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 De Rijck, J.
Right arrow Articles by Debyser, Z.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Rijck, J.
Right arrow Articles by Debyser, Z.

 Previous Article  |  Next Article 

Journal of Virology, December 2006, p. 11498-11509, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00801-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Overexpression of the Lens Epithelium-Derived Growth Factor/p75 Integrase Binding Domain Inhibits Human Immunodeficiency Virus Replication{triangledown}

Jan De Rijck,1,{dagger} Linos Vandekerckhove,1,{dagger} Rik Gijsbers,1 Anneleen Hombrouck,1 Jelle Hendrix,2 Jo Vercammen,2 Yves Engelborghs,2 Frauke Christ,1,{ddagger} and Zeger Debyser1,{ddagger}*

Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium,1 Biomolecular Dynamics, KULeuven, Celestijnenlaan 200D, B-3001 Leuven, Belgium2

Received 19 April 2006/ Accepted 30 August 2006

We initially identified lens epithelium-derived growth factor/p75 (LEDGF/p75) as a binding partner of human immunodeficiency virus type 1 (HIV-1) integrase. To investigate the role of LEDGF/p75 in HIV replication and its potential as a new antiviral target, we stably overexpressed two different fragments containing the integrase binding domain (IBD) of LEDGF/p75 fused to enhanced green fluorescent protein (eGFP). HIV-1 replication was severely inhibited by overexpression of the eGFP-IBD fusion proteins, while no inhibition was observed in cell lines overexpressing the interaction-deficient D366A mutant. Quantitative PCR pinpointed the block to the integration step, whereas nuclear import was not affected. Competition of the IBD fusion proteins with endogenous LEDGF/p75 for binding to integrase led to a potent defect in HIV-1 replication in both HeLaP4- and MT-4-derived cell lines. A previously described diketo acid-resistant HIV-1 strain remained fully susceptible to inhibition, suggesting that this strategy will also work in patients who harbor strains resistant to the current experimental integrase inhibitors. These data support LEDGF/p75 as an important cofactor for HIV replication and provide proof of concept for the LEDGF/p75-integrase interaction as a novel target for treating HIV-1 infection.

* Corresponding author. Mailing address: Molecular Medicine, KULeuven and IRC KULAK, Kapucijnenvoer 33 VCTB+5, B-3000 Leuven, Belgium. Phone: 32-16-332183. Fax: 32-16-336336. E-mail: zeger.debyser{at}med.kuleuven.be.

{triangledown} Published ahead of print on 20 September 2006.

{dagger} J.D.R. and L.V. contributed equally to this work.

{ddagger} F.C. and Z.D. are both senior authors of this work.

Journal of Virology, December 2006, p. 11498-11509, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.00801-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bartholomeeusen, K., Christ, F., Hendrix, J., Rain, J.-C., Emiliani, S., Benarous, R., Debyser, Z., Gijsbers, R., De Rijck, J. (2009). Lens Epithelium-derived Growth Factor/p75 Interacts with the Transposase-derived DDE Domain of PogZ. J. Biol. Chem. 284: 11467-11477 [Abstract] [Full Text]  
  • Adamson, C. S., Freed, E. O. (2009). Anti-HIV-1 Therapeutics: From FDA-approved Drugs to Hypothetical Future Targets. Mol. Interv. 9: 70-74 [Abstract] [Full Text]  
  • Shun, M.-C., Botbol, Y., Li, X., Di Nunzio, F., Daigle, J. E., Yan, N., Lieberman, J., Lavigne, M., Engelman, A. (2008). Identification and Characterization of PWWP Domain Residues Critical for LEDGF/p75 Chromatin Binding and Human Immunodeficiency Virus Type 1 Infectivity. J. Virol. 82: 11555-11567 [Abstract] [Full Text]  
  • McKee, C. J., Kessl, J. J., Shkriabai, N., Dar, M. J., Engelman, A., Kvaratskhelia, M. (2008). Dynamic Modulation of HIV-1 Integrase Structure and Function by Cellular Lens Epithelium-derived Growth Factor (LEDGF) Protein. J. Biol. Chem. 283: 31802-31812 [Abstract] [Full Text]  
  • Hou, Y., Mcguinness, D. E., Prongay, A. J., Feld, B., Ingravallo, P., Ogert, R. A., Lunn, C. A., Howe, J. A. (2008). Screening for Antiviral Inhibitors of the HIV Integrase--LEDGF/p75 Interaction Using the AlphaScreenTM Luminescent Proximity Assay. J Biomol Screen 13: 406-414 [Abstract]  
  • Hayouka, Z., Rosenbluh, J., Levin, A., Loya, S., Lebendiker, M., Veprintsev, D., Kotler, M., Hizi, A., Loyter, A., Friedler, A. (2007). Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc. Natl. Acad. Sci. USA 104: 8316-8321 [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»