In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance

Brian D. Brown, Giovanni Sitia, Andrea Annoni, Ehud Hauben, Lucia Sergi Sergi, Anna Zingale, Maria Grazia Roncarolo, Luca G. Guidotti, Luigi Naldini

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFNαβ response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFNαβ, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a celltype-specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected.

Original languageEnglish
Pages (from-to)2797-2805
Number of pages9
JournalBlood
Volume109
Issue number7
DOIs
Publication statusPublished - Apr 1 2007

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Gene transfer
Interferon Type I
Hepatocytes
Transgenes
Heterophile Antigens
Genes
Antigen-Presenting Cells
Genetic Therapy
Dendritic Cells
Antiviral Agents
Communicable Diseases
Gene therapy
Liver
Transient analysis
Animals
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. / Brown, Brian D.; Sitia, Giovanni; Annoni, Andrea; Hauben, Ehud; Sergi, Lucia Sergi; Zingale, Anna; Roncarolo, Maria Grazia; Guidotti, Luca G.; Naldini, Luigi.

In: Blood, Vol. 109, No. 7, 01.04.2007, p. 2797-2805.

Research output: Contribution to journalArticle

Brown, Brian D. ; Sitia, Giovanni ; Annoni, Andrea ; Hauben, Ehud ; Sergi, Lucia Sergi ; Zingale, Anna ; Roncarolo, Maria Grazia ; Guidotti, Luca G. ; Naldini, Luigi. / In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. In: Blood. 2007 ; Vol. 109, No. 7. pp. 2797-2805.
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