Intracellular transport of recombinant adeno-associated virus vectors
Open accessAbstract
Recombinant adeno-associated viral vectors (rAAVs) have been widely used for gene delivery in animal models, and are currently evaluated for human gene therapy after successful clinical trials in the treatment of inherited, degenerative or acquired diseases, such as Leber congenital amaurosis, Parkinson disease or heart failure. However, limitations in vector tropism, such as limited tissue specificity and insufficient transduction efficiencies of particular tissues and cell types, still preclude therapeutic applications in certain tissues. Wild-type adeno-associated viruses (AAVs) are defective viruses that require the presence of a helper virus to complete their life cycle. On the one hand, this unique property makes AAV vectors one of the safest available viral vectors for gene delivery. On the other, it also represents a potential obstacle because rAAV vectors have to overcome several biological barriers in the absence of a helper virus to transduce successfully a cell. Consequently, a better understanding of the cellular roadblocks that limit rAAV gene delivery is crucial and, during the last 15 years, numerous studies resulted in an expanding body of knowledge of the intracellular trafficking pathways of rAAV vectors. This review describes our current understanding of the mechanisms involved in rAAV attachment to target cells, endocytosis, intracellular trafficking, capsid processing, nuclear import and genome release with an emphasis on the most recent discoveries in the field and the emerging strategies used to improve the efficiency of AAV-derived vectors.
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After cellular uptake into endosomes, AAV escapes from the endosome/lysosome and traffics to the perinuclear compartment.
“After cellular uptake into endosomes, AAV subsequently escapes from the endosome/lysosome and traffics to the perinuclear compartment.20”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [20]
The AAV ENDOCYTOSIS and POST-ENDOCYTIC TRAFFICKING sections support uptake by endocytosis, subsequent escape into the cytoplasm, and accumulation of many particles in a perinuclear compartment. They do not establish the claimed order of escape *before* trafficking to that compartment; the latter section says AAV2 and AAV5 appear to accumulate in the Golgi before release into the cytoplasm. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese latter processes involve VP1- and VP2-specific portions of the capsid that contain acidification-responsive phospholipase domains and the nuclear localization signal.
“These latter processes involve VP1- and VP2-specific portions of the capsid that contain acidification-responsive phospholipase domains and the nuclear localization signal.20”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [20]
The Post-Endocytic Trafficking section identifies a phospholipase A2 domain in VP1 and describes exposure of the VP1 and VP2 N-termini during endosomal processing. The Nuclear Import section identifies nuclear-localization signals shared by VP1 and VP2. However, the paper does not place phospholipase domains in both proteins or describe those domains as acidification-responsive; it says acidic pH alone does not expose the VP1/VP2 N-termini. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe virus capsid protects the viral genome, determines tissue tropism, and remains intact while it escapes the endo/lysosomal pathway and traffics to the nucleus where the genome is released.
“The virus capsid is a critical component of its infectious lifecycle: it protects the viral genome, determines the tissue type that is targeted (tissue tropism) or treated, and remains intact while it escapes the endo/lysosomal pathway and traffics to the nucleus where the genome is released [9]”
From Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses (2017) · cites this paper as [9]
The Introduction (page unavailable) links AAV serotypes to different tissue tropisms, and Cellular Barriers to AAV Transduction and Nuclear Import (pages unavailable) describe escape followed by probable import of intact particles and DNA release after nuclear entry. The paper says the capsid contains the genome, but does not explicitly say it protects it; it also presents intact-particle nuclear import as likely rather than certain. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUpon nuclear entry, the AAV virion uncoats, followed by AAV genome second-strand synthesis and, finally, transgene expression.
“Upon nuclear entry, the AAV virion uncoats, followed by AAV genome second-strand synthesis and, finally, transgene expression.20”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [20]
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References 166 · Cited by 258
Research works printed but not linked: 2
- [9]Kerr JR Arnold Hodder Parvoviruses 2006 Distributed in the United States of America by Oxford University Press London New York
- [78]Stahnke S Lux K Uhrig S Kreppel F Hosel M Coutelle O Intrinsic phospholipase A2 activity of adeno-associated virus is involved in endosomal escape of incoming particles. Virology 2011 409 1 77 83 20974479
- Authors
- Nonnenmacher, M., & Weber, T.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Weber, T
- Venue
- Gene Therapy
- Published
- 2012-02-23
- Volume
- 19
- Issue
- 6
- Pages
- 649-658
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4465241
- OpenAlex
- W1988513056
- Cited by
- 258
- References
- 166
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 14 · 2023: 12 · 2022: 16 · 2021: 18 · 2020: 24 · 2019: 27 · 2018: 19 · 2017: 21 · 2016: 16 · 2015: 21 · 2014: 16 · 2013: 14 · 2012: 10
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P20HL100396, HL077322, HL100396, R01HL077322, HL-088434, R01HL088434)
- 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
- recombinant adeno-associated virus vectors, intracellular trafficking, gene delivery, vector tropism, endocytosis, nuclear import, genome release, gene therapy vectors
- MeSH terms
- Dependovirus, Biological Transport, Endocytosis, Genetic Vectors, Humans, Recombination, Genetic, Transduction, Genetic, Genetic Therapy, Gene Transfer Techniques, Tropism, Virus Attachment
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