Host factors for retroviral integration site selection

•LEDGF/p75 and BET are the targeting factors for lentiviral and gammaretroviral integration.•Both chromatin-readers link the fate of the provirus with the epigenetic status of the chromatin.•LEDGINs are novel antivirals that interfere with the interaction between HIV integrase and LEDGF/p75.•Re-engineered LEDGF/p75 and BET tethers may open new avenues for safer gene therapy.

To achieve productive infection, retroviruses such as HIV stably integrate their reverse transcribed RNA genome into a host chromosome. Each retroviral family preferentially integrates near a unique subset of genomic features. HIV integrase (IN) is targeted to the body of active transcription units through interaction with lens epithelium-derived growth factor (LEDGF/p75). We describe the successful effort to develop inhibitors of the interaction between IN and LEDGF/p75, referred to as LEDGINs. Gammaretroviruses display a distinct integration pattern. Recently, BET (bromo- and extraterminal domain) proteins were identified as the LEDGF/p75 counterparts that target the integration of gammaretroviruses. The identification of the chromatin-readers LEDGF/p75 and BET as cellular cofactors that orchestrate lentiviral or gammaretroviral integration opens new avenues to developing safer viral vectors for gene therapy.