title: Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication.
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.
authors.affiliation: Molecular Medicine, KU Leuven and IRC KULAK, Kapucijnenvoer 33 VCTB+5, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Linos
authors.initials: L
authors.lastname: Vandekerckhove
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Anneleen
authors.initials: A
authors.lastname: Hombrouck
authors.forename: Jelle
authors.initials: J
authors.lastname: Hendrix
authors.forename: Jo
authors.initials: J
authors.lastname: Vercammen
authors.forename: Yves
authors.initials: Y
authors.lastname: Engelborghs
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D002460:Cell Line; D015870:Gene Expression; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000166:cytology; D014161:Transduction, Genetic; D016662:Virus Integration; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor