Project description
“Lock-in and apoptosis” strategy for fighting HIV
Human immunodeficiency virus (HIV) continues to be a serious public health issue, having claimed more than 40 million lives so far. Despite efforts to tackle the HIV/AIDS epidemic, it has not been entirely possible. Recent observations indicate that even after treatment, a viral reservoir remains in the body and is too resistant to antiretroviral drug therapy. Funded by the Marie Skłodowska-Curie Actions programme, the Super-HIPPO project will develop a novel strategy called “lock-in and apoptosis.” This strategy is based on a non-natural derivative of inositol hexaphospate, L-HIPPO, which showed a strong effect on HIV-infected HeLa cells during the trial. The aim now is to develop a new, more efficient L-HIPPO derivative that can be administered orally.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-AG-UN - HORIZON Unit GrantCoordinator
35620 İzmir
Türkiye