LEDGFp75

LEDGF/p75, also known as lens epithelium-derived growth factor p75, is a human transcriptional coactivator and chromatin-binding protein encoded by the PSIP1 gene. It is widely expressed and is best known for its role as a host factor that facilitates the integration of HIV-1 DNA into the host genome.

Proteins in the LEDGF/p75 family contain several distinct domains. The N-terminal PWWP domain, together with adjacent AT-hook motifs, mediates binding to chromatin and targets LEDGF/p75 to actively transcribed regions, often associated with histone marks such as H3K36me3. The C-terminal integrase-binding domain (IBD) directly interacts with lentiviral integrases, including HIV-1 integrase, enabling the tethering of the viral pre-integration complex to chromatin.

Functionally, LEDGF/p75 acts as a transcriptional coactivator and chromatin organizer, contributing to gene regulation and the structure of transcriptionally active chromatin. Its ability to recruit HIV-1 integrase to favorable genomic sites explains, in part, how HIV-1 preferentially integrates into active genes. This integrase interaction has made LEDGF/p75 a focus of antiviral research, with efforts to disrupt the LEDGF/p75–integrase interface to inhibit infection.

Isoforms and alternative splicing yield LEDGF/p75 (~75 kDa) and LEDGF/p52 (~52 kDa). The p52 isoform lacks portions of the N-terminal chromatin-binding region, reducing its chromatin-tethering ability while preserving some interaction with integrase.

In research and therapeutic contexts, blocking the LEDGF/p75–integrase interaction with small molecules (LEDGINs) has shown antiviral activity. LEDGF/p75 remains a key model for studying how host chromatin-binding factors influence retroviral integration and transcriptional regulation.