Description du projet
Une stratégie de «verrouillage et apoptose» pour lutter contre le VIH
Le virus de l’immunodéficience humaine (VIH) reste un problème grave de santé publique, ayant fait plus de 40 millions de victimes à ce jour. Malgré les efforts déployés pour lutter contre l’épidémie de VIH/sida, cela n’a pas été entièrement possible. Des observations récentes indiquent que, même après le traitement, un réservoir viral demeure dans l’organisme et résiste trop bien à la pharmacothérapie antirétrovirale. Financé par le programme Actions Marie Skłodowska-Curie, le projet Super-HIPPO développera une nouvelle stratégie appelée «verrouillage et apoptose». Cette stratégie repose sur un dérivé non naturel de l’acide phytique, le L-HIPPO, qui a montré un effet puissant sur les cellules HeLa infectées par le VIH au cours de l’essai. L’objectif est désormais de mettre au point un nouveau dérivé du L-HIPPO, plus efficace et pouvant être administré par voie orale.
Objectif
Main challenge of fighting with the HIV is to eliminate the latent viral reservoir from the body. This reservoir is resistant to antiretroviral drug therapy and can cause viral rebound if the treatment is stopped. The removal of the reservoir enables HIV eradication, is urgently desired in HIV-AIDS research. For this purpose, a strategy called “kick and kill” was proposed, based on the hypothesis that activation of latent HIV (“kick”) leads to cell death (“kill”) by physical damage and/or immune activation. However, in clinical tests “kill” process was found to be not enough to reach HIV eradication.
To eradicate HIV from the body, my work has recently suggested a new strategy called “lock-in and apoptosis” instead of “kick and kill”. In development of this strategy, non-natural derivative of inositol hexaphosphate (IP6) named as L-HIPPO was designed based on the fact that the MA domain of Pr55gag which mediates membrane binding through its interaction with inositol phospholipid PIP2 in the host membrane. L-HIPPO was administrated to HIV infected HeLa cells as complex with a carrier α-CDE and suppressed membrane localization of HIV-1 Gag protein and induced strong apoptosis of the host cell containing the latent viruses. In contrast, α-CDE-L-HIPPO induced less apoptosis on T cell line. Besides, the complex of α-CDE-L-HIPPO is inapplicable for oral use. Toward this end, new L-HIPPO derivative with alternative carrier is required.
An ultimate goal of this work is to develop new L-HIPPO derivative (Super-HIPPO) with more potent and efficient activities. My objectives to reach this goal are (1) to synthesize new L-HIPPO derivatives and alternative carriers, (2) to evaluate their activities, (3) to repeat design, synthesis and biological evaluation, if the activities are not enough, (4) to confirm the binding mode of MA-compound, and (5) to achieve personal development and career advancement by performing this study.
Champ scientifique
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-AG-UN - HORIZON Unit GrantCoordinateur
35620 İzmir
Turquie