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 Asokan, A.
Right arrow Articles by Samulski, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Asokan, A.
Right arrow Articles by Samulski, R. J.

 Previous Article  |  Next Article 

Journal of Virology, September 2006, p. 8961-8969, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00843-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Adeno-Associated Virus Type 2 Contains an Integrin {alpha}5ß1 Binding Domain Essential for Viral Cell Entry

Aravind Asokan,1 Julie B. Hamra,1 Lakshmanan Govindasamy,2 Mavis Agbandje-McKenna,2 and Richard J. Samulski1*

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

Received 24 April 2006/ Accepted 7 June 2006

Integrins have been implicated as coreceptors in the infectious pathways of several nonenveloped viruses. For example, adenoviruses are known to interact with {alpha}V integrins by virtue of a high-affinity arginine-glycine-aspartate (RGD) domain present in the penton bases of the capsids. In the case of adeno-associated virus type 2 (AAV2), which lacks this RGD motif, integrin {alpha}Vß5 has been identified as a coreceptor for cellular entry. However, the molecular determinants of AAV2 capsid-integrin interactions and the potential exploitation of alternative integrins as coreceptors by AAV2 have not been established thus far. In this report, we demonstrate that integrin {alpha}5ß1 serves as an alternative coreceptor for AAV2 infection in human embryonic kidney 293 cells. Such interactions appear to be mediated by a highly conserved domain that contains an asparagine-glycine-arginine (NGR) motif known to bind {alpha}5ß1 integrin with moderate affinity. The mutation of this domain reduces transduction efficiency by an order of magnitude relative to that of wild-type AAV2 vectors in vitro and in vivo. Further characterization of mutant and wild-type AAV2 capsids through transduction assays in cell lines lacking specific integrins, cell adhesion studies, and cell surface/solid-phase binding assays confirmed the role of the NGR domain in promoting AAV2-integrin interactions. Molecular modeling studies suggest that NGR residues form a surface loop close to the threefold axis of symmetry adjacent to residues previously implicated in binding heparan sulfate, the primary receptor for AAV2. The aforementioned results suggest that the internalization of AAV2 in 293 cells might follow a "click-to-fit" mechanism that involves the cooperative binding of heparan sulfate and {alpha}5ß1 integrin by the AAV2 capsids.

* Corresponding author. Mailing address: CB No. 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.

Journal of Virology, September 2006, p. 8961-8969, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00843-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Excoffon, K. J. D. A., Koerber, J. T., Dickey, D. D., Murtha, M., Keshavjee, S., Kaspar, B. K., Zabner, J., Schaffer, D. V. (2009). Directed evolution of adeno-associated virus to an infectious respiratory virus. Proc. Natl. Acad. Sci. USA 106: 3865-3870 [Abstract] [Full Text]  
  • Daya, S., Berns, K. I. (2008). Gene Therapy Using Adeno-Associated Virus Vectors. Clin. Microbiol. Rev. 21: 583-593 [Abstract] [Full Text]  
  • Corti, A., Curnis, F., Arap, W., Pasqualini, R. (2008). The neovasculature homing motif NGR: more than meets the eye. Blood 112: 2628-2635 [Abstract] [Full Text]  
  • Grimm, D., Lee, J. S., Wang, L., Desai, T., Akache, B., Storm, T. A., Kay, M. A. (2008). In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses. J. Virol. 82: 5887-5911 [Abstract] [Full Text]  
  • DiPrimio, N., Asokan, A., Govindasamy, L., Agbandje-McKenna, M., Samulski, R. J. (2008). Surface Loop Dynamics in Adeno-Associated Virus Capsid Assembly. J. Virol. 82: 5178-5189 [Abstract] [Full Text]  
  • Grieger, J. C., Johnson, J. S., Gurda-Whitaker, B., Agbandje-McKenna, M., Samulski, R. J. (2007). Surface-Exposed Adeno-Associated Virus Vp1-NLS Capsid Fusion Protein Rescues Infectivity of Noninfectious Wild-Type Vp2/Vp3 and Vp3-Only Capsids but Not That of Fivefold Pore Mutant Virions. J. Virol. 81: 7833-7843 [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»