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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2797-2805.
Prepublished online as a Blood First Edition Paper on December 19, 2006December 14, 2006; DOI 10.1182/blood-2006-10-049312.
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Submitted October 8, 2006
Accepted November 22, 2006
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, and Luigi Naldini
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milano, Italy
Immunopathogenesis of Liver Infections Unit, San Raffaele Scientific Institute, Milano, Italy
Vita Salute San Raffaele University, Milano, Italy
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
* Corresponding author; email: brown.brian{at}hsr.it.
Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LV) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into non-dividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared to non-parenchymal 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 LV to mice triggers a rapid and transient IFN  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 LV was administered to animals that lack the capacity to respond to IFN, 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 cell-type 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 immunological barriers to gene therapy are less insurmountable than expected.
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