Characterization of Adeno-Associated Virus Genomes Isolated from Human Tissues
Open accessAbstract
Infection with wild-type adeno-associated virus (AAV) is common in humans, but very little is known about the in vivo biology of AAV. On a molecular level, it has been shown in cultured cells that AAV integrates in a site-specific manner on human chromosome 19, but this has never been demonstrated directly in infected human tissues. To that end, we tested 175 tissue samples for the presence of AAV DNA, and when present, examined the specific form of the viral DNA. AAV was detected in 7 of 101 tonsil-adenoid samples and in 2 of 74 other tissue samples (spleen and lung). In these nine samples, we were unable to detect AAV integration in the AAVS1 locus using a sensitive PCR assay designed to amplify specific viral-cellular DNA junctions. Additionally, we used a second complementary assay, linear amplification-mediated-PCR (LAM-PCR) to widen our search for integration events. Analysis of individual LAM-PCR products revealed that the AAV genomes were arranged predominantly in a head-to-tail array, with deletions and extensive rearrangements in the inverted terminal repeat sequences. A single AAV-cellular junction was identified from a tonsil sample and it mapped to a highly repetitive satellite DNA element on chromosome 1. Given these data, we entertained the possibility that instead of integrated forms, AAV genomes were present as extrachromosomal forms. We used a novel amplification assay (linear rolling-circle amplification) to show that the majority of wild-type AAV DNA existed as circular double-stranded episomes in our tissues. Thus, following naturally acquired infection, AAV DNA can persist mainly as circular episomes in human tissues. These findings are consistent with the circular episomal forms of recombinant AAV vectors that have been isolated and characterized from in vivo transduced tissues.
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rAAV genomes persist episomally as mostly circular concatamers in postmitotic cells, leading to long-term transgene expression.
“it is generally believed that rAAV genomes persist episomally as mostly circular concatamers 16 in postmitotic cells, leading to long-term transgene expression.”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [16]
The Discussion (page unavailable) reports that naturally acquired wild-type AAV persists mainly as circular episomes in human tissues and says this is consistent with circular episomal forms of recombinant AAV vectors. It does not establish that recombinant genomes are mostly circular concatamers in postmitotic cells or that this form leads to long-term transgene expression. The concatameric forms described in the Results are products of rolling-circle amplification, not evidence that the persisting genomes have that structure. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAAV vectors with two complementary ITRs can form circular concatamers.
“AAV vectors with two complementary ITRs can form circular concatamers. 13-16”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [16]
The Discussion (page unavailable) says recombinant AAV derivatives can assume circular multimeric structures, supporting the circular-concatamer part of the claim. It also suggests that ITRs contribute to circle formation, but does not establish the specific condition of two complementary ITRs. The concatameric arrays described in the Results were linear products of rolling-circle amplification, not circular vector concatamers. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAAV genomes can concatamerize in incorrect orientation, which can be at least partly counteracted using heterologous ITRs.
“Unfortunately, subsequent studies highlighted the possibility for AAV genomes to concatamerize in the incorrect orientation [39], which could be at least partly counteracted using heterologous ITRs (derived from different AAV serotypes) [40].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [39]
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- Authors
- Schnepp, B. C., Jensen, R. L., Chen, C.-L., Johnson, P. R., & Clark, K. R.
- Affiliations
- Abigail Wexner Research Institute (US)
- Corresponding author
- Clark, K. Reed
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2005-12-15
- Volume
- 79
- Issue
- 23
- Pages
- 14793-14803
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC1287572
- OpenAlex
- W2148601484
- Cited by
- 231
- References
- 50
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 12 · 2023: 8 · 2022: 7 · 2021: 20 · 2020: 11 · 2019: 13 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 8 · 2013: 11 · 2012: 6
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (2-P01-AI56454)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › Parvovirus B19 Infection Studies
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Keywords
- adeno-associated virus, AAV integration, AAVS1 locus, inverted terminal repeats, satellite DNA, tonsil
- MeSH terms
- Dependovirus, Chromosomes, Human, Pair 1, DNA, Viral, HeLa Cells, Humans, Lung, Spleen, Palatine Tonsil, Polymerase Chain Reaction, Virus Integration, Terminal Repeat Sequences
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