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Project

The impact of LEDGIN-mediated retargeting of HIV integration on reactivation of latent HIV

Even after decades of combined antiretroviral therapy (cART), a cure for Human Immunodeficiency Virus (HIV) through complete eradication of the virus remains an elusive goal. Viremia rebounds quickly if cART is interrupted. This is because HIV is a lentivirus that uses the viral proteins reverse transcriptase and integrase to stably integrate a provirus into the host cell genome, which leads to the existence of a latent HIV reservoir.Therefore, leading scientists shift to strategies that may functionally cure HIV infection allowing at least interruption of chronic cART. 
Lens-epithelium-derived Growth Factor (LEDGF)/p75 plays a crucial part in HIV integration through its interaction with HIV Integrase (IN), targeting integration towards actively transcribed genes and tethering it to the chromatin. Our lab has already contributed to the development of a new class of small molecule inhibitors that block the LEDGF/p75-IN interaction and are called LEDGINs. Previous studies in our lab have shown that in LEDGF/p75 knock-out cells, integration is shifted away from active transcription units. New data suggest that the residual HIV provirus is refractory to reactivation. Treatment with LEDGINs appears to phenocopy these effects: integration is retargeted to transcriptionally less active regions of the human chromosomes and the residual provirus is refractory to reactivation. cART including LEDGINs given early after infection could therefore lead to a reduction of the functional HIV reservoirs and possibly a prolonged or even sustained remission after interruption of cART. I intend to further investigate the effect of LEDGINs on HIV latency and reactivation during my PhD. Specifically, my project will focus on translating these results from in vitro experiments to in vivo experiments using humanized mice, and to ex vivo experiments using patient samples.
As HIV-2 is known for a less pathogenic disease phenotype compared to HIV-1, I also aim to investigate wether or not their are differences between HIV-1 and HIV-2 when it comes to latency.
Finally, anti-DFS70 antibodies are anti-nuclear auto-antibodies that are not linked to a specific auto-immune disease and that have been shown to target LEDGF/p75. Even more interesting, the epitope of these antibodies corresponds to the integrase binding domain, that interacts with IN during HIV-infection. I intend to investigate the prevalence of these antibodies in HIV-infected patients and wether or not they play a role in HIV pathogenesis, as this has not been studied previously.

Date:1 Oct 2016 →  30 Sep 2020
Keywords:HIV, Latency, LEDGINs
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