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Series GSE39129 Query DataSets for GSE39129
Status Public on Jul 05, 2013
Title A TLR- and non-TLR-mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Lentiviral vector (LV)-mediated gene transfer is a promising method of gene therapy. We previously reported that systemic injection of LV triggers a transient inflammatory response. Here, we carried out studies to better characterize this response, and to develop a strategy to overcome the effects of interferon (IFN) on LV-mediated gene transfer. We profiled gene expression in the liver after LV administration using deep-sequencing, and identified several innate response pathways. We examined the response to LV in MyD88-TRIF knock-out mice, which are incapable of toll-like receptor (TLR) signaling. The IFN response to LV was not reduced in the liver, indicating that a non-TLR pathway can recognize LV in this tissue. Indeed, blocking reverse-transcription with AZT reduced the IFN response only in the liver, suggesting that proviral DNA can be a trigger. To block the inflammatory response, we pre-treated mice with a short-course of dexamethasone. At 4 hours post-treatment, all of the IFN-induced genes were normalized. By blocking the inflammatory response, hepatocyte transduction was dramatically increased, which doubled the level of human factor-IX 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.
 
Overall design mRNA profiles from livers of untreated and LV-treated mice were generated by deep-sequencing in Illumina HiSeq 2000.
 
Contributor(s) Brown BD, Agudo J
Citation(s) 22871668
Submission date Jul 05, 2012
Last update date May 15, 2019
Contact name Brian Brown
E-mail(s) bdblab@gmail.com
Organization name Icahn School of Medicine at Mount Sinai
Department Genetics and Genomic Sciences
Street address 1470 Madison Avenue
City New York
State/province NY
ZIP/Postal code 10029
Country USA
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (6)
GSM956517 Liver + LV, rep1
GSM956518 Liver + LV, rep2
GSM956519 Liver + LV, rep3
Relations
BioProject PRJNA170059
SRA SRP014029

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE39129_Liver+LV_consolidated.txt.gz 74.7 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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