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Adeno-associated virus in the liver: natural history and consequences in tumor development

ABSTRACT: Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (40-80%). AAV infection has long been considered as non-pathogenic1, however few years ago we reported for the first time recurrent clonal AAV2 insertion in the pathogenesis of human hepatocellular carcinoma (HCC) developed on normal liver. These clonal viral insertions target cancer driver genes, including CCNA2, CCNE1, TERT, TNFSF10 and MLL4, leading to their overexpression. The viral inserted sequences involved in almost all the cases the 3’ inverse tandem repeat (ITR) of AAV2, which is important for virus integration in host DNA and exhibits a promoter/enhancer activity. Here, we used RNA sequencing (RNA-seq) to investigate their functional impact on the tissue, such as fusion transcript generation events.

PROVIDER: EGAS00001003310 | EGA |

REPOSITORIES: EGA

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EGAS00001003310 - samples

Project description:Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterize the natural history of AAV infection in the liver and its consequence in tumor development. In silico analyses using viral capture data explored viral variants and new clonal insertions. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.

| EGAD00001004484 | EGA

The Adeno-Associated Virus 2 (AAV2) genome and Rep 68/78 proteins interact with cellular sites of DNA damage.

Project description:We have previously developed a modified iteration of a viral chromosome conformation capture (V3C-seq) assay to show that the autonomous parvovirus Minute Virus of Mice (MVM) localizes spatially with cellular sites of DNA damage to establish viral replication centers. Similar V3C-seq assays to map AAV genome localization show that both replicating and non-replicating AAV2 genomes in the absence of helper virus colocalize with cellular sites of DNA damage. The AAV non-structural protein Rep 68/78, when ectopically expressed in the absence of viral infection or during AAV2 infection in the absence of helper proteins also localizes to cellular sites of DNA damage. Strikingly however, recombinant AAV gene therapy vector genomes derived from AAV do not colocalize with AAV and Rep at cellular DDR sites.

2021-10-20 | GSE178316 | GEO

Herpes Simplex Virus 1 and Adeno Associated Virus distribution in neurons of the murine trigeminal and superior cervical ganglia

Project description:After initial infection at mucosa, herpes simplex virus (HSV) establishes lifelong latency in neurons of the peripheral nervous system, which represents the source of recurrent disease. Current antiviral therapies reduce symptoms and viral shedding, but do not cure the infection. In contrast, gene editing offers the possibility to lethally mutate or even eliminate latent viral genomes. Delivery of gene editing enzymes by Adeno Associated Virus (AAV) vectors represents a promising approach to functionally curing HSV infection. In order to optimize in vivo gene therapy approaches it is necessary to understand which neuronal subtypes within peripheral ganglia are infected by HSV and which subtypes are efficiently targeted by various AAV serotypes. Here we use single cell RNA sequencing (scRNA-seq) to identify neurons expressing HSV genes as well as reporter genes for AAV1, AAV8, AAV-PhP.s, and AAV-Rh10 serotypes.

2020-06-05 | GSE151811 | GEO

RNA-seq data of nasopharyngeal carcinoma (NPC) in non-endemic areas

Project description:Epstein-Barr virus (EBV) related nasopharyngeal carcinoma (NPC) is an epithelial malignancy with higher incidence in Asian endemic area (EA) than in non-endemic area (NEA), where frequency is below 1/105/year. The causes of such difference are unclear and might be related to viral, environmental (e.g. diet) and genomic factors. We aimed at dissecting the gene expression (GE) and microenvironment landscape in NPC leading to the identification of molecular subtypes explaining the differences between EA and NEA.

