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LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration

¹ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Division of Medicine, Imperial College London, St. Mary’s Campus, London W2 1PG, United Kingdom; ³ Department of Infection, University College London, London W1T 4JF, United Kingdom

LEDGF/p75 directly interacts with lentiviral integrase proteins and can modulate their enzymatic activities and chromosomal association. A novel genetic knockout model was established that allowed us for the first time to analyze HIV-1 integration in the absence of LEDGF/p75 protein. Supporting a crucial role for the cofactor in viral replication, HIV-1 vector integration and reporter gene expression were significantly reduced in LEDGF-null cells. Yet, integrase processed the viral cDNA termini normally and maintained its local target DNA sequence preference during integration. Preintegration complexes extracted from knockout cells moreover supported normal levels of DNA strand transfer activity in vitro. In contrast, HIV-1 lost its strong bias toward integrating into transcription units, displaying instead increased affinity for promoter regions and CpG islands. Our results reveal LEDGF/p75 as a critical targeting factor, commandeering lentiviruses from promoter- and/or CpG island-proximal pathways that are favored by other members of Retroviridae. Akin to yeast retrotransposons, disrupting the lentiviral targeting mechanism significantly perturbs overall integration.

[Keywords: Integrase; LEDGF/p75; HIV-1; AIDS; transcription; integration]

Received April 25, 2007; revised version accepted June 6, 2007.

⁵ Present address: Avexa Limited, Richmond, Victoria 3121, Australia

⁶ Corresponding authors.

E-MAIL alan_engelman{at}dfci.harvard.edu; FAX (617) 632-3113.

⁷ E-MAIL p.cherepanov{at}imperial.ac.uk; FAX 44-20-7594-3906.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1565107

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