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J. Virol. doi:10.1128/JVI.00801-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Over-expression of the LEDGF/p75 Integrase Binding Domain Inhibits HIV Replication

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

^* To whom correspondence should be addressed. Email: zeger.debyser{at}med.kuleuven.be.

	Abstract

We initially identified LEDGF/p75 as a binding partner of HIV-1 integrase. To investigate the role of LEDGF/p75 in HIV replication and its potential as a new antiviral target, we stably over-expressed two different fragments containing the integrase binding domain (IBD) of LEDGF/p75 fused to the enhanced green fluorescent protein (eGFP). HIV-1 replication was severely inhibited by over-expression of the eGFP-IBD fusion proteins, while no inhibition was observed in cell lines over-expressing 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 leads to a potent defect in HIV-1 replication both in HeLaP4- and MT-4-derived cell lines. A previously described diketo acid-resistant HIV-1 strain remains fully susceptible to inhibition, suggesting that this strategy will also work in patients that harbour strains resistant to the current experimental integrase inhibitors. These data support LEDGF/p75 as an important co-factor for HIV replication and provide proof-of-concept for the LEDGF/p75-integrase interaction as a novel target to treat HIV-1 infection.

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