16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

THE LEDGF-INTEGRASE INTERACTION AS A NEW TARGET FOR ART

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0301

Vandekerckhove L., De Rijck J., Gijsbers R., Christ F. Witvrouw M., Debyser Z., Molecular Medicine
Catholic University Leuven, Molecular Medicine, Leuven, Belgium

BACKGROUND: HIV-1 integrase (IN) has recently been validated in clinical trials as an important new target for antiretroviral therapy. The p75 isoform of the transcriptional coactivator LEDGF (lens epithelium-derived growth factor) interacts tightly with lentiviral integrase (IN). We have now investigated whether interference with this interaction does affect HIV-1 replication.

METHODS: We generated HeLaP4 and MT-4 cell lines that stable over-express GFP fusions of C-terminal fragments of LEDGF containing the integrase binding domain (eGFP-Δ and eGFP-IBD). HIV-1 replication was analyzed using p24 ELISA and real time quantitative PCR. Clinical HIV strains as well as a strain resistant to a diketoacid (DKA) integrase inhibitor were evaluated.

RESULTS: Direct interaction between the IBD fragments and HIV-1 IN was demonstrated by in vitro pull-down, in vivo co-immunoprecipitation and co-localization. Transduction of the cell lines with a lentiviral vector was inhibited 10-fold, whereas Retroviral transduction was not inhibited at all. Replication of HIV-1 (NL4.3) even at high MOI was abrogated in HeLaP4 and MT4 cells stably over-expressing eGFP-Δ or eGFP-IBD whereas no inhibition at all was observed in cells expressing eGFP-Δ-D366A, a mutant defective for interaction with HIV IN. Identical results were obtained using various clinical HIV strains and a HIV-1(IIIB) strain resistant to the diketo acid L-708,906. Quantitative PCR pinpointed the replication block to the integration step.

CONCLUSIONS: The highly potent inhibition of HIV-1 replication by the IBD of LEDGF/p75 provides a proof-of-principle for a novel antiviral therapeutic strategy targeting the interaction of LEDGF/p75 with HIV-1 IN. By binding to HIV-1 IN, the IBD likely competes with the binding of native LEDGF/p75 that is required to dock the preintegration complex to the chromosomes. DKA resistant strains remain susceptible to inhibition by IBD. Peptides and small molecules targeting LEDGF/IN interaction offer great potential as future antiviral agents.

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2006-08-13
ThAa0301

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