2023-12-21 | GSE208281 | GEO

Manchanda2014 - Effect on Immune System by 4 different Influenza A virus strains

Project description:Himanshu Manchanda, Nora Seidel, Andi Krumbholz, Andreas Sauerbrei, Michaela Schmidtke & Reinhard Guthke. Within-host influenza dynamics: a small-scale mathematical modeling approach. Biosystems 118 (2014). The emergence of new influenza viruses like the pandemic H1N1 influenza A virus in 2009 (A(H1N1)pdm09) with unpredictable difficulties in vaccine coverage and established antiviral treatment protocols emphasizes the need of new murine models to prove the activity of novel antiviral compounds in vivo. The aim of the present study was to develop a small-scale mathematical model based on easily attainable experimental data to explain differences in influenza kinetics induced by different virus strains in mice. To develop a three-dimensional ordinary differential equation model of influenza dynamics, the following variables were included: (i) viral pathogenicity (P), (ii) antiviral immune defense (D), and (iii) inflammation due to pro-inflammatory response (I). Influenza virus-induced symptoms (clinical score S) in mice provided the basis for calculations of P and I. Both, mono- and biphasic course of mild to severe influenza induced by three clinical A(H1N1)pdm09 strains and one European swine H1N2 virus were comparatively and quantitatively studied by fitting the mathematical model to the experimental data. The model hypothesizes reasons for mild and severe influenza with mono- as well as biphasic course of disease. According to modeling results, the second peak of the biphasic course of infection is caused by inflammation. The parameters (i) maximum primary pathogenicity, (ii) viral infection rate, and (iii) rate of activation of the immune system represent most important parameters that quantitatively characterize the different pattern of virus-specific influenza kinetics.

2024-09-02 | BIOMD0000000712 | BioModels

Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Project description:Viral genetictools that target specificbraincell types could transform basicneuroscienceand targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome tocontrol gene expressionin adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection ofParvalbumin(PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primateneocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools.

2023-06-27 | GSE235997 | GEO

Consequences of perinatal bisphenol A exposure in a mouse model of multiple sclerosis

Project description:Multiple sclerosis (MS) is a complex disease influenced by genetic and environmental contributing factors. Endocrine disrupting compounds (EDCs) such as bisphenol A (BPA) affect gene expression and hormone-regulated systems throughout the body. We investigated the effects of BPA on Theiler’s-virus induced demyelination (TVID), a mouse model of MS. Perinatal BPA exposure, combined with viral infection, resulted in a decreased level of viral antibodies, accelerated the onset of TVID symptoms, increased inflammation in both the spinal cord and digestive tract, and amplified immune-related gene expression changes induced by viral infection. These results demonstrate the effect of BPA on the trajectory of TVID, and illustrate how multiple factors collectively influence autoimmune disease. For microarray: 7 samples

2013-08-01 | E-GEOD-46551 | biostudies-arrayexpress

A new HDV mouse model showing important features of human infection and identifying MAVS as a key player in IFN-β induction

Project description:Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the absence limited availability of small animal models. Here a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented. HDV- and HBV-replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV) (AAV-HDV and AAV-HBV). Viral load, antigen expression and genomes were quantified at different time points after AAV injection. Furthermore, liver pathology, genome editing, and the activation of the innate immune response were evaluated. AAV-HDV infection initiated HDV replication in mouse hepatocytes. Genome-editing was confirmed by the presence of small and large-HDV-antigens and sequencing. Viral replication was detected for 45 days, even after the AAV-HDV vector had almost disappeared. In the presence of HBV, HDV infectious particles were detected in serum. Furthermore, as observed in patients, co-infection was associated with the reduction of HBV antigen expression and the onset of liver damage that included the up/down-regulation of genes involved in the development of liver pathologies. HDV replication induced a sustained type-I IFN response, which was significantly reduced in immunodeficient mice and almost absent in MAVS-deficient mice. The animal model described here reproduces important characteristics of human HDV infection and provides a valuable tool for characterizing the viral infection and for developing new treatments. Furthermore, MAVS was identified as a main player in HDV detection and adaptive immunity was found to be involved in the amplification of the innate immune response.

2017-06-30 | GSE98342 | GEO

Gene expression profiling of HDAC3-depleted mouse liver rescued with wild-type exogenous HDAC3

Project description:We have shown that intravenous injection of HDAC3 floxed mice with adeno-associated virus (AAV) expressing Cre depletes hepatic HDAC3, upregulates lipogenic gene expression, and causes fatty liver. When AAV-Flag-HDAC3 wild-type (WT) is co-injected along with AAV-Cre, the exogenous HDAC3 is expressed at endogenous levels and can completely rescue fatty liver phenotype. Here we profile transcriptome of the rescued WT livers in comparison with HDAC3-depleted (KO) livers. 4-months old C57BL/6 male mice were co-injected with AAV-Cre or AAV-Cre plus AAV-Flag-HDAC3. Mice were fed ad libitum and harvested at 5 pm (ZT10) at 2-weeks post-injection. Liver total RNA was extracted and hybridized to Affymetrix Mouse Gene 1.0ST array.

2013-11-25 | E-GEOD-49386 | biostudies-arrayexpress

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

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