Adeno-associated virus capsid assembly is divergent and stochastic

Tobias P. Wörner, Antonette Bennett, Sana Habka, Joost Snijder, Olga Friese, Thomas Powers, Mavis Agbandje-McKenna and Albert J. R. Heck ()
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Tobias P. Wörner: University of Utrecht
Antonette Bennett: Department of Biochemistry and Molecular Biology, Center for Structural Biology, the McKnight Brain Institute
Sana Habka: University of Utrecht
Joost Snijder: University of Utrecht
Olga Friese: Biotherapeutics Pharmaceutical Sciences, Pfizer WRDM
Thomas Powers: Biotherapeutics Pharmaceutical Sciences, Pfizer WRDM
Mavis Agbandje-McKenna: Department of Biochemistry and Molecular Biology, Center for Structural Biology, the McKnight Brain Institute
Albert J. R. Heck: University of Utrecht

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Adeno-associated viruses (AAVs) are increasingly used as gene therapy vectors. AAVs package their genome in a non-enveloped T = 1 icosahedral capsid of ~3.8 megaDalton, consisting of 60 subunits of 3 distinct viral proteins (VPs), which vary only in their N-terminus. While all three VPs play a role in cell-entry and transduction, their precise stoichiometry and structural organization in the capsid has remained elusive. Here we investigate the composition of several AAV serotypes by high-resolution native mass spectrometry. Our data reveal that the capsids assemble stochastically, leading to a highly heterogeneous population of capsids of variable composition, whereby even the single-most abundant VP stoichiometry represents only a small percentage of the total AAV population. We estimate that virtually every AAV capsid in a particular preparation has a unique composition. The systematic scoring of the simulations against experimental native MS data offers a sensitive new method to characterize these therapeutically important heterogeneous capsids.

Date: 2021
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DOI: 10.1038/s41467-021-21935-5

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