This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pajusola, K.
Right arrow Articles by Büeler, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pajusola, K.
Right arrow Articles by Büeler, H.

 Previous Article  |  Next Article 

Journal of Virology, November 2002, p. 11530-11540, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11530-11540.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cell-Type-Specific Characteristics Modulate the Transduction Efficiency of Adeno-Associated Virus Type 2 and Restrain Infection of Endothelial Cells

Katri Pajusola,1* Marcin Gruchala,2 Hana Joch,3 Thomas F. Lüscher,3 Seppo Ylä-Herttuala,2 and Hansruedi Büeler1

Institute of Molecular Biology, University of Zurich, 8057 Zurich,1 Department of Cardiology and Cardiovascular Research, University Hospital, 8091 Zürich, Switzerland,3 A. I. Virtanen Institute, University of Kuopio, 70210 Kuopio, Finland2

Received 14 June 2002/ Accepted 7 August 2002

Adeno-associated viruses (AAVs) are promising vectors for various gene therapy applications due to their long-lasting transgene expression and wide spectrum of target cells. Recently, however, it has become apparent that there are considerable differences in the efficiencies of transduction of different cell types by AAVs. Here, we analyzed the efficiencies of transduction and the transport mechanisms of AAV type 2 (AAV-2) in different cell types, emphasizing endothelial cells. Expression analyses in both cultured cells and the rabbit carotid artery assay showed a remarkably low level of endothelial cell transduction in comparison to the highly permissive cell types. The study of the endosomal pathways of AAV-2 with fluorescently labeled virus showed clear targeting of the Golgi area in permissive cell lines, but this phenomenon was absent in the endothelial cell line EAhy-926. On the other hand, the response to the block of endosomal acidification by bafilomycin A1 also showed differences among the permissive cell types. We also analyzed the effect of proteasome inhibitors on endothelial cells, but their impact on the primary cells and in vivo was not significant. On the contrary, analysis of the expression pattern of heparan sulfate proteoglycans (HSPGs), the primary receptors of AAV-2, revealed massive deposits of HSPG in the extracellular matrix of endothelial cells. The matrix-associated receptors may therefore compete for virus binding and reduce transduction in endothelial cells. Accordingly, in endothelial cells detached from their matrix, AAV-2 transduction was significantly increased. Altogether, these results point to a more complex cell-type-specific mode of transduction of AAV-2 than previously appreciated.

* Corresponding author. Mailing address: Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Phone: 41-1-635 3181. Fax. 41-1-635 6830. E-mail: pajusola{at}molbio.unizh.ch.

Journal of Virology, November 2002, p. 11530-11540, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11530-11540.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fu, Y.-Y., Sibley, E., Tang, S.-C. (2008). Transient cytochalasin-D treatment induces apically administered rAAV2 across tight junctions for transduction of enterocytes. J. Gen. Virol. 89: 3004-3008 [Abstract] [Full Text]  
  • Zhong, L., Li, B., Mah, C. S., Govindasamy, L., Agbandje-McKenna, M., Cooper, M., Herzog, R. W., Zolotukhin, I., Warrington, K. H. Jr., Weigel-Van Aken, K. A., Hobbs, J. A., Zolotukhin, S., Muzyczka, N., Srivastava, A. (2008). Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc. Natl. Acad. Sci. USA 105: 7827-7832 [Abstract] [Full Text]  
  • Sonntag, F., Bleker, S., Leuchs, B., Fischer, R., Kleinschmidt, J. A. (2006). Adeno-Associated Virus Type 2 Capsids with Externalized VP1/VP2 Trafficking Domains Are Generated prior to Passage through the Cytoplasm and Are Maintained until Uncoating Occurs in the Nucleus. J. Virol. 80: 11040-11054 [Abstract] [Full Text]  
  • Muller, O. J., Leuchs, B., Pleger, S. T., Grimm, D., Franz, W.-M., Katus, H. A., Kleinschmidt, J. A. (2006). Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors. Cardiovasc Res 70: 70-78 [Abstract] [Full Text]  
  • Mani, B., Baltzer, C., Valle, N., Almendral, J. M., Kempf, C., Ros, C. (2006). Low pH-Dependent Endosomal Processing of the Incoming Parvovirus Minute Virus of Mice Virion Leads to Externalization of the VP1 N-Terminal Sequence (N-VP1), N-VP2 Cleavage, and Uncoating of the Full-Length Genome. J. Virol. 80: 1015-1024 [Abstract] [Full Text]  
  • Sugano, E., Tomita, H., Ishiguro, S.-i., Abe, T., Tamai, M. (2005). Establishment of Effective Methods for Transducing Genes into Iris Pigment Epithelial Cells by Using Adeno-associated Virus Type 2. IOVS 46: 3341-3348 [Abstract] [Full Text]  
  • Baker, A. H., Kritz, A., Work, L. M., Nicklin, S. A. (2005). Cell-selective viral gene delivery vectors for the vasculature. Exp Physiol 90: 27-31 [Abstract] [Full Text]  
  • Melo, L. G., Gnecchi, M., Pachori, A. S., Kong, D., Wang, K., Liu, X., Pratt, R. E., Dzau, V. J. (2004). Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease. Arterioscler. Thromb. Vasc. Bio. 24: 1761-1774 [Abstract] [Full Text]  
  • White, S. J., Nicklin, S. A., Buning, H., Brosnan, M. J., Leike, K., Papadakis, E. D., Hallek, M., Baker, A. H. (2004). Targeted Gene Delivery to Vascular Tissue In Vivo by Tropism-Modified Adeno-Associated Virus Vectors. Circulation 109: 513-519 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»