Differentiated neuroprogenitor cells incubated with human or canine adenovirus, or lentiviral vectors have distinct transcriptome profiles

• Published in: PloS one Vol. 8; no. 7; p. e69808
• Main Authors: Piersanti, Stefania, Astrologo, Letizia, Licursi, Valerio, Costa, Rossella, Roncaglia, Enrica, Gennetier, Aurelie, Ibanes, Sandy, Chillon, Miguel, Negri, Rodolfo, Tagliafico, Enrico, Kremer, Eric J, Saggio, Isabella
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.07.2013; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Adenoviruses, Canine - physiology; Adenoviruses, Human - physiology; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; Biochemistry, Molecular Biology; Biocompatibility; Biology; Brain; Brain diseases; Cell Cycle - genetics; Cell Differentiation - genetics; Cell survival; Central nervous system; Cloning; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Dogs; Down-Regulation - genetics; Endocytosis - genetics; Expression vectors; Gene expression; Gene Expression Profiling; Gene therapy; Gene transfer; Genetic Vectors - genetics; Genetic Vectors - metabolism; Genomes; Genomics; Growth factors; HIV; Homeostasis; Human immunodeficiency virus; Humans; Hyaluronic acid; Immune response; Immune system; Immunity - genetics; Immunology; In vivo methods and tests; Inflammation; Innate immunity; Interferon; Interferons - genetics; Interferons - metabolism; Kinases; Lentivirus; Life Sciences; Mesencephalon - cytology; Morphogenesis; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neural Stem Cells - virology; Neurobiology; Neurons; Neurons - cytology; Neurons - virology; Neurons and Cognition; p53 Protein; Proteins; Receptors; Signal Transduction - genetics; Toll-like receptors; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; Toxicity; Transcription; Transcriptional Activation; Transcriptome - genetics; Transduction, Genetic; Vectors (Biology); Wnt Proteins - genetics; Wnt Proteins - metabolism; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069808

Several studies have demonstrated the potential for vector-mediated gene transfer to the brain. Helper-dependent (HD) human (HAd) and canine (CAV-2) adenovirus, and VSV-G-pseudotyped self-inactivating HIV-1 vectors (LV) effectively transduce human brain cells and their toxicity has been partly analysed. However, their effect on the brain homeostasis is far from fully defined, especially because of the complexity of the central nervous system (CNS). With the goal of dissecting the toxicogenomic signatures of the three vectors for human neurons, we transduced a bona fide human neuronal system with HD-HAd, HD-CAV-2 and LV. We analysed the transcriptional response of more than 47,000 transcripts using gene chips. Chip data showed that HD-CAV-2 and LV vectors activated the innate arm of the immune response, including Toll-like receptors and hyaluronan circuits. LV vector also induced an IFN response. Moreover, HD-CAV-2 and LV vectors affected DNA damage pathways--but 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, presumably with the goal of re-establishing homeostasis. These data are complementary to in vivo studies on brain vector toxicity and allow a better understanding of the impact of viral vectors on human neurons, and mechanistic approaches to improve the therapeutic impact of brain-directed gene transfer.