Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication.
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.
De Rijck
Jan
J
Molecular Medicine, KU Leuven and IRC KULAK, Kapucijnenvoer 33 VCTB+5, B-3000 Leuven, Belgium.
Vandekerckhove
Linos
L
Gijsbers
Rik
R
Hombrouck
Anneleen
A
Hendrix
Jelle
J
Vercammen
Jo
J
Engelborghs
Yves
Y
Christ
Frauke
F
Debyser
Zeger
Z
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*
D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor