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Response of mouse liver to Adenovirus, Helper Dependent Adenovirus, and Adeno-Associated Virus

ABSTRACT: Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a "first-generation"adenoviral (Ad) vector, a helper-dependent "gutless" adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction.

ORGANISM(S): Mus musculus

PROVIDER: GSE16047 | GEO | 2009/05/13

SECONDARY ACCESSION(S): PRJNA115521

REPOSITORIES: GEO

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Response of mouse liver to Adenovirus, Helper Dependent Adenovirus, and Adeno-Associated Virus

Project description:Understanding host responses to viral gene therapy vectors is necessary for the development of safe and efficacious in vivo gene transfer agents. We describe the use of high-density spotted complementary DNA microarrays in monitoring the in vivo host transcriptional responses in mouse liver upon administration of either a "first-generation"adenoviral (Ad) vector, a helper-dependent "gutless" adenoviral (HD) vector, or an adeno-associated viral (AAV) vector containing human factor IX (hFIX) expression cassettes. Since HD and AAV do not contain any viral genes, they allow us to assess the host response to the viral capsid and packaged nonviral DNA in whole animals. Comparison of the host response to Ad and HD helps assess the importance of leaky adenoviral gene expression. While all three vectors induced characteristic temporally sequenced programs of gene expression, the gene expression programs induced by the Ad and HD adenovirus vectors were remarkably similar, including the induction of a prominent type I interferon (IFN)-dependent cluster within 6 hours of administration. In contrast, the AAV-based vector caused far fewer alterations of host-gene expression. Our results indicate that recognition of the Ad capsid or double-stranded DNA (of nonviral origin) in the vector elicits a robust type I IFN response that is, however, not elicited by AAV-derived vector transduction. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract.

2010-06-25 | E-GEOD-16047 | biostudies-arrayexpress

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVitro]

Project description:Recombinant adeno-associated viral vectors (rAAVs) are among the most commonly used vehicles for in vivo based gene therapies. However, it is hard to predict which AAV capsid will provide the most robust expression in human subjects due to the observed discordance in vector-mediated transduction between species. We used a primate specific capsid, AAV-LK03, and demonstrated that the limitation of this capsid towards transduction of mouse cells was unrelated to cell entry and nuclear transport but rather due to depleted histone H3 chemical modifications related to active transcription, namely H3K4me3 and H3K27ac, on the vector DNA itself. A single-amino acid insertion into the AAV-LK03 capsid enabled efficient transduction and the accumulation of active-related epigenetic marks on the vector chromatin in mouse without compromising transduction efficiency in human cells. Our study suggests that the capsid protein itself is involved in driving the epigenetic status of the vector genome, most likely during the process of uncoating. Programming viral chromatin states by capsid design may enable facile DNA transduction between vector and host species and ultimately led to rationale selection of AAV capsids for use in humans.

2023-02-28 | GSE226264 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [CnT_InVivo]

2023-02-28 | GSE226167 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVivo]

2023-02-28 | GSE226165 | GEO

The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner [Tn5_InVitro]

2023-02-28 | GSE226164 | GEO

Vector-transduced neurons transcriptome profiles

Project description:With the goal of specifically dissecting the toxicogenomic signatures of the helper-dependent (HD) human (HAd5) and canine (CAV-2) adenovirus, the VSV-G-pseudotyped SIN HIV-1 (LV) and the Adenoviral-associated vector 2/9 for human neurons (AAV2/9), we transduced a bona fide human neuronal system with HD-HAd5, HD-CAV-2, LV and AAV2/9, we analysed the transcriptional response of more than 47,000 transcripts using gene chips. Chip data showed that HD-CAV-2 and LV vectors both activated the innate arm of the immune response, including Toll-like receptors and hyaluronan circuits. LV vector induced as well an IFN response. Moreover, HD-CAV-2 and LV vectors affected DNA damage pathways - at 5 days in opposite directions - suggesting a differential response of the p53 and ATM pathways to the vector genomes. As a general response to the vectors, human neurons activated pro-survival genes and neuron morphogenesis.

2013-05-22 | GSE47130 | GEO

Transcriptomic Analysis Reveals the Inability of Recombinant AAV8 to Activate Human Monocyte-Derived Dendritic Cells

Project description:Recombinant Adeno-Associated Virus (rAAV) is considered as one of the most successful and widely used viral vector for in vivo gene therapy. However, host immune responses to the vector and/or the transgene product remain a major hurdle to successful AAV gene transfer. In contrast to anti-vector adaptive immunity, the initiation of the innate immunity towards rAAV is still poorly understood but is directly dependent on the interaction between the viral vector and innate immune cells. Here, we used a quantitative transcriptomic-based approach to determine the activation of inflammatory and anti-viral pathways after rAAV8-based infection of monocyte-derived Dendritic Cells (moDC) obtained from 12 healthy human donors. We have shown that rAAV8 particles are efficiently internalized, but that this uptake does not induce any detectable transcriptomic change in moDC cells in contrast to an adenoviral infection which upregulates anti-viral pathways. These findings suggest an immunological favorable profile for rAAV8 serotype with regards to in vitro activation of moDC cell model. Transcriptomic analysis of rAAV-infected innate immune cells is a powerful method to determine the ability of the viral vector to be seen by these sensor cells, which remains of great importance to better understand the immunogenicity of rAAV vectors and to design immune-stealth products.

2023-09-12 | GSE228649 | GEO

Vector-transduced neurons transcriptome profiles

2013-05-22 | E-GEOD-47130 | biostudies-arrayexpress

Effect of TTF-1/NKX2-1 expression on TGF-beta induced gene expression in A549 lung cancer cell line.

Project description:TTF-1/NKX2-1 was expressed by adenoviral vector and changes in gene expression were determined by RNA-sequencing. A549 cells were infected with Ad-TTF-1 or Ad-LacZ vectors and stimulated with TGF-beta for 24 hours or left untreated. Expression of polyA RNA was determined.

2014-07-27 | E-GEOD-56356 | biostudies-arrayexpress

F8 intein precise CodopN6 reconstitution

Project description:Liver gene therapy with adeno-associated viral (AAV) vectors is under clinical investigation for hemophilia A (HemA), the most common inherited X-linked bleeding disorder. Major limitations are the large size of the F8 transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti-F8 antibodies which neutralize F8 activity. Taking advantage of split inteins-mediated protein trans-splicing, we divided the coding sequence of the large and highly secreted F8-N6 variant in two separate AAV split-inteins vectors whose co-administration to HemA mice results in F8 protein reconstitution and expression of therapeutic levels of F8 over time without anti-F8 antibodies development.

2022-03-31 | PXD031884 | Pride

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