HIV preferentially integrates into active genes in the human genome but, until now, how the virus targets these sites has been unknown. Frederic Bushman and colleagues show for the first time that a cellular protein called lens epithelium-derived growth factor (LEDGF/p75) controls the site of HIV DNA integration in human cells. Reporting in Nature Medicine, they outline a mechanism by which this protein directs HIV to active genes.

Because integration-target preferences differ among different retroviruses, researchers have suggested that DNA- or chromatin-bound nuclear proteins might interact with retroviral integration complexes, promoting viral integration at nearby DNA. In particular, the transcriptional co-activator LEDGF/p75 was proposed as a potential tethering protein because it binds tightly to HIV integrase and is linked to the chromosomal localization of integrase. Bushman and co-workers knocked down LEDGF/p75 in three human cell lines and showed that the integration of HIV into active genes was reduced compared with controls. Then they focused on genes that were regulated by LEDGF/p75, identifying these loci by transcriptional profiling. In several human cell lines, LEDGF/p75-regulated genes were preferred HIV-integration sites, whereas in cells depleted of LEDGF/p75, this differential integration pattern was not observed. Furthermore, knockdown of LEDGF/p75 resulted in increased HIV integration into chromosomal regions with a higher GC content.

The authors conclude by proposing a model for HIV DNA-integration targeting. LEDGF/p75 binds to RNA polymerase subunits and also to transcription factors, which results in its enrichment at active genes. Simultaneous binding to HIV integrase could tether HIV to these active loci. LEDGF/p75 comprises an AT hook, a motif that binds preferentially to AT-rich DNA. This could explain why LEDGF/p75 depletion shifts HIV integration to GC-rich DNA.