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Cited by 47Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Enhanced Transgene Expression from Recombinant Single-Stranded D-Sequence-Substituted Adeno-Associated Virus Vectors in Human Cell Lines In Vitro and in Murine Hepatocytes In Vivo

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Ling, Chen, Wang, Yuan, Lu, Yuan, Wang, Lina, Jayandharan, Giridhara R., Aslanidi, George V., Li, Baozheng, Cheng, Binbin +7 more·2015·Journal of Virology
DOI 10.1128/jvi.02581-14PMC PMC4300666
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Abstract

Unlabelled We have previously reported that the removal of a 20-nucleotide sequence, termed the D sequence, from both ends of the inverted terminal repeats (ITRs) in the adeno-associated virus serotype 2 (AAV2) genome significantly impairs rescue, replication, and encapsidation of the viral genomes (X. S. Wang, S. Ponnazhagan, and A. Srivastava, J Mol Biol 250:573-580, 1995; X. S. Wang, S. Ponnazhagan, and A. Srivastava, J Virol 70:1668-1677, 1996). Here we describe that replacement of only one D sequence in either ITR restores each of these functions, but DNA strands of only single polarity are encapsidated in mature progeny virions. Since most commonly used recombinant AAV vectors contain a single-stranded DNA (ssDNA), which is transcriptionally inactive, efficient transgene expression from AAV vectors is dependent upon viral second-strand DNA synthesis. We have also identified a transcription suppressor sequence in one of the D sequences, which shares homology with the binding site for the cellular NF-κB-repressing factor (NRF). The removal of this D sequence from, and replacement with a sequence containing putative binding sites for transcription factors in, single-stranded AAV (ssAAV) vectors significantly augments transgene expression both in human cell lines in vitro and in murine hepatocytes in vivo. The development of these genome-modified ssAAV vectors has implications not only for the basic biology of AAV but also for the optimal use of these vectors in human gene…

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  • By replacing the D-sequence in one of the flanking ITRs with an unrelated sequence, packaging of genomes with only positive or negative polarity can be achieved.

    “By replacing the D-sequence in one of the flanking ITRs with an unrelated sequence, the packaging of genomes with only positive or negative polarity can be achieved [49].”

    From Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses (2017) · cites this paper as [49]

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Authors
Ling, C., Wang, Y., Lu, Y., Wang, L., Jayandharan, G. R., Aslanidi, G. V., Li, B., Cheng, B., Ma, W., Lentz, T., Ling, C., Xiao, X., Samulski, R. J., Muzyczka, N., & Srivastava, A.
Affiliations
  • Second Military Medical University (CN)
  • University of Florida Health (US)
  • Christian Medical College, Vellore (IN)
  • University of North Carolina at Chapel Hill (US)
ORCID
Venue
Journal of Virology
Publisher
American Society for Microbiology
Published
2015-01-15
Volume
89
Issue
2
Pages
952-961
ISSN
  • 0022-538X (ISSN-L)
  • 1098-5514
DOI
10.1128/jvi.02581-14
PMC
PMC4300666
OpenAlex
W1978052389
Cited by
47
References
7
Citations by year
2026: 3 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 6
FWCI
2.84
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Journal of Virology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • Alex's Lemonade Stand Foundation for Childhood Cancer
  • University of Florida (UL1TR000064)
  • National Natural Science Foundation of China (30730114)
  • Government of Jiangxi Province
  • National Institutes of Health (UL1TR000064, TR000064)
  • National Heart, Lung, and Blood Institute (R01HL097088)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058327)
  • National Institute of Biomedical Imaging and Bioengineering (R21EB015684)
  • National Center for Advancing Translational Sciences (TR000064)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
adeno-associated virus, AAV2, inverted terminal repeats, d-sequences, single-stranded DNA, transgene expression, transcriptional repression, transcription factor binding sites, viral encapsidation, viral replication, gene therapy vectors
MeSH terms
Dependovirus, Animals, Cell Line, Genetic Vectors, Humans, Male, Mice, Inbred C57BL, Genetic Therapy, Gene Expression, Sequence Deletion, Virus Assembly, Transgenes, Hepatocytes

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