Study of the role of LEDGF/p75-IN interplay on HIV integration and latency.

Like other viruses, HIV employs the host cell machinery to complete allsteps in its replication cycle. Our lab identified LEDGF/p75 as an essential cellular co-factor of HIV integration. HIV integration is a non random process: integration occurs near specific loci in the genome and within the nuclear sphere, integration appears to occur primarily in the nuclear periphery. During HIV infection, LEDGF/p75 functions as a molecular tether that escorts the virus to the chromatin, targeting integrationinto the body of active genes. We showed before that the replacement ofthe chromatin binding domains of LEDGF/p75 with other domains, activelyretargets integration to loci on the genome bound by these domains. In this project we continue our study on the mechanism of lentiviral integration and the role of LEDGF/p75 therein. We will exploit LEDGF/p75 as a tool to better understand the relationship between integration site selection, chromatin structure and subnuclear positioning. In addition, since HIV-derived viral vectors are frequently used for gene correction strategies, we will apply LEDGF-fusions to retarget integration to safe sites within the genome, overcoming insertional mutagenesis, a serious adverse event in some of the current gene therapy trials.

Keywords:HIV, LEDGF/p75, Lentivirus, Latency, Integration, Insertional mutagenesis, Gene therapy

Disciplines:Microbiology, Systems biology, Laboratory medicine, Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering

Project type:PhD project