The latest study from the Jill Roberts Institute, "The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation," was published on September 6 in Nature. To read more, click here.     Dr. Gregory Sonnenberg wins inaugural award from the Society for Mucosal Immunology. To read more, click here.  The Kenneth Rainin Foundation awarded Dr. Iliyan Iliev and colleagues from Mount Sinai a $250,000 Synergy Award to examine the composition of the fungal community in babies born to mothers with inflammatory bowel disease. To read more, click here. Dr. Randy Longman received the Irma T. Hirschl Career Scientist Award and the New York Crohn’s Foundation Award.    

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A TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade.

TitleA TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade.
Publication TypeJournal Article
Year of Publication2012
AuthorsAgudo, J, Ruzo, A, Kitur, K, Sachidanandam, R, J Blander, M, Brown, BD
JournalMol Ther
Volume20
Issue12
Pagination2257-67
Date Published2012 Dec
ISSN1525-0024
KeywordsAdaptor Proteins, Vesicular Transport, Animals, Cells, Cultured, Flow Cytometry, Hepatocytes, Immunity, Innate, Immunohistochemistry, Lentivirus, Liver, Mice, Mice, Knockout, Myeloid Differentiation Factor 88, Toll-Like Receptors
Abstract

Lentiviral vector (LV)-mediated gene transfer is a promising method of gene therapy. We previously reported that systemic injection of HIV-based LV triggers a transient inflammatory response. Here, we carried out studies to better characterize this response, and to develop a strategy to overcome the adverse effects of interferon (IFN) on LV-mediated gene transfer. We profiled gene expression in the liver after LV administration using deep-sequencing (RNA-seq), and identified several innate response pathways. We examined the response to LV in MyD88-TRIF knockout mice, which are incapable of toll-like receptor (TLR) signaling. Unexpectedly, the IFN response to LV was not reduced in the liver indicating that a non-TLR pathway can recognize LV in this organ. Indeed, blocking reverse transcription with azidothymidine (AZT) reduced the IFN response only in the liver, suggesting that proviral DNA can be a trigger. To block the inflammatory response, we pretreated mice with a short course of dexamethasone (Dex). At 4 hours post-treatment, all the IFN-induced genes were normalized. By blocking the inflammatory response, hepatocyte transduction was dramatically increased, which in turn doubled the level of human factor IX (FIX) produced by a hepatocyte-specific LV. Our studies uncover new insights into LV-induced immune responses in the liver, and provide a means to increase the safety and efficiency of LV-mediated gene transfer.

DOI10.1038/mt.2012.150
Alternate JournalMol. Ther.
PubMed ID22871668
PubMed Central IDPMC3519984
Grant ListDP2 DK083052 / DK / NIDDK NIH HHS / United States
R01 AI073899 / AI / NIAID NIH HHS / United States
1R01AI073899-01 / AI / NIAID NIH HHS / United States
DP2DK083052-01 / DK / NIDDK NIH HHS / United States