A Large U3 Deletion Causes Increased In Vivo Expression from a Nonintegrating Lentiviral Vector
Open accessAbstract
The feasibility of using nonintegrating lentiviral vectors has been demonstrated by recent studies showing their ability to maintain transgene expression both in vitro and in vivo. Furthermore, human immunodeficiency virus-1 (HIV-1) vectors packaged with a mutated integrase were able to correct retinal disease in a mouse model. Interestingly, these results differ from earlier studies in which first-generation nonintegrating lentiviral vectors yielded insignificant levels of transduction. However, to date, a rigorous characterization of transgene expression from the currently used self-inactivating (SIN) nonintegrating lentiviral vectors has not been published. In this study, we characterize transgene expression from SIN nonintegrating lentiviral vectors. Overall, we found that nonintegrating vectors express transgenes at a significantly lower level than their integrating counterparts. Expression from nonintegrating vectors was improved upon introducing a longer deletion in the vector's U3 region. A unique shuttle-vector assay indicated that the relative abundance of the different episomal forms was not altered by the longer U3 deletion. Interestingly, the longer U3 deletion did not enhance expression in the corpus callosum of the rat brain, suggesting that the extent of silencing of episomal transcription is influenced by tissue-specific factors. Finally, and for the first time, episomal expression in the mouse liver was potent and sustained.
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Removing cis-acting genes can reduce the use of inhibitors to episomal transgene expression, although this is still insignificant and requires further studies.
“On the other hand, one can also reduce the use of inhibitors to episomal transgene expression, by removing cis-acting genes, although this is still insignificant [73] and requires further studies.”
From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [73]
The Introduction and Results report that deleting more of the U3 region improved episomal transgene expression, and the Discussion calls for further characterization. But the paper describes the improvement as significant, not insignificant; it says expression from nonintegrating vectors remained lower than from integrating vectors. The deleted material is a cis-acting region or sequence, not a gene. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNILVs encoding for in vivo expression of GFP have been reported in organs such as the brain, liver, and spinal cord via stable gene transfer for up to months.
“NILVs encoding for in vivo expression of GFP have been reported in organs such as the brain, liver, and spinal cord via stable gene transfer for longer periods (up to months) in several studies [22,73,131,132,133,134].”
From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [73]
The Results (page not provided) report GFP expression from nonintegrating vectors in rat brain tissue three months after infusion. They also report largely stable expression in mouse liver for six months, but the liver transgene was luciferase, not GFP. The paper does not report spinal-cord expression. (LLM, conf=0.88)
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References 51 · Cited by 94
- Authors
- Bayer, M., Kantor, B., Cockrell, A., Ma, H., Zeithaml, B., Li, X., McCown, T., & Kafri, T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Kafri, Tal
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 16
- Issue
- 12
- Pages
- 1968-1976
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2587457
- OpenAlex
- W2033627909
- Cited by
- 94
- References
- 51
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 10
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (183-H12-5C, 5r01dk058702-17, DK065988, 5-PO1-HL066973-05, 2-R01-DK058702-06)
- Center for AIDS Research, University of Washington
- National Heart, Lung, and Blood Institute (R21HL086406, 5-R21-HL086406, P01HL066973, 5-P01-HL066973-05)
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK058702, 2-R01-DK058702-06, P30DK065988)
- Center for AIDS Research, University of North Carolina at Chapel Hill
- 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 › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- self-inactivating vectors, transgene expression, HIV-1 integrase, tissue-specific gene expression, hepatic gene expression, corpus callosum, gene therapy vectors
- MeSH terms
- Animals, Brain, Cell Line, Genetic Vectors, Humans, Liver, Male, Plasmids, Gene Expression, Lentivirus, Genome, Viral, Gene Deletion, Mice, Rats
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