD8 T cell responses against the intracelllular transgene product with the generation of Th1 cytokines, development of in vivo cytotoxic activity and establishment of T cell immune memory. The targeting of dendritic cells by recombinant viral vaccines must therefore be assessed in vivo but this strategy is feasible, effective for immunization and cross-presentation and constitutes a potentially safe alternative to limit off-target gene expression in gene-based vaccination strategies with integrative vectors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • CD11c Antigen / genetics
  • CD11c Antigen / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cytotoxicity, Immunologic
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Gene Expression
  • Genes, MHC Class II*
  • Genetic Vectors
  • Immunity, Cellular / drug effects*
  • Immunization
  • Immunologic Memory
  • Injections, Intravenous
  • Lentivirus / genetics*
  • Lentivirus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Th1-Th2 Balance
  • Vaccines, Synthetic
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / biosynthesis
  • Viral Vaccines / genetics
  • Viral Vaccines / immunology*

Substances

  • CD11c Antigen
  • Vaccines, Synthetic
  • Viral Vaccines

Grant support

Financial support for this study was obtained from PERSIST (EC FP7 large-scale integrating project GA n°222878) to AG, Fondation pour la Recherche Médicale and the French Ministry of Research via Ecole Doctorale B2T, University Paris Diderot to A.G and S.C. and from the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessian Ministry of Higher Education, Research and the Arts (III L 4- 518/17.004 (2010)) to C.J.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.