Role of the PWWP Domain of Lens Epithelium-derived Growth Factor (LEDGF)/p75 Cofactor in Lentiviral Integration

LEDGF/p75 is a chromatin-interacting, cellular cofactor of HIV integrase that dictates lentiviral integration site preference. In this study we determined the role of the PWWP domain of LEDGF/p75 in tethering and targeting of the lentiviral pre-inte-gration complex, employing potent knockdown cell lines allow-ing analysis in the absence of endogenous LEDGF/p75. Deletion of the PWWP domain resulted in a diffuse subnuclear distribu-tion pattern, loss of interaction with condensed chromatin, and failure to rescue proviral integration, integration site distribu-tion, and productive virus replication. Substitution of the PWWP domain of LEDGF/p75 with that of hepatoma-derived growth factor or HDGF-related protein-2 rescued viral replica-tion and lentiviral integration site distribution in LEDGF/p75-depleted cells. Replacing all chromatin binding elements of LEDGF/p75 with full-length hepatoma-derived growth facto