| Project Detail |
A ‘kick and kill’ cure strategy for HIV
Human immunodeficiency virus (HIV) is no longer a death sentence. One cure strategy is the elimination of viral reservoirs from the body. Removal enables HIV eradication since the reservoir is resistant to antiretroviral drug therapy. The so-called ‘kick and kill’ strategy has been proposed based on the hypothesis that activation of latent HIV (kick) leads to cell death (kill) by physical damage and/or immune activation. However, clinical tests show that the ‘kill’ process is not enough to reach HIV eradication. The EU-funded Super-HIPPO project will explore latency-reverting agents that can perform the ‘kick’. The newly synthesised compound L-HIPPO is under the microscope. Super-HIPPO will develop a new L-HIPPO derivative (Super-HIPPO) with optimised activities.
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 a-CDE and suppressed membrane localization of HIV-1 Gag protein and induced strong apoptosis of the host cell containing the latent viruses. In contrast, a-CDE-L-HIPPO induced less apoptosis on T cell line. Besides, the complex of a-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. |
