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Development of artificial phosphoinositides aiming at HIV eradication

Descripción del proyecto

Una estrategia de «golpear y eliminar» para tratar el VIH

El virus de la inmunodeficiencia humana (VIH) ya no constituye una sentencia de muerte. Una estrategia de tratamiento consiste en eliminar los reservorios virales del organismo, lo que permite erradicar el VIH, ya que el reservorio es resistente los tratamientos antirretrovíricos. En este sentido, se ha propuesto la estrategia denominada «golpear y eliminar, basada en la hipótesis de que la activación del VIH latente (golpear) conduce a la muerte celular (eliminar) por daño físico o activación inmunitaria. Con todo, las pruebas clínicas revelan que el proceso de «eliminar» no basta para lograr la erradicación del VIH. El equipo del proyecto Super-HIPPO, financiado con fondos europeos, examinará agentes de reversión de la latencia que puedan «golpear». En concreto, se estudiará el compuesto recién sintetizado L-HIPPO. En Super-HIPPO se desarrollará un nuevo derivado de L-HIPPO (Super-HIPPO) con actividades optimizadas.

Objetivo

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.

Coordinador

IZMIR KATIP CELEBI UNIVERSITESI
Aportación neta de la UEn
€ 148 478,40
Dirección
IZMIR KATIP CELEBI UNIVERSITESI HAVAALANI SOSESI C NO.33, D.2
35620 İzmir
Turquía

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Región
Ege İzmir İzmir
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
Sin datos