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Updated: May 19, 2026
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Production, Purification, and Quality Control for Adeno-associated Virus-based Vectors
Published on: January 29, 2019
AAV2 Crosslinks Actin Filaments: Implications for AAV Gene Therapy Vector Design
Mitchell Gulkis1, James B Heidings2, Juha T Huiskonen3
1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
Biorxiv : the Preprint Server for Biology
|May 18, 2026
Summary
Adeno-associated virus 2 (AAV2) directly interacts with actin filaments, bundling them into a hexagonal lattice. This interaction may trap viral capsids, impacting gene therapy efficiency and offering new engineering targets.
Area of Science:
- Molecular Biology
- Virology
- Biophysics
Background:
- Adeno-associated virus (AAV) capsids are crucial gene therapy vectors for monogenetic disorders.
- Clinical success is limited by low transduction efficiencies, necessitating high doses and leading to immune responses.
- Understanding AAV capsid nuclear trafficking post-endocytosis is a key knowledge gap.
Purpose of the Study:
- To investigate the mechanism of Adeno-associated virus 2 (AAV2) nuclear trafficking after cell entry.
- To identify direct interactions between AAV2 capsids and host cell components.
- To explore the implications of these interactions for AAV-based gene therapy.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) to determine the structure of AAV2-actin filament complexes.
- Biochemical assays to identify specific interaction interfaces between AAV2 and actin.
- Protein engineering to create AAV2 capsid variants with altered actin-binding properties.
Main Results:
- A direct interaction between AAV2 capsids and actin filaments was identified.
- AAV2 was shown to bundle actin filaments into a periodic hexagonal lattice.
- Cryo-EM revealed the structural basis of the AAV2-actin interaction.
- Engineered AAV2 variants lacking actin bundling capability were generated.
Conclusions:
- AAV2 may represent a new class of actin-binding proteins, termed actin bundling viruses (ABVs).
- The AAV2-actin interaction could be responsible for capsid trapping and peri-nuclear accumulation.
- This finding enhances understanding of AAV2 biology and opens avenues for capsid engineering to improve gene therapy vectors.
