Cellular cofactors of HIV integrase: from target identification to discovery of ledgins

Published on August 30, 2011 Updated on March 3, 2021   52 min

Other Talks in the Category: Diseases, Disorders & Treatments

0:00
In the next presentation, I will describe cellular co-factors of the integrase of the human immunodeficiency virus (HIV). I will discuss how we identified novel targets and how this led to the discovery of new anti-HIV drugs, the LEDGINs, that are inhibitors of the interaction between HIV integrase and the co-factor LEDGF.
0:26
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 be accomplished by drugs that are only have to be taken once a day. It should be produced at low cost so that it is also affordable 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.
1:30
Here we illustrate the HIV replication cycle. The HIV particle, via its envelope proteins, will interact with the receptor and the co-receptor on the target cell. After release of the 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 of viral proteins and cellular proteins, should then be transported into the nucleus through the nuclear pore, where integrase will catalyze the integration of the insertion of the pro-viral DNA into the genome of the host cell. This is a point of no return. After this step, the viral DNA will remain present 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 DNA HIV proteins will be generated, and together with RNA genomes new viral particles will arise. Protease, through proteolytic cleavage, will then be involved in the maturation of 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 in the cytoplasm and the nucleus and involves many steps. Integrase will bind to the long terminal repeat ends of the viral DNA after completion of reverse transcription, it is involved in importing the DNA into the nucleus and then catalyzes the insertion of the DNA into the genome. It has become clear in recent years (and this is illustrated to the left) that these steps are taking place within a protein-DNA complex that 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 HIV uses these cellular co-factors to achieve its 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.
Hide

Cellular cofactors of HIV integrase: from target identification to discovery of ledgins

Embed in course/own notes