Title: Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication
Authors: De Rijck, Jan
Vandekerckhove, Linos
Gijsbers, Rik
Hombrouck, Anneleen
Hendrix, Jelle
Vercammen, Jo
Engelborghs, Yves
Christ, Frauke
Debyser, Zeger # ×
Issue Date: Dec-2006
Series Title: Journal of Virology vol:80 issue:23 pages:11498-509
Abstract: 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.
ISSN: 0022-538X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

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