Lentiviral vectors with CMV or MHCII promoters administered in vivo: Immune reactivity versus persistence of expression

Takahiro Kimura, Richard C. Koya, Laura Anselmi, Catia Sternini, He Jing Wang, Begonya Comin-Anduix, Robert M. Prins, Emmanuelle Faure-Kumar, Nora Rozengurt, Yan Cui, Noriyuki Kasahara, Renata Stripecke

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Lentiviral vectors (LVs) are potential tools for genetic vaccination. To improve the safety of LV vaccines, we evaluated the selectivity, bio-distribution, persistence of expression, and immune potency of vesicular stomatitis virus G (VSV-G)-pseudotyped vectors transcriptionally targeted to antigen presenting cells (APCs) through a major histocompatibility complex class II (MHCII) promoter. Control vectors contained the ubiquitous cytomegalovirus (CMV) promoter. Bio-distribution studies after intravenous injections of LVs expressing green fluorescent protein (GFP) or luciferase were conducted by a combination of flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (RT-Q-PCR) and whole-body bioluminescence analyses. GFP-expressing vectors showed selective expression in MHCII+ cells of spleen and LV-CMV-GFP administration produced noticeable spleen inflammation, whereas LV-MHCII-GFP did not. Long-term optical imaging analyses of C57BL/6 mice injected with LV-CMV-LUC showed diminishing luciferase expression in the liver and spleen over time. Vaccination/boost with LV-CMV expressing the melanoma antigen tyrosinase-related protein 2 (TRP2) yielded dose-dependent antigen-specific CD8+ T-cell reactivity and high protection against B16 melanoma challenge. Unexpectedly, administration of LVs containing the MHCII promoter resulted in persistence of luciferase expression and viral integration in MHCII+ splenocytes and virtually no CD8+ T-cell responses against TRP2. These studies reveal that APC transduction by LVs could lead to immune reactivity (LV-CMV) or persistence of transgene expression (LV-MHCII), providing a relevant paradigm for vaccination and gene replacement approaches.

Original languageEnglish (US)
Pages (from-to)1390-1399
Number of pages10
JournalMolecular Therapy
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kimura, T., Koya, R. C., Anselmi, L., Sternini, C., Wang, H. J., Comin-Anduix, B., Prins, R. M., Faure-Kumar, E., Rozengurt, N., Cui, Y., Kasahara, N., & Stripecke, R. (2007). Lentiviral vectors with CMV or MHCII promoters administered in vivo: Immune reactivity versus persistence of expression. Molecular Therapy, 15(7), 1390-1399. https://doi.org/10.1038/sj.mt.6300180