DOI: 10.1128/jvi.01304-07. Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector

Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector

10.1128/jvi.01304-07

Crossref journal-article

American Society for Microbiology

Journal of Virology (235)

Abstract

ABSTRACT Adeno-associated viruses (AAVs) are being developed as gene therapy vectors, and their efficacy could be improved by a detailed understanding of their viral capsid structures. AAV serotype 8 (AAV8) shows a significantly greater liver transduction efficiency than those of other serotypes, which has resulted in efforts to develop this virus as a gene therapy vector for hemophilia A and familial hypercholesterolemia. Pseudotyping studies show that the differential tissue tropism and transduction efficiencies exhibited by the AAVs result from differences in their capsid viral protein (VP) amino acids. Towards identifying the structural features underpinning these disparities, we report the crystal structure of the AAV8 viral capsid determined to 2.6-Å resolution. The overall topology of its common overlapping VP is similar to that previously reported for the crystal structures of AAV2 and AAV4, with an eight-stranded β-barrel and long loops between the β-strands. The most significant structural differences between AAV8 and AAV2 (the best-characterized serotype) are located on the capsid surface at protrusions surrounding the two-, three-, and fivefold axes at residues reported to control transduction efficiency and antibody recognition for AAV2. In addition, a comparison of the AAV8 and AAV2 capsid surface amino acids showed a reduced distribution of basic charge for AAV8 at the mapped AAV2 heparin sulfate receptor binding region, consistent with an observed non-heparin-binding phenotype for AAV8. Thus, this AAV8 structure provides an additional platform for mutagenesis efforts to characterize AAV capsid regions responsible for differential cellular tropism, transduction, and antigenicity for these promising gene therapy vectors.

Bibliography

Nam, H.-J., Lane, M. D., Padron, E., Gurda, B., McKenna, R., Kohlbrenner, E., Aslanidi, G., Byrne, B., Muzyczka, N., Zolotukhin, S., & Agbandje-McKenna, M. (2007). Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector. Journal of Virology, 81(22), 12260â12271.

Authors 11

Hyun-Joo Nam (first)
Michael Douglas Lane (additional)
Eric Padron (additional)
Brittney Gurda (additional)
Robert McKenna (additional)
Erik Kohlbrenner (additional)
George Aslanidi (additional)
Barry Byrne (additional)
Nicholas Muzyczka (additional)
Sergei Zolotukhin (additional)
Mavis Agbandje-McKenna (additional)

References 62 Referenced 202

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Dates

Type	When
Created	18 years ago (Aug. 29, 2007, 8:59 p.m.)
Deposited	3 years, 5 months ago (March 5, 2022, 6:22 a.m.)
Indexed	1 week, 1 day ago (Aug. 23, 2025, 9:50 p.m.)
Issued	17 years, 9 months ago (Nov. 15, 2007)
Published	17 years, 9 months ago (Nov. 15, 2007)
Published Print	17 years, 9 months ago (Nov. 15, 2007)

Funders 0

None

BibTeX

@article{Nam_2007, title={Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector}, volume={81}, ISSN={1098-5514}, url={http://dx.doi.org/10.1128/jvi.01304-07}, DOI={10.1128/jvi.01304-07}, number={22}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Nam, Hyun-Joo and Lane, Michael Douglas and Padron, Eric and Gurda, Brittney and McKenna, Robert and Kohlbrenner, Erik and Aslanidi, George and Byrne, Barry and Muzyczka, Nicholas and Zolotukhin, Sergei and Agbandje-McKenna, Mavis}, year={2007}, month=nov, pages={12260–12271} }

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