Structure of the Gene Therapy Vector, Adeno-associated Virus with Its Cell Receptor, AAVR

Overview

Journal Elife

Specialty Biology

Date 2019 May 23

PMID 31115336

Citations 50

Authors

Nancy L Meyer

Guiqing Hu

Omar Davulcu

Qing Xie

Alex J Noble

Craig Yoshioka

Drew S Gingerich

Andrew Trzynka

Larry David

Scott M Stagg

Michael Stewart Chapman

Affiliations

Soon will be listed here.

Abstract

Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. -electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. -electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 Å resolution. AAVR binds between AAV's spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR's footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.

Citing Articles

Development of an adipose-tropic AAV capsid ablating liver tropism.

Huang W, Bates R, Appana B, Mohammed T, Cao L iScience. 2024; 27(10):110930.

PMID: 39398244 PMC: 11467673. DOI: 10.1016/j.isci.2024.110930.

Coarse-Grained Simulations of Adeno-Associated Virus and Its Receptor Reveal Influences on Membrane Lipid Organization and Curvature.

Pipatpadungsin N, Chao K, Rouse S J Phys Chem B. 2024; 128(41):10139-10153.

PMID: 39356546 PMC: 11492248. DOI: 10.1021/acs.jpcb.4c03087.

Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder.

Shay T, Jang S, Brittain T, Chen X, Walker B, Tebbutt C Nat Commun. 2024; 15(1):7853.

PMID: 39245720 PMC: 11381518. DOI: 10.1038/s41467-024-52149-0.

Therapeutic Application and Structural Features of Adeno-Associated Virus Vector.

Matsuzaka Y, Yashiro R Curr Issues Mol Biol. 2024; 46(8):8464-8498.

PMID: 39194716 PMC: 11353222. DOI: 10.3390/cimb46080499.

Natural Adeno-Associated Virus Serotypes and Engineered Adeno-Associated Virus Capsid Variants: Tropism Differences and Mechanistic Insights.

Lopez-Gordo E, Chamberlain K, Riyad J, Kohlbrenner E, Weber T Viruses. 2024; 16(3).

PMID: 38543807 PMC: 10975205. DOI: 10.3390/v16030442.

References

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

Shen S, Troupes A, Pulicherla N, Asokan A . Multiple roles for sialylated glycans in determining the cardiopulmonary tropism of adeno-associated virus 4. J Virol. 2013; 87(24):13206-13. PMC: 3838263. DOI: 10.1128/JVI.02109-13. View

Russell S, Bennett J, Wellman J, Chung D, Yu Z, Tillman A . Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097):849-860. PMC: 5726391. DOI: 10.1016/S0140-6736(17)31868-8. View

Wobus C, Girod A, Petersen G, Hallek M, Kleinschmidt J . Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection. J Virol. 2000; 74(19):9281-93. PMC: 102127. DOI: 10.1128/jvi.74.19.9281-9293.2000. View

Chapman M, Trzynka A, Chapman B . Atomic modeling of cryo-electron microscopy reconstructions--joint refinement of model and imaging parameters. J Struct Biol. 2013; 182(1):10-21. PMC: 3662558. DOI: 10.1016/j.jsb.2013.01.003. View

Xie Q, Spilman M, Meyer N, Lerch T, Stagg S, Chapman M . Electron microscopy analysis of a disaccharide analog complex reveals receptor interactions of adeno-associated virus. J Struct Biol. 2013; 184(2):129-35. PMC: 3866096. DOI: 10.1016/j.jsb.2013.09.004. View

Xie Q, Spear J, Noble A, Sousa D, Meyer N, Davulcu O . The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide. Mol Ther Methods Clin Dev. 2017; 5:1-12. PMC: 5415311. DOI: 10.1016/j.omtm.2017.02.004. View

Meyer N, Hu G, Davulcu O, Xie Q, Noble A, Yoshioka C . Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR. Elife. 2019; 8. PMC: 6561701. DOI: 10.7554/eLife.44707. View

Ilca S, Kotecha A, Sun X, Poranen M, Stuart D, Huiskonen J . Localized reconstruction of subunits from electron cryomicroscopy images of macromolecular complexes. Nat Commun. 2015; 6:8843. PMC: 4667630. DOI: 10.1038/ncomms9843. View

10.

Gurda B, Raupp C, Popa-Wagner R, Naumer M, Olson N, Ng R . Mapping a neutralizing epitope onto the capsid of adeno-associated virus serotype 8. J Virol. 2012; 86(15):7739-51. PMC: 3421660. DOI: 10.1128/JVI.00218-12. View

11.

Calcedo R, Vandenberghe L, Gao G, Lin J, Wilson J . Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009; 199(3):381-90. PMC: 10826927. DOI: 10.1086/595830. View

12.

Pillay S, Meyer N, Puschnik A, Davulcu O, Diep J, Ishikawa Y . An essential receptor for adeno-associated virus infection. Nature. 2016; 530(7588):108-12. PMC: 4962915. DOI: 10.1038/nature16465. View

13.

Horowitz E, Rahman K, Bower B, Dismuke D, Falvo M, Griffith J . Biophysical and ultrastructural characterization of adeno-associated virus capsid uncoating and genome release. J Virol. 2012; 87(6):2994-3002. PMC: 3592113. DOI: 10.1128/JVI.03017-12. View

14.

Lander G, Stagg S, Voss N, Cheng A, Fellmann D, Pulokas J . Appion: an integrated, database-driven pipeline to facilitate EM image processing. J Struct Biol. 2009; 166(1):95-102. PMC: 2775544. DOI: 10.1016/j.jsb.2009.01.002. View

15.

Mikals K, Nam H, Van Vliet K, Vandenberghe L, Mays L, McKenna R . The structure of AAVrh32.33, a novel gene delivery vector. J Struct Biol. 2014; 186(2):308-17. PMC: 4085184. DOI: 10.1016/j.jsb.2014.03.020. View

16.

Gotze M, Pettelkau J, Schaks S, Bosse K, Ihling C, Krauth F . StavroX--a software for analyzing crosslinked products in protein interaction studies. J Am Soc Mass Spectrom. 2011; 23(1):76-87. DOI: 10.1007/s13361-011-0261-2. View

17.

Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus M . Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 2010; 21(6):704-12. DOI: 10.1089/hum.2009.182. View

18.

Chen J, Sachse C, Xu C, Mielke T, Spahn C, Grigorieff N . A dose-rate effect in single-particle electron microscopy. J Struct Biol. 2007; 161(1):92-100. PMC: 2213720. DOI: 10.1016/j.jsb.2007.09.017. View

19.

Zhang K . Gctf: Real-time CTF determination and correction. J Struct Biol. 2015; 193(1):1-12. PMC: 4711343. DOI: 10.1016/j.jsb.2015.11.003. View

20.

Bell C, Gurda B, Van Vliet K, Agbandje-Mckenna M, Wilson J . Identification of the galactose binding domain of the adeno-associated virus serotype 9 capsid. J Virol. 2012; 86(13):7326-33. PMC: 3416318. DOI: 10.1128/JVI.00448-12. View