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Journal of Virology, November 2006, p. 11393-11397, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01288-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Single Amino Acid Changes Can Influence Titer, Heparin Binding, and Tissue Tropism in Different Adeno-Associated Virus Serotypes{triangledown}

Zhijian Wu,1 Aravind Asokan,1 Joshua C. Grieger,1 Lakshmanan Govindasamy,2 Mavis Agbandje-McKenna,2 and R. Jude Samulski1*

Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,1 Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 326102

Received 19 June 2006/ Accepted 22 August 2006

Despite the high degree of sequence homology between adeno-associated virus (AAV) serotype 1 and 6 capsids (99.2%), these viruses have different liver transduction profiles when tested as vectors. Examination of the six amino acid residues that differ between AAV1 and AAV6 revealed that a lysine-to-glutamate change (K531E) suppresses the heparin binding ability of AAV6. In addition, the same mutation in AAV6 reduces transgene expression to levels similar to those achieved with AAV1 in HepG2 cells in vitro and in mouse liver following portal vein administration. In corollary, the converse E531K mutation in AAV1 imparts heparin binding ability and increases transduction efficiency. Extraction of vector genomes from liver tissue suggests that the lysine 531 residue assists in preferential transduction of parenchymal cells by AAV6 vectors in comparison with AAV1. Lysine 531 is unique to AAV6 among other known AAV serotypes and is located in a basic cluster near the spikes that surround the icosahedral threefold axes of the AAV capsid. Similar to studies with autonomous parvoviruses, this study describes the first example of single amino acid changes that can explain differential phenotypes such as viral titer, receptor binding, and tissue tropism exhibited by closely related AAV serotypes. In particular, a single lysine residue appears to provide the critical minimum charged surface required for interacting with heparin through electrostatic interaction and simultaneously plays an unrelated yet critical role in the liver tropism of AAV6 vectors.

* Corresponding author. Mailing address: CB #7352, Gene Therapy Center, 7113 Thurston Building, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7352. Phone: (919) 962-3285. Fax: (919) 966-0907. E-mail: rjs{at}med.unc.edu.

{triangledown} Published ahead of print on 30 August 2006.

Journal of Virology, November 2006, p. 11393-11397, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01288-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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