Debyser, Z. (2021, March 3). Cellular cofactors of HIV integrase: from target identification to discovery of ledgins [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved March 2, 2024, from https://hstalks.com/bs/2077/.
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Published on August 30, 2011
Updated on March 3, 2021
Prof. Zeger Debyser has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
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In the next presentation,I will describe cellular co-factors ofthe integrase of the human immunodeficiency virus (HIV).I will discuss how we identifiednovel targets and how this led to the discovery of new anti-HIV drugs,the LEDGINs, that are inhibitors of the interactionbetween HIV integrase and the co-factor LEDGF.
In the fight against HIV/AIDS,we're still looking for novel anti-HIV drugs preferentially targeting new targets.What are we looking for? We're looking for drugs,new-virs that are associated with a high genetic barrier,meaning that it will be difficult for the virus to become resistant against the drug.There should be no cross-resistance with existing drugs on the market.The compounds should be associated with no side-effects,also not in the long term, since HIV causes chronic disease.There should be optimal adherence, and this can beaccomplished by drugs that are only have to be taken once a day.It should be produced at low cost so that it is alsoaffordable for people living in developing countries.Last but not least,we should at least consider the possibility of developing drugs that could lead to a cure,to eradicate HIV from the blood of infected patients.
Here we illustrate the HIV replication cycle.The HIV particle, viaits envelope proteins, will interact with the receptor and the co-receptor onthe target cell. After release ofthe viral contents (RNA and proteins) reverse transcriptase will copy,will retro-transcribe the RNA into a double-stranded DNA copy.The copy, in the presence ofviral proteins and cellular proteins, should then betransported into the nucleus through the nuclear pore,where integrase will catalyze the integration of the insertion ofthe pro-viral DNA into the genome of the host cell.This is a point of no return.After this step, the viral DNA will remainpresent in the cell as long as it lives.After cell division,it will also transfer the viral DNA into the daughter cells.From this pro-viral DNAHIV proteins will be generated, and together withRNA genomes new viral particles will arise.Protease, through proteolytic cleavage, will then be involved in the maturationof the viral proteins. After this step the viral particles become infectious.As illustrated by the blue circle on the bottom of the slide,my research group has been studying the integration process.This is a complex process, it is taking place both inthe cytoplasm and the nucleus and involves many steps.Integrase will bind tothe long terminal repeat ends of the viral DNA after completion of reverse transcription,it is involved in importing the DNA intothe nucleus and then catalyzes the insertion of the DNA into the genome.It has become clear in recent years (and this isillustrated to the left) that these steps are takingplace within a protein-DNA complexthat we refer to as the 'pre-integration complex' (or the PIC).This is composed of the viral DNA,viral protein such as integrase matrix,VPR, and also cellular proteins which we refer to as cellular co-factors.The central theme of my research group is the insight that HIVuses these cellular co-factors to achieveits viral replication cycle, and also the integration step.We consider these cellular co-factors as novel targets for anti-HIV drug discovery.LEDGF/p75, a prototypical target within this concept, is highlighted in the cartoon.