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Journal of Virology, December 2009, p. 12512-12525, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01754-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Transcriptional Analysis of the Adeno-Associated Virus Integration Site{triangledown}

Nathalie Dutheil,1 Els Henckaerts,1 Erik Kohlbrenner,2 and R. Michael Linden1,2*

Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom,1 Department of Gene and Cell Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 100292

Received 20 August 2009/ Accepted 11 September 2009

The nonpathogenic human adeno-associated virus type 2 (AAV-2) has adopted a unique mechanism to site-specifically integrate its genome into the human MBS85 gene, which is embedded in AAVS1 on chromosome 19. The fact that AAV has evolved to integrate into this ubiquitously transcribed region and that the chromosomal motifs required for integration are located a few nucleotides upstream of the translation initiation start codon of MBS85 suggests that the transcriptional activity of MBS85 might influence site-specific integration and thus might be involved in the evolution of this mechanism. In order to begin addressing this question, we initiated the characterization of the human MBS85 promoter region and compared its transcriptional activity to that of the AAV-2 p5 promoter. Our results clearly indicate that AAVS1 is defined by a complex transcriptional environment and that the MBS85 promoter shares key regulatory elements with the viral p5 promoter. Furthermore, we provide evidence for bidirectional MBS85 promoter activity and demonstrate that the minimal motifs required for AAV site-specific integration are present in the 5' untranslated region of the gene and play a posttranscriptional role in the regulation of MBS85 expression. These findings should provide a framework to further elucidate the complex interactions between the virus and its cellular host in this unique pathway to latency.

* Corresponding author. Mailing address: Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom. Phone: 44 (0) 20 7188 1183. Fax: 44 (0) 20 7188 3385. E-mail: michael.linden{at}kcl.ac.uk

{triangledown} Published ahead of print on 16 September 2009.

Journal of Virology, December 2009, p. 12512-12525, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01754-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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