ArticleJournal of virology2014
Adeno-associated virus type 2 wild-type and vector-mediated genomic integration profiles of human diploid fibroblasts analyzed by third-generation PacBio DNA sequencing.
Article in Journal of virology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Future-use consent and human virome research: ethical challenges.Journal of virology · 2026Review
- Adeno-Associated Virus Gene Therapy: Is There a Risk of Insertional Mutagenesis?Toxicologic pathology · 2026Review
- RAAVioli: A comprehensive approach to characterizing AAV vector integrations and rearrangements.Molecular therapy. Advances · 2026Article
- Gene regulation technologies for gene and cell therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration.Nature biotechnology · 2024Article
- Comparing molecular and computational approaches for detecting viral integration of AAV gene therapy constructs.Molecular therapy. Methods & clinical development · 2023Article
- AAV- based vector improvements unrelated to capsid protein modification.Frontiers in medicine · 2023Review
- Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- The adeno-associated virus 2 genome and Rep 68/78 proteins interact with cellular sites of DNA damage.Human molecular genetics · 2022Article
- AAV-mediated gene therapy: Advancing cardiovascular disease treatment.Frontiers in cardiovascular medicine · 2022Review
- Nanopore sequencing of native adeno-associated virus (AAV) single-stranded DNA using a transposase-based rapid protocol.NAR genomics and bioinformatics · 2020Article
- Molecular characterization of precise in vivo targeted gene integration in human cells using AAVHSC15.PloS one · 2020Article
- Gene Therapy for Hemophilia: Facts and Quandaries in the 21st Century.Mediterranean journal of hematology and infectious diseases · 2020Review
- Article
- Adeno-associated virus Rep proteins antagonize phosphatase PP1 to counteract KAP1 repression of the latent viral genome.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Exchange of functional domains between a bacterial conjugative relaxase and the integrase of the human adeno-associated virus.PloS one · 2018Article
- Article
- High Prevalence of Infectious Adeno-associated Virus (AAV) in Human Peripheral Blood Mononuclear Cells Indicative of T Lymphocytes as Sites of AAV Persistence.Journal of virology · 2017Article
- Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Reply to "Wild-type AAV Insertions in Hepatocellular Carcinoma Do Not Inform Debate Over Genotoxicity Risk of Vectorized AAV".Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
unlabelledGenome-wide analysis of adeno-associated virus (AAV) type 2 integration in HeLa cells has shown that wild-type AAV integrates at numerous genomic sites, including AAVS1 on chromosome 19q13.42. Multiple GAGY/C repeats, resembling consensus AAV Rep-binding sites are preferred, whereas rep-deficient AAV vectors (rAAV) regularly show a random integration profile. This study is the first study to analyze wild-type AAV integration in diploid human fibroblasts. Applying high-throughput third-generation PacBio-based DNA sequencing, integration profiles of wild-type AAV and rAAV are compared side by side. Bioinformatic analysis reveals that both wild-type AAV and rAAV prefer open chromatin regions. Although genomic features of AAV integration largely reproduce previous findings, the pattern of integration hot spots differs from that described in HeLa cells before. DNase-Seq data for human fibroblasts and for HeLa cells reveal variant chromatin accessibility at preferred AAV integration hot spots that correlates with variant hot spot preferences. DNase-Seq patterns of these sites in human tissues, including liver, muscle, heart, brain, skin, and embryonic stem cells further underline variant chromatin accessibility. In summary, AAV integration is dependent on cell-type-specific, variant chromatin accessibility leading to random integration profiles for rAAV, whereas wild-type AAV integration sites cluster near GAGY/C repeats. IMPORTANCE: Adeno-associated virus type 2 (AAV) is assumed to establish latency by chromosomal integration of its DNA. This is the first genome-wide analysis of wild-type AAV2 integration in diploid human cells and the first to compare wild-type to recombinant AAV vector integration side by side under identical experimental conditions. Major determinants of wild-type AAV integration represent open chromatin regions with accessible consensus AAV Rep-binding sites. The variant chromatin accessibility of different human tissues or cell types will have impact on vector targeting to be considered during gene therapy.
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