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Journal of Virology, August 2008, p. 7875-7885, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00649-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Adeno-Associated Virus Vector Genomes Persist as Episomal Chromatin in Primate Muscle{triangledown}

Magalie Penaud-Budloo,1,{dagger} Caroline Le Guiner,1,{dagger} Ali Nowrouzi,2 Alice Toromanoff,1 Yan Chérel,3 Pierre Chenuaud,1 Manfred Schmidt,2 Christof von Kalle,2 Fabienne Rolling,1 Philippe Moullier,1,4,5 and Richard O. Snyder1,5,6*

INSERM UMR 649, CHU Hôtel Dieu, 44035 Nantes, France,1 National Center for Tumor Diseases Heidelberg, Department of Translational Oncology, German Cancer Research Center, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany,2 INRA UMR 703, Ecole Nationale Vétérinaire, 44000 Nantes, France,3 Etablissement Français du Sang Pays de la Loire, 44000 Nantes, France,4 Department of Molecular Genetics and Microbiology, College of Medicine,5 Center of Excellence for Regenerative Health Biotechnology, University of Florida, Gainesville, Florida 326106

Received 23 March 2008/ Accepted 21 May 2008

Recombinant adeno-associated virus (rAAV) vectors are capable of mediating long-term gene expression following administration to skeletal muscle. In rodent muscle, the vector genomes persist in the nucleus in concatemeric episomal forms. Here, we demonstrate with nonhuman primates that rAAV vectors integrate inefficiently into the chromosomes of myocytes and reside predominantly as episomal monomeric and concatemeric circles. The episomal rAAV genomes assimilate into chromatin with a typical nucleosomal pattern. The persistence of the vector genomes and gene expression for years in quiescent tissues suggests that a bona fide chromatin structure is important for episomal maintenance and transgene expression. These findings were obtained from primate muscles transduced with rAAV1 and rAAV8 vectors for up to 22 months after intramuscular delivery of 5 x 1012 viral genomes/kg. Because of this unique context, our data, which provide important insight into in situ vector biology, are highly relevant from a clinical standpoint.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 1600 SW Archer Road, Gainesville, FL 32610-0266. Phone: (386) 418-1642. Fax: (352) 392-4290. E-mail: rsnyder{at}cerhb.ufl.edu

{triangledown} Published ahead of print on 4 June 2008.

{dagger} These authors contributed equally.

Journal of Virology, August 2008, p. 7875-7885, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00649-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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