Structural insight into the unique properties of adeno-associated virus serotype 9
Open accessAbstract
Adeno-associated virus serotype 9 (AAV9) has enhanced capsid-associated tropism for cardiac muscle and the ability to cross the blood-brain barrier compared to other AAV serotypes. To help identify the structural features facilitating these properties, we have used cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction (cryo-reconstruction) and X-ray crystallography to determine the structure of the AAV9 capsid at 9.7- and 2.8-Å resolutions, respectively. The AAV9 capsid exhibits the surface topology conserved in all AAVs: depressions at each icosahedral two-fold symmetry axis and surrounding each five-fold axis, three separate protrusions surrounding each three-fold axis, and a channel at each five-fold axis. The AAV9 viral protein (VP) has a conserved core structure, consisting of an eight-stranded, β-barrel motif and the αA helix, which are present in all parvovirus structures. The AAV9 VP differs in nine variable surface regions (VR-I to -IX) compared to AAV4, but at only three (VR-I, VR-II, and VR-IV) compared to AAV2 and AAV8. VR-I differences modify the raised region of the capsid surface between the two-fold and five-fold depressions. The VR-IV difference produces smaller three-fold protrusions in AAV9 that are less “pointed” than AAV2 and AAV8. Significantly, residues in the AAV9 VRs have been identified as important determinants of cellular tropism and transduction and dictate its antigenic diversity from AAV2. Hence, the AAV9 VRs likely confer the unique infection phenotypes of this serotype.
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No nucleotide was observed in the AAV2, AAV5, and AAV9 structures.
“Despite this conservation, no nucleotide was observed in the AAV2, AAV5, and AAV9 structures (DiMattia et al., 2012; Govindasamy et al., 2013; Guenther et al., 2019; Xie et al., 2002).”
From Structure comparison of the chimeric AAV2.7m8 vector with parental AAV2 (2020) · cites this paper as DiMattia et al., 2012
The Results and Discussion (pp. 6–7) describe the AAV9 structure and say that interior positive densities were not modeled, which is consistent with no nucleotide being identified in that structure. The paper does not establish the same observation for AAV2 or AAV5; its structural comparisons instead focus on AAV2, AAV4, and AAV8. (LLM, conf=0.72)
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AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects
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Structure-guided AAV capsid evolution strategies for enhanced CNS gene delivery
Gonzalez, T. J., Mitchell-Dick, A., Blondel, L. O., Fanous, M. M., Hull, J. A., Oh, D. K., Møller-Tank, S., Rivera, R. M. C., Piedrahita, J. A., & Asokan, A. (2023) · Nature Protocols · doi:10.1038/s41596-023-00875-y · Cited by 39 · see citing works
Fast Retrograde Access to Projection Neuron Circuits Underlying Vocal Learning in Songbirds
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Peptide ligands for the affinity purification of adeno‐associated viruses from HEK 293 cell lysates
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Self-citationArtificial Intelligence‐Based Approaches for AAV Vector Engineering
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Atomic structure of a rationally engineered gene delivery vector, AAV2. 5
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Biomaterial-Guided Gene Delivery for Musculoskeletal Tissue Repair
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- Authors
- DiMattia, M. A., Nam, H.-J., Van Vliet, K., Mitchell, M., Bennett, A., Gurda, B. L., McKenna, R., Olson, N. H., Sinkovits, R. S., Potter, M., Byrne, B. J., Aslanidi, G., Zolotukhin, S., Muzyczka, N., Baker, T. S., & Agbandje-McKenna, M.
- Affiliations
- University of Florida (US)
- Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
- University of California San Diego (US)
- University of Florida Health (US)
- ORCID
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2012-06-15
- Volume
- 86
- Issue
- 12
- Pages
- 6947-6958
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC3393551
- OpenAlex
- W2012799865
- Cited by
- 219
- References
- 91
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 17 · 2023: 16 · 2022: 26 · 2021: 23 · 2020: 18 · 2019: 16 · 2018: 15 · 2017: 6 · 2016: 11 · 2015: 9 · 2014: 12 · 2013: 11 · 2012: 4
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health (4r37gm033050-27)
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (P01HL059412, P01 HL 59412)
- National Institute of General Medical Sciences (R37GM-033050, R37 GM-33050, DMR-0225180, R01GM082946)
- Division of Materials Research
- National Center for Research Resources (RR-01646, S10RR020016, P41RR001646, P41RR001081)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › Parvovirus B19 Infection Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- AAV9, viral tropism, blood-brain barrier penetration, antigenic diversity, 3D reconstruction
- MeSH terms
- Dependovirus, Capsid, Crystallography, X-Ray, Cryoelectron Microscopy, Imaging, Three-Dimensional, Capsid Proteins
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